"...Cinderella of the Heart...
Once upon a time, in a kingdom far away, there lived a lovely maiden named Endo. She had a sweet and gentle nature and always went about her chores with a song and a smile. Endo lived with her cruel stepmother, Cardia, and two ugly stepsisters, Myo and Peri. Cardia forced Endo to work as a maid for the family, doing all of the cooking and cleaning. Endo's stepsisters were jealous of her beauty and sweet disposition, and forced her to wear rags while they were dressed in fine gowns. But beautiful clothes could not hide their nasty natures and rags could not hide Endo's gentle grace. Through all of her hardships, she remained pleasant and kind..."
The text above was extracted from "The Endocardium", by Brutsaert1 and it should reinforce that cardiac endothelium is not a passive barrier between blood and myocardium, as we thought in the past, but indeed, its regulatory function on myocardium is now unquestionable.
The endocardium endothelium (EE) is one of the most primitive strucuture in the human heart. Its development preceeds that of the coronary vessels. Between the primitive endocardium and the embrionary myocardium, there is the cardiac jelly. Therefore, this last one and the EE are the only structures separating myocardium from the tubular heart lumen blood of the fetus. Before coronary vessels develop, substances diffuse through sinusoids to reach adjacent miocytes. ( The Tebessian veins may be the remanescent sinusoids ). The coronary vessels in Pisces and Reptilia only exist in epicardial surface while there is no coronary circulation in cyclostome, and in this latter, exchange of substances between myocardium and blood occurs through EE. Therefore the EE, together with heterometric autoregulation (Frank-Starling mechanism), seems to be one of the earliest organ to develop and modulate cardiac function, interacting with the superfusing blood and with the subjacent myocardium.
Endothelial cells structure differ in many ways depending on its location and this feature can be explained, at least in part, by different microenviroments. The EE cell is thin, with numerous microvillis and invaginations on its surface membrane. This called attention for a possible sensor sign role of these cells, since they are exposed to a large surface-area. They own a bulging nucleus and relatively well developed Golgi apparatus, speaking in favor of a secretory role of this cells. Numerous intercellular gap juctions were showed on electronic microscopic technics, speaking again in favor of their sign-transducing function, as we know that gap junctions are low-resistance channels and ions or second messagers can pass through them easier, amplifing a specific signal. Stress fibers (actin filaments) are components of the cytoskeleton and are oriented mainly by shear-stress forces. (In aorta endothelium they are oriented more vertically). Weibel-Palade bodies has been shown too, as well as some EE receptors: atrial natriuretic pepide (ANP), endothelin (ET), A and B types, and angiotensin converting enzyme (ACE) ones.
The question is: What happens with cardiac function if EE is damaged ?
This can be answered by plotting force development (in Newtons) with time and comparing the two curves (intact versus denuded endothelium). The latter shows a smaller and faster curve but with no significant changes in the slope of the curve, indicating that Vmax (slope of the curve) remained unchangable. This differs from virtually all others forms of negative inotropic interventions such as reduced extracellular calcium or cAMP-mediated effects, which are all associated with a decrease in Vmax. The substance used to injury EE was Triton x-100, a mild detergent. Intracardiac US was the method used by investigation in vivo animal models, and the results were similar. We can extrapolate this curve to the entire heart by plotting LVP with time, and a similar pattern is found. In other words, the presence of an intact EE helps modulating left ventricular function (LVF) by prolonging ejection duration and slightly increasing systolic peak performance.
Myocardial inotropic state depends primarilly on the amount of transient intracellular calcium [Ca2+]i and the affinitty of the contractile proteins for the avaiable calcium. Wang and Morgan reported the effects of a denuded EE in differents [Ca2+]i. Even when the latter was increased, the final results were of that described above. Therefore, EE seems to modulate the affinity of the contractile proteins. With EE damage, there is a decreased responsiveness of these proteins thereby decreasing contractile permormance.
How EE can alter the affinity of these proteins ?
