Essay On The Diastolic Dysfunction By (Name)

The Diastolic Dysfunction

Introduction
Diastolic dysfunction is characterised by mechanical abnormalities attributing to defects in cardiac diastole. Clinically, diastole refers to the tenure in which myocardium expands and looses the potential of exerting force leading to the cardiac output. However, the diastolic dysfunction is the direct outcome of the insufficiency of diastolic processes, as evidenced by the clinical literature. The cardiac diastole includes the isovolumetric relaxation resulting in cardiac filling through the active and passive mechanisms. Indeed, the systematic reduction in ventricular pressure is the outcome of myocardial relaxation governed by uncoupling between actin and myosin cross bridges and transfer of calcium ions from myofilaments during the cardiac cycle. The sustained defects in the isovolumetric tenure of the ventricular pressure result in variation in the relaxation time constant (tau) attributing to ventricular hypertrophy during cardiac loading. The evidence based clinical literature reveals myocardial hypertrophy as the preliminary cause of diastolic dysfunction attributing to abnormalities in the tensile strength of myocardial collagen matrix (Ingels, et al., 1995, p. 29). The cellular basis of cardiac contraction relate to the coupling processes of excitation-contraction under the influence of action potential on the cell surface of myocyte inducing the cytosolic calcium delivery resulting in myocardial contraction (Klein and Garcia, 2008). Indeed, the entry of calcium ions in myocyte by the assistance of voltage gated L type channels induce the sudden release of further calcium ions from sarcoplasmic reticulum through its calcium ions releasing channels RyR2 by the mechanism of CICR (calcium induced calcium release). The localized release of calcium ions results in the sustained generation of several synchronized calcium ions sparks resulting in contraction of cardiac myocardium. Indeed, the defects in this calcium regulation metabolism result in the development of cardiac hypertrophy attributing to diastolic cardiac dysfunction.

