Cellular Basis of Diastolic Dysfunction - Essay Example

Cellular basis of diastolic dysfunction CELLULAR BASIS OF DIASTOLIC DYSFUNCTION Order # 281541 www.academia-research.com Cellular basis of diastolic dysfunction TABLE OF CONTENTS 1. What is diastolic dysfunction? ………………………………………….. 2 2. Brief overview ………………………………………………………….... 3 3. Functional changes in diastolic dysfunction …………………………… 4 4. Role of myocytes in relaxation phase of cardiac cycle ………………… 4 5. Factors affecting the calcium transient ………………………………… 5 6. Potassium depletion and diastolic dysfunction ………………………… 8 7. Other possible mechanisms involved …………………………………… 8 8. Discussion ………………………………………………………………… 9 9. References ………………………………………………………………... 11 Cellular basis of diastolic dysfunction 2 WHAT IS DIASTOLIC DYSFUNCTION? The cardiac cycle consists of systole and diastole. Systole is the contraction phase of heart and diastole is the relaxation phase of heart. A single cardiac cycle takes about one second to complete. With the return of blood to the right and left atria, the SA node sends out a signal, causing the atria to contract. The contraction of atria leads to the opening of the mitral and tricuspid valves, thus pushing the blood into the ventricles. This comprises of the diastolic function of the heart, the longer one of the two. With the filling of the ventricles, the signals from SA node travel to the ventricles, causing them to contract. This phase comprises of the systole. As soon as the systole begins, the mitral and tricuspid valves shut close tightly in order to prevent any backflow of blood into the atria. At the same time, the pulmonary and the aortic valves are pushed open, leading to a flow of blood from right ventricle to lungs and from the left ventricle to the whole body, after getting oxygenated from the lungs. If the diastolic phase of the cardiac cycle becomes abnormal, it is called as the diastolic dysfunction. In the patients with diastolic dysfunction, the ventricles fail to relax normally during this phase of cardiac cycle. This leads to an increase in the pressure inside the ventricles when the blood returns from the second heart beat. This pressure is thus transferred to the lungs vasculature as well, leading to the pulmonary congestion as well as to the blood vessels, returning back to the heart, leading to the systemic congestion. Most commonly, the patients suffering from one or the other type of cardiomyopathy, show the symptoms of diastolic dysfunction. [1] Cellular basis of diastolic dysfunction 3 The primary abnormality in left diastolic dysfunction is the left ventricular relaxation. This results in a high diastolic pressure along with the poor filling of the ventricles. As a compensatory mechanism, the left atrial pressure increases in order to increase the diastolic filling. This increase in the left atrial pressure continues, until it exceeds the hydrostatic and oncotic pressures in the pulmonary capillaries and eventually leading to pulmonary edema. These patients generally show the symptoms of exertion when there is a reduction in the ventricular filling time, during the times of increased cardiac activity. The circulating catecholamines further worsen the whole scenario. [5] BRIEF OVERVIEW: According to Michael R. Zile, MD, Charles Ezra Daniel, Professor of Medicine, Division of Cardiology, Medical University of South Carolina; the difference between the systolic heart failure and the diastolic heart failure lies in the amount of ejection fraction during the two conditions. In systolic heart failure, there is heart failure, but with a decreased ejection fraction, while in diastolic heart failure, there is heart failure, but with a normal ejection fraction. But both of these conditions show a very high incidence of developing the hypertensive heart disease; yet the two can be distinguished on the basis of structure and function of the heart. The patients with systolic heart failure show almost a very little or absolutely no change in the wall thickness and a noticeably increase in the left ventricular volume. Both of these are the characteristics of the eccentric remodeling. While in the diastolic dysfunction, there is a marked increase in the wall thickness, and there is almost a very little or absolutely no change in the end-diastolic volume. Both of these are the characteristics of concentric remodeling. Dr. Zile noticed that the diastolic dysfunction of heart is the result of more than one disease processes, and not a product of a single pathological process. These structural changes in the left ventricular chamber are the result of the changes in the constituent components of the left ventricular myocardium. These include the Cellular basis of diastolic dysfunction 4 cardiomyocytes and the surrounding extracellular matrix. Among other changes, following are noticed in the diastolic dysfunction: 1. Increase in the diameter of the cardiomyocytes. 