The embryological development of the heart is one of the most fascinating phenomena in nature and so is its final structure and function. The various ontogenetic passages form the evolutive basis of the final configuration of the heart. Each key step can be recognized in the final features, as the heart maintains a kind of “memory” of these passages. We can identify the major lines of development of the heart and trace these lines up to the mature organ. The aim of this review is to identify these key parameters of cardiac structure and function as essential elements of the heart’s proper functioning and bases for its treatment. We aim to track key steps of heart development to identify what it “remembers” and maintains in its final form as positively selected. A new vision based on the whole acquired knowledge must guide an in-depth scientific approach in future papers and guidelines on the topic and a complete, farsighted therapeutic conduct able to ensure the physiological correction of cardiac pathologies. The application of this modern, functional vision of the heart could improve the clinical treatment of heart disease, filling the gaps still present. The embryological development of the heart is one of the most fascinating phenomena in nature and so is its final structure and function . The heaFollowing the theory that ontogenesis summarizes phylogeny, various constructs have been expressed to recognize within the embryological development the bases (and phases) of the final structural and functional aspects, even after the Torrent–Guasp theory that identifies a continuous muscle band that constitutes the whole heart . The demNevertheless, the various ontogenetic passages form the logical basis of the final structure and function of the heart. Each step can be traced up to its final characteristics, so that we can deduce that the heart maintains a certain “memory” of these passages. We cannot make a close parallelism between each embryological phase and its final result, just as we cannot find all the evolutionary steps in embryonic development, but only those positively selected. However, we can identify the great lines of development of the heart and find these lines  in the final organ.The aim of this review is to identify and trace these key parameters of cardiac structure and function in order to better understand the essential bases of the heart’s proper functioning. We aim to follow key steps of heart development to identify what the heart “remembers”, what it maintains in its final form as positively selected. This to identify which fundamental parameters we must try to restore in case of heart disease, given that the mature heart preserves just the positively selected elements of its development.The memory is what remains forever, what stays during our life  and is preserved in the next generations (species memory). The memory is made by experiences and assures the evolution, both of the individual and of the species. In multicellular organisms, all the processes that lead to the development of the embryo are set down in the genetic memory and gene regulation drives cellular differentiation and morphogenesis leading to the creation of different cell types that possess different gene expression profiles from the same genome sequence. This explains how evolution actually works at a molecular level  and then brings the functional effects of the molecular structure on a larger scale. In the same way, the scientific approach to any subject requires a revision of what is already known and every potential future improvement starts from it. The “scientific memory” remains of fundamental importance in every new finding.The evolutionary pathway to mature four-chambered heart is very long and complex and it lasted for the past 600 millions of years . An ontoAny single step brings an improvement in efficiency, power, functional anatomy and physiology of the myocardium, driving future developments and assuring blood supply to the increasing metabolic need of more complex living beings. If we go along that path we will see all the basic features of the complex mature heart and recognize the anatomical and functional steps it went through, selecting the most adapted to its function.Over the centuries the macroscopic anatomical aspect of the heart has been clarified and its function has been correctly framed, but a sort of erroneous vision has lasted up to the present day: that relating to its three-dimensional, integrated, multidimensional structure. Although known since the time of Erysistratus and demonstrated by Harvey (1468), the real three-dimensional structure of the heart muscle was not taken into consideration, nor used in clinical practice if not recently. One of the main reasons for that was the technical limitation of not having an instrumental examination that could show it. Just with the advent of magnetic resonance and 2D echo speckle-tracking and strain , we haveA primitive tubular contracting vessel encounters a looping process on its long axis which approximates opposite regions (inflow and outflow) and creates hollow ventricles from the central portion of original vessel. Lateralization of the heart loop is driven by rotation around its dorsal mesocardium and this has two consequences: lateral displacement of its bending portion and torsion of the cardiac bend into a helical structure. The normal