There are two main theories that try to answer this question, though they may act together:
1) Stimulus-Secretion Coupling and EE mediators -- Many studies indicated that the resting membrane potential (Vm) is important for endothelium Ca2+ homeostasis and the release of endothelium-derived factors. The Vm is influenced by a variety of ion channels, such as K+, Na+/K+ ATPase pump, Cl-, and substances such as ATP, ADP, AMP, histamine and substance P. There is now increasing evidence suggesting that EE may release chemical mediators, which may determine the myocyte inotropic response. Nitrous oxide (NO), prostaglandins and endothelins are suggested in this setting.
a) NO - this substance is produced from L-arginine by the NO synthase enzyme. Its main subcellular action is activation of guanylate cyclase, which elevates [cGMP]i . The latter seems to reduce the responsiveness of the myofilaments to intracellular calcium, thereby the net effect is a negative inotropism. However, it seems surprisingly, that some in vivo and in vitro studies have shown positive inotropic properties of basal cGMP contents. The hypothesis is: NO and cGMP inotropic actions would depend, at least in part, of the myocardial [cGMP]i which may be determined by the integrity of the EE
.b) Prostaglandins - PGI2 may also contribute to the underlying myocardium function. Tissue cyclooxygenase has been found twice in the endocardium fraction compared with that of the myocardium. Its inotropic properties are very poorly known, but new researches suggest that basal release of NO and prostaglandins and their interaction may modulate myocardial relaxation. The subcellular actions of PGs at myocardial level are not fully understood.
c) Endothelin - This 21 amino-acid peptide has at least two receptors, ET-A and ET-B, found in myocytes, conduction system and vascular and EE cells. It is a very potent positive inotropic substance, and its action resembles that of the EE, also increasing responsiveness of the contractile proteins bu through activation of a sarcolemmal Na /H exchanger. Besides of these effects, ET also has positive chronotropism properties, is a potent vasoconstrictor and can induce proliferation of vascular smooth cell and cardiac muscle. It is difficult to to understand the physiological role of ET in the heart if its net effect is an increase in MVO2. There is growing evidence that ET may bind to its receptors in a stoichiometrical pattern, suggesting that ET may act in an autocrine way, binding to ET-B receptor and stimulating NO an PGs release, rather than causing direct vasoconstriction. Some studies suggest the protective effect of ET during ischemia, opposing the adverse actions of cathecolamines mainly on cardiac electrophysiology, thereby preventing arrythmias. Conversely, one study showed that ACE inhibitors, by supressing ET secretion, improved coronary function and the stabilization of cardiac rhythm after ischemia in rat hearts, suggesting the use of ET receptors antagonists as an antiarrhythmic drug.
2) Blood-Heart Barrier - The most studied endothelium barrier is the blood-brain barrier (BBB), which has unique features that are crucial to keep neural tissue in optimal conditions. Some of these features include thigh endothelial junctions and selective ions transporters, which help to modulate ionic concentrations in interstitial milieau. Similar to the BBB, the EE may function as a blood-heart barrier (BHB), providing optimal environment for myocytes function. One feature of the EE that suggests this role is the different density of ionic channels on the luminal side comparing with the abluminal one. Therefore, there may be a transendothelial transport regulating ionic composition of extracellular space, which is crucial for myocyte function. Further studies are needed to confirm this hypothesis.
Cardiac endothelium is a modulator of ventricular function and its damage or dysfunction is actually a factor in the development of heart disease. Understanding clearly how EE modulates underlying myocardium is undoubtely useful, since new drugs can be experimented in this relatively new field, improving myocardial function by interacting directly or indirectly with the EE. One of the most utilized animal model of chronic heart failure is the dog one. Multiple sequential coronary microembolizations are performed during a specific period of time until ejection fraction reaches a low, pre-determined value. Endothelin blood levels, like cathecolamines, angiotensin ones, are increased in chronic heart failure. In one sudy, performed in this dog model described above, bosentan (endothelin receptor antagonist) improved LVF in a short-term basis and this drug could be proved useful in humans patients with heart failure.
1) Brutsaert DL: The endocardium. Annu. Rev. Physiol 51:263-273, 1989
2) Brutsaert DL et al: The cardiac endothelium: functional morphology, development and physiology. Progress in Cardiovascular Diseases 39(3): 239-262, 1996
3) Shimoyama H et al: Short-term hemodynamic effects of endothelin receptor blockade in dogs with chronic heart failure. Circulation 94:779-784, 1996
4) Brunner F, Kukovetz WR: Postischemic antiarrhythmic effects of angiotensin-converting enzyme inhibitors. Circulation 94:1752-1761, 1996
5) Filho JB: Doenças cardiovasculares e substâncias vasoativas derivadas do endotélio. An Acad Nac Med 156 (3): 133, 1996
6) De Hert SG: The role of cardiac endothelium in the regulation of ventricular function in Warltier DC: Ventricular Function - Society of Cardiovascular Anesthesiologists - Ed. Williams&Wilkins. pg. 69-111, 1995.
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