2. Increase in the amount and thickness of in the extracellular fibrillar collagen 3. More connectivity between the collagen fibrils. [3] FUNCTIONAL CHANGES IN DIASTOLIC DYSFUNCTION: Both the passive stiffness of the heart along with the active relaxation and filling components lead to the functional changes in diastolic dysfunction. The relaxation abnormalities comprise of a reduction in the rate of decline of pressure in the left ventricle, and a reduction in the early diastolic recoil. There is also a marked decrease in the rate of early filling, until the late diastole is reached, thus leading to an increase in the atrial contraction induced filling. Secondly, there is an increase in the passive stiffness of the ventricles; thereby leading to an increase in the diastolic pressures. So, these all changes collectively lead to the diastolic dysfunction. [3] ROLE OF MYOCYTES IN RELAXATION PHASE OF CARDIAC CYCLE: During the systole, or contraction of heart, the actin and myosin filaments are strongly bound to each other in an attempt to forcefully contract the heart and push the oxygenated blood Cellular basis of diastolic dysfunction 5 to the systemic circulation. It is important that these filaments may shift to a state that generates a lower force, in order to carry out the relaxation phase or the diastole of the cardiac cycle. There are certain factors that can actually cause a delay in this relaxation phase, either by causing disturbance in the cross-bridge detachment or in the preceding process of removal of calcium from the cytosole. These include: 1. Reduction in the process of resequestration of calcium into the sarcoplasmic reticulum, leading to a prolonged calcium transient. 2. Abnormalities in the sodium/calcium exchange (NCX). 3. An abnormal high energy phosphate metabolism, leading to a disturbance in the process of cross-bridge uncoupling. 4. Abnormalities of the contractile proteins (actin/myosin) themselves; this affects their interaction or the calcium sensitivity. [2] FACTORS AFFECTING THE CALCIUM TRANSIENT: There are certain important factors responsible for the alterations in normal process of calcium transient from the myocytes. Changes in structure and function of the myocyte-calcium handling proteins are one of them. Some of these proteins include: 1. Sarcoplasmic reticular calcium-ATPase (SERCA2a) and its modulator phospholambin (PLB). 2. The SR-calcium release channel and its modulator FK-506 binding protein 12.6 (FKBP12.6) and 3. NCX Out of these proteins, discussing the SR-calcium release channel is affected in the heart failure. In this case, often there is accompanied reduction in the gene and protein expression of both of these enzymes. There can be serin-phosphorylation of both of these proteins by the Cellular basis of diastolic dysfunction 6 enzyme protein kinase A (PKA). Also, a decreased phosphorylation of PLB is found to be an important factor for delay relaxation. The enzyme protein kinase C can also bring about the phosphorylation of PLB, despite the fact that a higher level of PKC can actually lead to a reduction in phosphorylation by activating PPI. Describing the phosphorylation of SERCA2a by PKA, there are still many things to be discovered. The study of molecular structure of PLB-SERCA2a gives a possibility of presence of additional sites, affecting their molecular coupling. An important step of research is that both of these proteins have been modified by the gene transfer or genetic engineering; and this has confirmed their role in relaxation. Another factor in determining the calcium transient alterations is the alteration in ryanodine-sensitive calcium release channel. It is suggested that the diastolic SR-calcium leakage is induced by PKA hyperphosphorylation and a reduction in the levels of FKBP12.6-stabilizing protein. However, this leakage can be reduced by the beta adrenergic blockade. However, the process is still not fully understood and there is no direct evidence that this abnormality can actually cause a delayed relaxation. NCX upregulation in a failing myocardium plays its role by working in a forward mode to extrude intracellular calcium thus offsetting the depressed SR-calcium uptake. Despite the fact that NCX mediates the calcium entry by maintaining a reduced-peak calcium, higher sodium and action potential prolongation, this can delay relaxation. Yet, there are still many things not fully understood in this regard. Another process for the modification of relaxation is by bringing about a change in the interaction of calcium with the regulatory thin filaments, or by the modification of proteins themselves. As for example: Cellular basis of diastolic dysfunction 7 1. Relaxation can be lengthened by genetically replacing the troponin I (TnI) to a skeletal isoform, that cannot be PKA phosphorylated, or 2. Relaxation can be shortened by bringing about the overexpression of a TnI that behaves in an order as if it is being constitutively phosphorylated at PKA sites. Tightly bound cross bridges can be produced by the pharmacological manipulation of the force-calcium dependence by small molecule inhibitors. Another possible mechanism for bringing about relaxation is by changes in the ‘molecular motors’ themselves. To understand this, consider the following examples: 1. Beta myosin heavy chain isoform: It prolongs the relaxation and the force rise. However, this is not expected to bring about any significant change in the large mammals and humans, as it dominates under the normal conditions. 