loop presents as a D-loop (towards the right side of the embryo) with left-handed helical winding (left-handed sense of twisting) .At the beginning the heart is formed by an inner endothelial tube without valves, a middle layer of extracellular matrix (cardiac jelly), and an outer myocardial tube. This tubular heart starts beating around the 21st day and pushing the blood cells in a laminar, unidirectional way, despite the absence of valves. The two predominant theories about the kind of propulsion of this primitive circulation are that the tubular heart could be a peristaltic or an impedance (Liebau) pump . The embCardiac jelly is a gelatinous a-cellular material, a relatively homogenous network of collagen fibrils and fine filaments. The structural part of the jelly is ensured by the elastin and collagen scaffold, whereas its gel like appearance is controlled by glycosaminoglycan, a protein involved in the degree of hydration of the jelly. The cardiac jelly is populated by several types of proteins that participate in paracrine cell-to-cell communication, and proteins that promote cell migration and tissue remodeling. There is evidence that the cardiac jelly is a resilient component of the embryonic heart wall, which becomes deformed during systole and springs back to its original shape during diastolic relaxation and, thereby, might suck the blood into the inflow segment of the heart tube . The carThe traveling contraction waves of the tubular embryonic chick heart thus are accompanied by corresponding waves of lumen occlusion during the initial phase of its pumping activity when all embryonic cardiac segments downstream to the primitive atrium have a thick layer of cardiac jelly. The peristaltic-like pattern of lumen occlusion is present until developmental stages when the embryonic ventricles start formation of a trabeculated muscle layer . The forSoon after the initial contractions, the heart tube bends and twists (loops) into a curved tube with its convex surface normally directed toward the right side of the embryo. When looping is complete, the heart has assumed the basic configuration necessary for further development into a four-chambered pump. There is a quite simultaneous onset of three different key changes: the first myofibrils appear , the firLooping consists of two main phases : c-loopiBefore looping, actin microfilaments in the outer myocardium cell layer are arranged in a net-like pattern at cell borders , while cExternal forces supplied by the splanchnopleure and omphalo-mesenteric veins appear to play prominent roles in the torsional component of c-looping. The omphalo-mesenteric vein may force the heart tube slightly rightward and then the splanchnopleure pushes it dorsally and farther rightward as the tube rotates about the dorsal mesocardium. Looping direction could be determined by a left-right difference in lateral forces exerted by the omphalo-mesenteric veins: the left omphalo-mesenteric vein is larger and exerts more pushing force than the right vein, causing the heart tube to twist rightward. Experiments have also shown that little torsion occurs when the splanchnopleure is removed. In 3D vision, the looped heart acquires a helical shape .Cardiac looping has also another important meaning: it is the first expression of asymmetry in the embryo. At the very initial stage this asymmetry is due to nodal flow, that is the flow generated by ciliar elements in the node region, a transient midline structure formed during gastrulation. It has a ciliated pit with monocilia that have a peculiar microtubule arrangement and generate a clockwise, leftward motion of fluids . This reThe subsequent morphological development of an embryonic heart is dependent of a balanced interaction between a genetic program, fluid mechanical stimuli and the inter- and intracellular processes that link them. The dynamics of the flow at these early stages has been studied in zebrafish. The tube is narrow and only few blood cells can pass through it, necessarily positioning themselves in a linear manner (laminar flow). A blood cell takes 1050 msec to cover the entire tube in this pumping system . The stuAt the same time as the looping process starts, there are profound modifications to the dynamics of the flow along the cardiac tube. The curvature of the system makes the passage of blood more difficult, but at the same time exploits the centrifugal force of the curvature itself . To guarDuring systole, the endocardial tube becomes compressed so that its lumen is almost completely occluded at end-systole. The diastolic expansions and systolic contractions of the ventricular myocardial wall of earlier heart tubes mainly run along the ventro-dorsal heart axis (c-loop), while during advanced stages of heart looping they run along the baso-apical heart axis (s-loop). The development of the ventricular segment is then characterized by the formation of trabeculated myocardium at its outer  curvature .3/s and the velocity of blood cells reaches 26 mm/s. It appears that the endocardial cushions act as primitive valves and induce a transition from peristaltic to pulsatile flow while increasing both pressure and flow rate.Parallel to the unidirectionality of the flow, there is a need for an increased flow of blood: the developing heart increases its rate but mainly cavity volume , by furtAmong the valves of the heart, the mitral (between left atrium and left ventricle) has a particular function and is involved in many pathological states. In humans, the mitral valve develops between the 5th and the 15th week of embryonic life. The leaflet and chordal tissue derive from the endocardial cushion tissue lying on the inner surface of the AV junction. As the cushion tissue elongates and grows toward the ventricular cavity, it becomes progressively delaminated from the underlying myocardium, and the leaflet are transformed into a funnel-like structure completely attached to the myocardium. Then, perforations into the valve leaflet appear. The perforations grow and form the chordae tendineae, generated by the ventricular layer. The development of the papillary muscle takes place at the same time and is originated from the myocardium. As they increase in size, they progressively loose contact with the myocardial wall and stay in contact with the cushion tissue at their tip, finally connecting with chordae tendineae . This deThe heart has to beat in order to support circulation well before its morphogenesis is complete. This is a fundamental passage that marks forever the indissoluble link between form and function of the heart, since both mature at the same time, and one could not develop without the other.As stated, the peristaltic mechanics of the tubular heart is gradually replaced by a suction pump model. At the tubular stage, there is complete obstruction of the lumen by apposition of endocardium reinforced by cardiac jelly with 100% ejection fraction, which is never achieved at later stages. This geometry alternates between cylindrical, optimal for generating pressure, and spherical, optimal for volume displacement . The conSoon after the beginning of looping, morphological differentiation of myocardium along the cardiac tube becomes apparent. This includes disappearance of cardiac jelly in the atria and ventricles, coinciding with the process of development of trabeculae and pectinate muscles in the atria. The conduction system starts to show mature characteristics once the chambers are formed. The outflow valve function is exercised by a combination of close apposition of the outflow tract cushions and contraction of the slowly conducting myocardium of the outflow tract. Also the trabeculated embryonic heart observes the Frank–Starling relationship. As the conduction system develops, the transition from primitive base-to-apex activation of the ventricles to mature apex-to-base sequence becomes evident and correlates with ventricular septation. The fetal heart not only grows in size, but further develops spiraling myocardial architecture of the compact layer, with myofibrils of cardiomyocytes that tend to dispose along the maximal stress directions .All these modifications take place while and because the heart has to cope with the growing metabolic needs of the new organism, without being able to wait for its own complete development.The left ventricle is a remarkable system characterized by the unique ability to translate 15% linear sarcomere shortening into ejection fractions of greater than 50% and wall thickening greater than 30%. This is obtained by a multidimensional network of myocardial fibers with different angles in the various layers of the myocardium, if observed in cross sections. Predominant orientation of myocardial fibers varies with wall thickness, and the pattern is reminiscent of multiple concentric layers of hoops . The hisThe shortening of the fibers that intersect each other with different angles of direction works like a cooperating system that gets a contraction, as Harvey said, in all directions and a shortening along the major axis. The interlaced structure allows ventricular systole with low energy expenditure, thanks above all to a fundamental parameter such as the torsion of the left ventricle. The oblique fibers rotate the ventricle on its axis in the opposite direction between the apex and the base. This “squeezes” the ventricle like a “wet cloth”.As mentioned, the growth of the heart occurs simultaneously with the development of its pump function. This feature of having to ensure the circulation of the evolving organism while it has not yet finished its own organogenesis is the determining fact of what we see today: the structure and the function are strictly related since they developed simultaneously. In this setting, the growing needs of circulating blood of the embryo condition the incremental development of the myofibrils and myocardial fibers, the maturation of a more suitable and capillary electrical conduction system, its own coronary support circulation, a suitable geometry of ventricular chambers etc. Embryologically speaking, what occurs is in practice a sort of “on demand” development, according to the needs that the embryo “asks” to the organ that assures its perfusion.Early scientists framed the complex structure of the heart since the time of Erysistratus (304–250 BC), a Greek anatomist and royal physician who described the valves of the heart, and concluded that the heart was not the center of sensations, but instead it functioned as a pump. Later we can find a precise description of the course of the fibers and its usefulness in the work of William Harvey , Lower , VesalioIf one envisions the looping process of the primitive heart tube while it contracts, it wraps itself, thickens its