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.

Inflammation Mediators

March 9, 2015 Infectious Diseases, Pharmacology, Pharmacotherapy, Physiology and Pathophysiology No comments , , , , , , ,

The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. The most important inflammation mediators include vasoactive amineslipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation. These mediators induce various components of the inflammatory response typically by distinct mechanisms, which is why inhibiting each has been therapeutically beneficial. However, there is also some overlap (redundancy) in the actions of the mediators.

The inflammation mediators have some common characteristics, like

  • Mediators are either secreted by cells or generated from plasma proteins. Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesised de novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are the sentinels that detect invaders and damage in tissues, that is, macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia can also be induced to elaborate some of the mediators. Plasma derived mediators (e.g., complement proteins) are produced mainly in the liver and are present in the circulation as inactive precursors that must be activated. When activated a series of proteolytic and protein-protein interactions are initiated that ultimately to acquire their biologic properties.
  • Ative mediators are produced only in response to various stimuli. These stimuli include microbial products and substances released from necrotic cells. Some of the stimuli trigger well-defined receptors and signalling pathways.
  • Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. There is thus a system of checks and balances that regulates mediator actions.
  • One mediator can stimulate the release of other mediators. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying or, in certain instances, counteracting the initial action off a mediator.

Vasoactive Amines: Histamine and Serotonin

The two major vasoactive amines, so named because they have important actions on blood vessels, are histamine and serotonin. They are stored as preformed molecules in cells and are therefore among the first mediators to be released during inflammation. The richest sources off histamine are the mast cells that are normally present in the connective tissue adjacent to blood vessels. It is also found in blood basophils and platelets. Histamine is stored in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli, including 1.physical injury, such as trauma, cold, or heat, by unknown mechanisms;2.binding of antibodies to mast cells, which underlies immediate hypersensitivity (allergic) reactions; and 3.products of complement called anaphylatoxins (C3a and C5a). Antibodies and complement products bind to specific receptors on mast cells and trigger signalling pathways that induce rapid degranulation. In addition, leukocytes are thought to secrete some histamine-releasing proteins but these have not been characterised. Neuropeptides (e.g., substance P) and cytokines (IL-1, IL-8) may also trigger release of histamine.

Histamine causes dilation of arterioles and increases the permeability of venules. Histamine is considered to be the principle mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in venules. Its vasoactive effects are mediated mainly via binding to receptors, called H1 receptors, on microvascular endothelial cells. Histamine also causes contraction of some smooth muscles.

Serotonin is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells, such as in the gastrointestinal tract, and in mast cells in rodents but not humans. Its primary function is as a neurotransmitter in the gastrointestinal tract. It is also a vasoconstrictor, but the importance of this action in inflammation is unclear.

Arachidonic Acid Metabolites

The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation. AA does not occur free in the cell but is normally esterified in membrane phospholipids. Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids through the action of cellular phospholipases, mainly phospholipase A2. The biochemical signals involved in the activation of phospholipase A2 include an increase in cytoplasmic Ca2+ and activation of various kinases in response to external stimuli. AA-derived mediators, also called eicosanoids are synthesised by two major classes of enzymes: cyclooxygenases (for prostaglandins) and lipoxygenases (for leukotrienes). Eicosanoids bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation, including vasodilation (PGI2, PGE1, PGE2 PGD2), vasoconstriction (TxA2/Thromboxane A2, leukotrienes C4/D4/E4), increased vascular permeability (Leukotrienes C4/D4/E4), Chemotaxis, leukocyte adhesion (Leukotrienes B4/HETE or Hydroxyeicosatetraenoic acid).

  • Prostaglandins

Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation. They are generated by the actions of two cyclooxgenases, called COX-1 and COX-2. COX-1 is produced in response to inflammatory stimuli and is also constitutively expressed in most tissues, where it may serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). In contrast, COX-2 is induced by inflammatory stimuli and thus generates the prostaglandins that are involved in inflammatory reactions, but it is low or absent in most normal tissues. Prostaglandins include many subtype PGs, such as TxA2, PGI2, PGD2, PGE2, PGF2a etc. These subtype prostaglandins are derived by the action of different enzymes on an intermediate in the pathways, respectively.

TxA2, a potent platelet-aggregating agent and vasoconstrictor is derived by the enzyme thromboxane synthase which locates in the platelets. Prostacyclin synthase in vascular endothelium catalyze the production of PGI2 and PGI2 has functions as vasodilator,  a potent inhibitor of platelet aggregation, and markedly potentiates the permeability-increasing and chemotactic effects of other mediators. PS: a thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels. PGD2 is the major prostaglandin made by mast cells; along with PGE2 (which is more widely distributed), it causes vasodilation and increases the permeability of post capillary venules, thus potentiating edema formation. Also it has a function of chemoattractant for neutrophils. PGF2a stimulates the contraction of uterine and bronchial smooth muscle and small arterioles.

In addition to their local effects, the prostaglandins are involved in the pathogenesis of pain and fever in inflammation. PGE2 is hyperalgesic and makes the skin hypersensitive painful stimuli, such as intradermal injection of suboptimal concentrations of histamine and bradykinin. It is also involved in cytokine-induced fever during infections.