Pathophysiology and Cellular Basis of Diastolic Dysfunction

The regulation of cytosolic calcium levels influenced through numerous calcium channels governed by the coordinated functionality of calcium ions binding proteins, transporters and ATPase pumps resulting in periodic efflux and influx of calcium ions. The abnormalities in these calcium channels result in defects in signal transduction, heart rhythm and mitochondrial metabolism leading to diastolic dysfunction. Topol et al. (2007, p. 421) illustrate the determinants of diastolic functionality including isovolumic relaxation, rapid filling, slow filling (diastasis) and contraction (atrial filling). Indeed, the cardiac diastole corresponds to the tenure between the aortic valve closure and the termination of mitral inflow. The diastolic dysfunction mechanism attributes to the development of sustained cardiac resistance against ventricular inflow leading to the reduction in ventricular diastolic capacity. Furthermore, the impairment in myocardial relaxation, increase in diastolic calcium overload, defects in collagen matrix and myocardial fibrosis result in impaired cardiovascular filling and defective atrioventricular compliance.
The diastolic dysfunction is the outcome of defects in active myocardial relaxation and diastolic compliance, as evidenced by the clinical literature. Indeed, the myocardial relaxation directly governed by the active transport of intracellular ATP and calcium across myocardium (Otto, 2012, p. 198). The factors including cardiac overloading due to arterial impedance and wall stress, and reduction in myocardial contraction under the influence of neurohormonal and metabolic factors attribute to the patterns of diastolic dysfunction among the cardiac patients. The process of ventricular relaxation reciprocally related to calcium uptake mechanism by sarcoplasmic reticulum and release of calcium ions from myocytes requiring the utilization of ATP dependent chain of events including sarcolemmal calcium pumps and SERCA (sarcoplasmic reticulum calcium adenosine triphosphatase). The hypertrophy in cardiac myocytes attributes to the defects in ATP dependent calcium metabolism related to the patterns of sustained disturbances in SERCA. The evidence based clinical literature reveals reduction of calcium ions – ATPase (SERCA) in cardiomyocytes through the increased activity of SERCA inhibitor phospholamban (Ashton, 2013, p. 134). These quantitative variations in SERCA further attribute to the abnormalities in ryanodine receptors affecting the release of calcium ions by sarcoplasmic reticulum. The disruption of calcium metabolism by SERCA adversely influences the sarcoplasmic calcium ion cycling resulting in defective myocardial relaxation leading to diastolic dysfunction and ventricular hypertrophy. The presence of comorbidities like myocardial ischemia further reduces active myocardial relaxation, thereby adding to the diastolic abnormality of the cardiac patients (Lorrel and Grossman, 1994, p. 334).
Brasington (2014) advocates the contention of the influence of myocardial fibrosis and increased pulmonary afterload on the patterns of diastolic dysfunction. Indeed, myocardial stiffening is the result of thickening of interstitial fibrillar collagen due to myocardial fibrosis. This thickening of fibrillar collagen attributes to defects in collagen (I & III) microstructure passively enhancing myocardial viscoelasticity leading to diastolic dysfunction. Blankesteijn and Altara (2015, p. 9) discuss the influence of Transforming growth factor beta (TGF-B) on the patterns of myocardial fibrosis and diastolic dysfunction. The research studies reveal the properties of TGF-B in context to inducing collagen production and generation of myofibroblasts from fibroblasts. The activation of myofibroblasts enhances the production of cytokines resulting in cardiac inflammation. These cellular events result in the formation of myocardial fibrosis attributing to diastolic dysfunction. From the molecular perspective, the performance of cardiomyocytes influenced by the complex interactions within the troponin complex through the regulatory mechanisms by phosphatases and kinases resulting in site-specific phosphorylation leading to reuptake of calcium ions by sarcoplasmic reticulum (Thiriet, 2015, p. 360).
The clinical studies reveal the importance of Cardiac troponin I (cTnI) and Cardiac troponin T (cTnT) biomarkers in evaluating the patterns of myocardial dysfunction. The myocardial damage results in degradation of calcium sensitive proteases including calpain-I leading to active release of cTnI through the blood stream. Indeed, the relaxation and contraction pattern of sarcomere regulated through the coordinated movements by cTnI, cTnC and cTnT potentially controlling the functionality of tropomyosin on cardiac filaments with respect to the calcium ions metabolism. The cardiac diastole characterized by decreased intracellular calcium concentration leading to active binding of cTnI with actin resulting in potential blockage of myosin binding sites, thereby preventing the cardiac force responsible for ventricular diastole. Conversely, the systolic events include the active binding of calcium ions with cTnC resulting in configurational alteration in the troponin complex inducing segregation of cTnI from actin filaments and tropomyosin displacement leading to cardiomyocyte activation. The defects in these cardiac troponin mechanisms result in episodes of diastolic dysfunction and cardiac failure. Indeed, the conformational alterations in actin-troponin-tropomyosin complex induced through the defects in actin binding and toponin C mechanisms under the influence of mutations in TNN13 genes attribute to the events of diastolic dysfunction and cardiac hypertrophy (Baars, Smagt and Doevendans, 2011, p. 133).
The evidence based clinical literature reveals the occurrence of diastolic dysfunction in patients of cardiac failure with preserved ventricular ejection fraction (Lilly, 2011, pp. 225-226). Indeed, the impairment in ventricular relaxation and ventricular stiffness result in transient inhibition of diastolic relaxation attributing to the abnormalities in end diastolic volume and pressure of cardiac ventricles. These defects passively enhance the diastolic pressure and volume and ventricular pressure resulting in decrease of end-diastolic-volume (EDV) and proportionate increase in end-diatolic-pressure (EDP) attributing to the filling defects due to ventricular stiffness leading to the development of diastolic dysfunction. Indeed, the cardiac failure derives its etiology from diastolic dysfunction arising from abnormalities in ventricular filling and myocardial relaxation under the influence of defects in excitation-contraction-coupling attributing to cardiac arrhythmias. Permyakov (2007, p. 123) reveals the impairment in ventricular relaxation as primarily responsible for diastolic dysfunction attributing to the episodes of cardiac failure among 40% patients with pre-existing cardiac conditions. Indeed, the sustained reduction in cardiac myocyte relaxation arises from cytosolic calcium ions overload, neurohormonal induction and conformational alterations in cardiac myofilament. The increased concentration of intracellular sodium ions in the myocytes of cardiac patients results in progression of calcium ions loading through electrogenic transporters (NCX). However, this alternative mechanism in patients of diastolic dysfunction fails to antagonise the impact of reduction in SERCA, as evidenced by clinical literature. Dhalla, Nagano and Ostadal (2011, pp. 336-337) advocate the contention of NCX mediated calcium ions channelization in cardiac muscles attributing to the episodes of endothelium dependent cardiac contraction and relaxation. However, the SERCA induction is still highly necessary in maintaining the concentration of calcium ions in cardiac smooth muscles in context to challenging the predisposition to diastolic dysfunction.
The evidence based clinical literature reveals the adverse influence of β-AR activation on diastolic dysfunction in chronic cardiac failure. Indeed, the CaMKII knockout potentially influences the expression of β-AR leading to defective cardiac contraction attributing to diastolic dysfunction (Mann and Felker, 2011, p. 98). The down regulation of β-AR reduces the density of β1-AR that inversely increases the ratio of β2-AR: β1-AR under the influence of G-protein-receptor-kinase activation resulting in erroneous cardiac responses attributing to diastolic dysfunction. Zipes and Jalife (2014, p. 326) explain the over-expression of CaMKII on the sarcolemmal ion channels in endocardial myocytes. Indeed, the influence of CaMKII on the endocardium and epicardium of heart leads to the amplification of transmural dispersion of repolarisation resulting in cardiac arrhythmias predisposing to diastolic dysfunction. The store operated or capacitative calcium ions entry mechanism facilitates the induction of calcium release activated channels during the deficit of intracellular calcium ions for actively maintaining calcium ions homeostasis across plasma membrane (Thiriet, 2015a, p. 20). Indeed, the store operated calcium ions entry in cardiomyocytes facilitated by StIM1 (stromal interaction molecule) in coordination with plasmalemmal calcium-ions-release-activated-calcium-channels and TRPC (canonical transient receptor potential protein) attribute to calcium ions processes under the influence of RyR1 receptors. The StIM1 is located in the membrane of sarcoplasmic reticulum and potentially detects the depletion in calcium ions for activating CRAC (calcium-release-activated calcium) channels to facilitate influx of calcium ions into cytosol. The abnormal expression of StIM1 results in proportional enhancement of store operated calcium ions entry resulting in cardiac hypertrophy and subsequently diastolic dysfunction.
The research studies reveal the influence of site-specific phosphorylation of Threonine 143 and Serine 42/44 on cardiomyocytes. Indeed, the phosphorylation mediated by protein kinase A (PKA) on cTnI-Ser23/24 decreases the sensitivity of myofilament calcium ions while inversely enhancing the endocardial relaxation for maintaining the diastolic performance during tachycardia. The research studies reveal the significance of the abnormal ventricular relaxation resulting in ventricular stiffness attributing to the diastolic dysfunction (Kruger and Ludman, 2009, p. 115). Indeed, the reduced active relaxation is the direct outcome of passive ventricular stiffness resulting in the potential reduction of ventricular compliance in context to diastolic dysfunction. These findings further clinically correlated with the manifestations of exercise intolerance. The patients affected by diastolic abnormalities display an increase in left ventricular end diastolic pressure and altered periods of ventricular diastole and systole leading to impaired atrioventricular coupling, as evidenced by the clinical literature. However, the chamber size or volume of the left ventricle may remain normal during these pathophysiological events in context to diastolic dysfunction. The patients affected with left ventricular hypertrophy and complicated by microvascular dysfunction exhibit cardiovascular ischemia resulting in diastolic impairment. The pathophysiological disturbances in cardiac afterload and V-A (ventriculoarterial coupling) attribute to the reduction in cardiac performance and diastolic dysfunction in patients diagnosed with heart failure with normal ejection fraction (HFNEF).