walls, divides into four different pressure chambers and pumps blood into an increasingly complex organism, it is conceivable how its final form is the suitable result of this process. The heart keeps on contracting as it does from its twenty-first day of life but with a structure and shape that continuously changes over time. The perinatal period is that which definitively shapes the myocardial mass as an adaptive consequence of the major haemodynamic changes occurring after birth that generate major parietal stress variations and parietal remodeling in different parts of the heart. The plasticity of myocardial tissue arrangement still present in this phase allows such adaptation. The ventricular myocardial architecture becomes more inhomogeneous, revealed by a variation of the regional isotropy index .The knowledge of cardiac function has progressed in a very fragmented and poorly integrated way among the different involved disciplines, at least until the high level of knowledge currently achieved. The need for advanced technologies has certainly slowed down this process. However, now the knowledge reached in embryology, physiology, pathology, in medical and surgical treatment and in specific instrumental examinations allows a more complete and integrated vision of cardiac function. From the whole sum of knowledge we can deduce that cardiac morphology and its related function maintain the fundamental characteristics of its development. We then list major characteristics of the mature heart that derive from its crucial embryonic steps: laminar flow, sequential electrical activation of contraction, elliptical geometry of ventricular chambers, fibers disposition, left ventricular torsion and valve function with special mention for the mitral valve. We add a clinical perspective for each of them that summarizes the state of the art of relative pathological states and outlines possible future improvements. Some of these perspectives are purely speculative but for most of them there are already important early evidences.If you imagine bending a straight tube and keeping a linear flow within it, the final shape must have as little bending as possible. The final conical shape of the left ventricle  recalls a straight tube with a single fold at the apex. The inflow and outflow sections are connected by an acute angle at the apex of the heart. This configuration allows maintaining a laminar flow in both anatomical areas, obtains the almost complete occlusion of the ventricular chamber and exploits the apex as a sort of parabolic curve to favor the blood exit in systole. In this way, also in the elliptical shape of the mature left ventricle, in normal conditions, the blood flow maintains a linear pattern, just following the curved apical region. Although it is an important variation in the linear aspect of the blood path, the elliptical shape of the ventricle with the presence of the cardiac apex has been positively selected exploiting the diastolic vortex, an important parameter in the dynamics of the blood. The profound modifications due to the looping also induce a chiral  asymmetrThe two components of the flow are both linear and are connected by the apical vortex during the diastolic phase, which accounts for the transportation of 10% of the whole filling volume. The septation of the ventricular cavity doubles this configuration in a “W” shape of the left and right flows of blood .Apart from the different flow vortices that are generated inside the heart due to the different morphology of the cardiac chambers, this behavior could be considered a remnant of the original linear flow in the cardiac straight tube. These two main flow components are also synchronous with the activation of the descending and the ascending muscular bands. The advantages of linear flow are well known and are positively selected during the growth process of the heart . Thanks In pathological situations , the linear flow is disturbed with negative consequences on the ventricular efficiency  . When flThe conduction system maintains its embryonic characteristics of an inflow kickstart center (sinus node) and a conduction pathway that sequentially  activates all the myocardium following the muscular bands (looped myocardium) development and evolution. Given the looped and twisted structure of the latter, the peripheral branches of the conduction system have a reversed direction towards the base of the heart (Purkinje fibers), following the bended and twisted ventricular portion of the old cardiac tube .The importance of resynchronization therapy is well known in heart failure treatment as well as in late definitive pacemaker de-synchronization. Sometimes the only resynchronization is able to reduce a mitral regurgitation on the basis of a better wall motion (papillary muscles synchronism). De-synchronization alone is sufficient to cause irreversible heart failure. Nevertheless, at the best of its results resynchronization therapy has still a 30% of non-responders . That coAn elliptic cross-section has a higher mechanical efficiency compared with tubular cross-section, and the elliptical shape of the final heart assures the highest efficiency for blood expulsion with a narrow cavity squeezed nearly completely. Elliptical shape guarantees a laminar flow, offering the smallest diameter in the folded mature heart. Need for feeding a wider organism, higher