  • Leukotrienes

Leukotrienes are produced by leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment. There are three different lipoxygenases, 5-lipoxygenase being the predominant one in neutrophils. This enzyme converts AA (arachidonic acid) to 5-hydroxyeicosatetraenoic acid, which is chemotactic for neutrophils, and is the precursor of the leukotrienes. Among leukotrienes, LTB4 is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to ventral endothelium, generation of ROS (reactive oxygen species), and release of lysosomal enzymes. The LTC4, LTD4, and LTE4 cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules. Leukotrienes are more potent than is histamine in incresing vascular permeability and causing bronchospasm.

  • Lipoxins

Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium. They are also unusual in that two cell populations are required for the transcellular biosynthesis of these mediators. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes.

Cytokines and Chemokines

  • Cytokines

Cytokines are proteins produced by many cell types (principally activated lymphocytes, macrophages, and dendritic cells, but also endothelial, epithelial, and connective tissue cells) that mediate and regulate immune and inflammatory reactions. They include TNF (tutor necrosis factor) and Interleukin-I (IL-1). These cytokines are produced mainly by activated macrophages and dendritic cells; TNF is also produced by T lymphocytes and mast cells, and IL-1 is produced by some epithelial cells as well. The most important roles of these cytokines in inflammation are the following:

Screen Shot 2015-11-11 at 7.40.44 PM1.Endothelial activation. Both TNF and IL-1 act on endothelium to induce a spectrum of changes referred to as endothelial activation. These changes include increased expression of endothelial adhesion molecules, mostly E- and P-selectins and ligands for leukocyte integrins; increased production of various mediators, including other cytokines and cheekiness, growth factors, and eicosanoids; and increased procoagulant activity of the endothelium.

2.Activation of leukocytes and other cells. TNF augments responses of neutrophils to other stimuli such as bacterial endotoxin and stimulates the microbicidal activity of macrophages, in part by inducing production of NO. IL-1 activates fibroblasts to synthesize collagen and stimulates proliferation of synovial and other mesenchymal cells. IL-1 also stimulates TH17 responses, which in turn induce acute inflammation.

3.Systemic acute-phase response. IL-1 and TNF induce the systemic acute-phase responses associated with infection or injury, including fever. They are also implicated in the syndrome of sepsis, resulting from disseminated bacterial infection. TNF regulates energy balance by promoting lipid and protein mobilisation and by suppressing appetite. Therefore, sustained production of TNF contributes to cachexia, a pathologic state characterised by weight loss and anorexia that accompanies some chronic infections and neoplastic disease.

  • Chemokines

Cheekiness are a family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. Inflammatory chemokines stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins, and they stimulate migration (chemotaxis) of leukocytes in tissue to the site of infection or tissue damage. Also, some chemokines are produced constitutively in tissues and are sometimes called homeostatic chemokines. These organize various cell types in different anatomic regions of the tissues.

Complement System

The complement system is a collection of soluble proteins and membrane receptors that function mainly in host defines against microbes and in pathologic inflammatory reactions. This system of complement functions in both innate and adaptive immunity for defines against microbial pathogens. In the process of complement activation, several cleavage products of complement proteins are elaborated that cause increased vascular permeability, chemotaxis, and opsonization.

Complement system acts as the bridge between innate and adaptive immune system. This concept is due to the fact that complement proteins can be activated directly by antigen-antibody complexes.

Primary Functions

There are three main effects of complement: 1.lysis of cells such as bacteria, allografts, and tumor cells; 2.generation of mediators that participate in inflammation and attract neutrophils; and 3.opsonization – enhancement of phagocytosis.

C3b is the central molecule of the complement cascade. It has two core functions: combines with other complement components to generate C5 convertase, the enzyme that leads to the production of the  membrane attack complex (first it adhere to the surface of the targets); and opsonises bacteria because phagocytes have receptors for C3b on their surface.

How to activate?

In the classic pathway, antigen-antibody complexes activate C12 to form a protease and thereafter the complement cascade starts. In the lectin pathway,  MBL (mannas-binding lectin/mannose-binding protein) binds to the surface of microbes bearing mannan. This activates proteases associated with MBL that activates complement cascade. In the alternative pathway, many unrelated cll surface substances can initiate the process by binding C3 and factor B. This complex is cleaved by a protease and finally the complement cascade initiates.

Other Mediators

  • Platelet-Activating Factor (PAF)

PAF is a phospholipid-derived mediator that was discovered as a factor that caused platelet aggregation, but it is now known to have multiple inflammatory effects. A variety of cell types, including platelets themselves, basophils, mast cells, neutrophils, macrophages, and endothelial cells, can elaborate PAF, in both recreated and cell-bound forms. In addition to platelet aggregation, PAF causes vasoconstriction and bronchoconstriction, and at low concentrations it induces vasodilation and increased ventral permeability.

  • Products of Coagulation

Protease-activated receptors (PARs) are activated by thrombin (converting fibrinogen to fibrin), and are expressed on platelets and leukocytes.

  • Kinins

Kinins are vasoactive peptides derived from plasma proteins called kininogens, by the action of specific proteases called kallikreins. The enzyme kallikrein cleaves a plasma glycoprotein precursor, high-molecular-weight kininogen, to produce bradykinin, a substance that increases vascualar permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin. These effects are similar to those of histamine. The action of bradykinin is short-lived, because it is quickly inactivated by an enzyme called kininase.

  • Neuropeptides

Neuropeptides are secreted by sensory nerves and various leukocytes, and may play a role in the initiation and regulation of inflammatory responses. These small peptides, such as substance P and neurokinin A, are produced in the central and peripheral nervous systems. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of hormone secretion by endocrine cells, and increasing vascular permeability.