2. Myosin mutations: Causing a direct affect on its binding capacity with actin. The experiments on mice have shown that the mice with heterozygous mutation R403Q in the alpha MHC, manifest a profound prolongation of relaxation, even at a younger age, with no chances of hypertrophy, myofibrillar disarray, or an altered systolic function. With an increasing age, these mice showed the changes like hyperdynamic contraction along with the intracavitary pressure gradients, while the relaxation still remains significantly delayed. But what is important to note here is that, these mice did not show any evidence of heart failure or an increased diastolic pressure. This points out that the link between the diastolic heart failure and prolonged relaxation is far from automatic. Cellular basis of diastolic dysfunction 8 Despite this whole discussion, we still must accept that the effect of all these molecular mechanisms on heart failure are still not completely understood, and a lot more needs to be done in this regard in order to fully understand the relationship between these mechanisms and the occurrence of heart failure. [2] POTASSIUM DEPLETION AND DIASTOLIC DYSFUNCTION: The concentration of extracellular potassium is an important determinant for the normal function of the heart. A decrease in the normal potassium concentration can lead to a number of changes: 1. Changes in rising membrane potential. 2. Changes in the membrane conductance for sodium and potassium. 3. Changes in the repolarization time. 4. Changes in the relative refractory time. 5. Changes in the conduction velocity. However, still the direct effect of hypokalemia on the mechanical function of heart has yet not been defined fully. [4] OTHER POSSIBLE MECHANISMS INVOLVED: There are many possible causative mechanisms described for the occurrence of the diastolic dysfunction. Some of them include: 1. Microangiopathy 2. Autonomic nervous dysfunction 3. Defective cellular calcium transport Cellular basis of diastolic dysfunction 9 4. Structural changes in the myocardial contractile proteins (already described above) However, despite all these efforts, the exact mechanism by which the diastolic dysfunction occurs is still not completely understood. Some of the recent studies have shown that the changes in myocardial energy metabolism, produced as a result of the altered substrate supply and the utilization by cardiac myocytes, can be suggested as the foremost injury in the pathogenesis of diastolic dysfunction. An example of this is the case of diabetes. In a diabetic heart, the level of free fatty acids is increased. So, this can cause a reduction in the status of the myocardial energy, when this elevated number of free fatty acids is used inappropriately as a substrate. This in turn is cycled through the intra myocardial lipolysis and re-esterified. This eventually ends in the production of the potentially toxic intermediates and the suppression of the glucose metabolism. [6] DISCUSSION: The ventricular function is largely dependent upon what we call as the ‘preload’. This fact is explained by the famous ‘Frank Starling relationship’ as well. According to the Frank Starling’s law: “the ability of the heart to change its force of contraction and therefore stroke volume in response to changes in venous return” Thus, the less is the preload, the lesser will be the resulting stroke volume of the heart. It is found that about 50% of the patients of heart failure have diastolic dysfunction. These patients can have a normal systolic function in terms of the ejection fractions. [7] The body tries to recover from this whole situation by using the ‘compensatory mechanisms of the heart’. As a result of these compensatory mechanisms, the atria contract more than normal, especially the left atrium, but owing to the reduced capacity of the left ventricle, there is less filling of the ventricle, leading to the less effective stroke volume of the heart. Cellular basis of diastolic dysfunction 10 Although a lot of studies have been carried out in order to explain the underlying mechanisms of diastolic dysfunction, yet many issues still remain unsolved. Much more studies are still under process. In a brief account, what mechanisms are believed to carry out the diastolic dysfunction, as seen from the results of these studies, are listed below: 1. Microangiopathy 2. Autonomic nervous dysfunction 3. Defective cellular calcium transport 4. Structural changes in the myocardial contractile proteins These are already discussed above. The most usefully described among till now it the changes in the structure and function of the myocardial contractile proteins; actin and myosin. This is mostly believed to be carried out as a result of the genetic changes, which are the result of any mutation over time. Cellular basis of diastolic dysfunction 11 REFERENCES 1. Diastolic dysfunction. Texas Heart Institiute, Heart Information Center. Retrieved March 26th, 2009, from the World Wide Web: http://www.texasheartinstitute.org/HIC/Topics/Cond/ddisfunc.cfm 2. Circulation Research. American Heart Association. Retrieved March 26th, 2009 from the World Wide Web: http://circres.ahajournals.org/cgi/content/full/94/12/1533 3. Diastolic dysfunction. Cardiology Review. Retrieved March 26th, 2009 from the World Wide Web: http://www.cardiologyreviewonline.com/pdf/M540_HFSA_Nov07.pdf 4. Potassium depletion and diastolic dysfunction. American Heart Association; Hypertension. Retrieved March 26th, 2009 from the World Wide Web: http://hyper.ahajournals.org/cgi/content/full/48/2/201 5. Heart Failure. Cleaveland Clinic. Retrieved March 26th, 2009 from the World Wide Web: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/heart-failure/#cesec3 6. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. Clinical Research: Diastolic Dysfunction and Diabetes Mellitus. Retrieved March 26th, 2009 from the World Wide Web: http://content.onlinejacc.org/cgi/content-nw/full/42/2/328/ Cellular basis of diastolic dysfunction 7. Diastolic dysfunction. Cardiovascular Physiology Concepts. Retrieved March 26th 2009, from the World Wide Web: http://www.cvphysiology.com/Heart%20Failure/HF006.htm Read More