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Conclusion
The vascular stiffness of cardiac vessels is determined as effective arterial elastance influenced by age advancement and episodes of hypertension, and reported in patients of HFNEF. Indeed, the enhancement of effective arterial elastance potentially influences the ventricular systolic stiffness in context to the metabolic challenge by vascular overload in conditions of diastolic dysfunction. The cardiac abnormalities related to the end systolic volume and load predominantly determine the probability of an early diastolic dysfunction. The increase in effective arterial elastance further hampers the myocardial oxygen cycle leading to the predisposition toward cardiac ischemia and proportionate increase in left ventricular end diastolic pressure.
The diastolic dysfunction is indeed, determined by cardiac afterload attributing to the sustained increase in blood pressure and circulatory volume leading to disfigured v-a coupling reactions. The patterns of ventricular stiffness under the influence of arterial stiffening exhibited in context to the blood volume alterations related to systolic overload. The abnormal diastolic pressure volume is indeed detrimental in diagnosing the patterns of diastolic dysfunction in clinical practice. The evidence based clinical literature reveals the abnormal findings (of > 48 ms) pertaining to left ventricular relaxation time constant (Tau) in context to diastolic dysfunction with the prerequisite of normal left ventricular end diastolic volume.
The clinical findings reveal the impact of perivascular inflammation on the patterns of diastolic dysfunction under the influence of pressure overload. Indeed, the cardiac overload derived from left ventricular mechanical stress results in myocyte hypertrophy leading to sustained diastolic dysfunction. Furthermore, the coronary hypertension in context to arterial stress induces proinflammatory communications that trigger MCP-1 and ICAM-1 responses leading to the accumulation of macrophages and consequently reactive fibrosis under the influence of TGF-β.
Therefore, the research studies reveal the vascular inflammatory processes, myocardial fibrosis, cytosolic calcium mechanism, genetic and neurohormonal factors attributing to the patterns of diastolic dysfunction among cardiac patients. Therapeutic targeting on calcium ion metabolism, inflammatory processes, phosphorylation pathways and LV pressure and volume patterns will indeed open new gateways for devising proactive approaches in context to the prophylaxis and treatment of diastolic dysfunction. Furthermore, the clinical diagnosis of diastolic dysfunction requires biomechanical analysis of the molecular mechanisms attributing to the active or passive diastolic dysfunction. Undoubtedly, the evaluation of tau (time constant of relaxation) and EDPVR (End diastolic pressure-volume relationship) clinically warranted in determining the pathophysiological and cellular basis of diastolic dysfunction.
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References

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