pressure mature system and the creation of a ventricular chamber made necessary the development of and end-systolic volume, lowering the 100% ejection fraction of the embryonic heart. That is the reason why end-systolic volume must be the smallest possible and why it was soon recognized as a sensitive marker of left ventricular dysfunction , a negat2 and 50 mL/m2, respectively [2), with an increase during 7-year follow-up of only 8–10 mL/m2. The elliptical shape is fundamental in obtaining a small ventricular volume: in a box-shaped or spherical heart would be impossible to maintain volumes at a low value and have at the same time the squeezing systolic efficiency [The results of STICH trial , even ifectively . In our ficiency .Left ventricular torsion is essential for efficient ejection , and manTorsion is altered in all cardiac pathologic states, with different degrees according to the severity of disease and its alteration is reversible if the pathologic injury can be removed ,69. IschWe personally hypothesized  and thenThis surgical reconstruction was based on current human diffusion tensor imaging of myocardial fiber orientation . This knWith our surgical suture we surely are not able to restore a microscopic, histological contiguity of myocardial layers, but the renewal of torsion shows that the final effect of rotation can be obtained even at a gross, tissutal level, if the remaining still normal tissue is re-hinged to a near-physiologic disposition .The recovery of the torsion is so specific that it can only be due to the matching of the structurally normal residual fibers, excluding the non-contractile fibrotic zone. We observed the recovery of apical rotation just after the surgical correction in the operating room and then confirmed it with a comparative echocardiographic 2D speckle tracking study. The early timing of torsion restoration testifies a mechanic correction due to surgical treatment and not to a positive remodeling occurring over time.Rapidly evolving imaging techniques will make possible a preoperative exploration of cardiac fiber mapping, giving the surgeon the possibility to plan a more precise surgical operation focused on the restoration of normal fiber orientation. Some of the negative results obtained so far could be due to the involuntary incorrect reconstruction of the residual bundles of fibers.The renewal of torsion reinstates to the ventricle part of that energy efficiency lost through dilatation and dysfunction, and this can translate into a significant clinical improvement, especially in ventricles that work at a critical level in the Frank–Starling relationship.One of the fundamental steps for cardiac development is the guarantee of a one-way flow obtained through the formation of the valves. Their efficiency remains essential for the proper functioning of the heart. Valve diseases are known to significantly reduce cardiac function over time, so that if the correction arrives too late in the natural history of the disease it is no longer possible to recover normal contractility and efficiency even after valve repair or replacement. It is also known that the negative consequences on the heart differ according to the diseased valve and the type of disease: valve regurgitation is worse tolerated than valvular stenosis and the mitral valve disease is more complex than that of the aortic valve. This is also an embryological memory: the regurgitation nullifies the unidirectionality of the flow, which is precisely the reason why the development of the valves has been positively selected. Valvular regurgitation not only wastes contractile energy, but mainly wastes part of the antegrade flow, so cardiac mechanics suffers from a double loss of efficiency, energetic and functional. In valvular stenosis, instead, the myocardium must spend more contractile energy to overcome the valve obstacle but, at least for a long time, this higher energy expenditure ensures an adequate systemic flow.The guidelines for the treatment of valve disease are still very indulgent on the precocity of the treatment itself . In factThere is a big difference in the embryological development between atrioventricular (inflow) valves  and outflow valves (aortic and pulmonary). The former in fact grow and implant inside the ventricle and are connected to it, i.e., to the moving muscle. The outflow valves instead are implanted in the tributary vessel and are thus disconnected from the systo-diastolic movement of the myocardium. This makes the mitral valve (and tricuspid) very special: its proper functioning does not depend only on the integrity of its leaflets but also on the conditions of the left ventricular muscle. Abnormalities of contractility, perfusion, synchronism, fibers’ disposition and ventricular geometry can all interfere with its normal functioning .The complexity of the mitral pathology finds its maximum expression in left ventricular dysfunction and heart failure, both idiopathic and ischemic. Especially in ischemic heart disease, thousands of articles have been written about the best treatment to follow. The long diatribe if repair or replacement was preferable ran ashore in some recent key studies that demonstrated the poor results of the repair of ischemic mitral disease ,90,91. TAnother theory of mitral repair has been unconfirmed over time due to poor results ,95,96, nThe heart is undoubtedly the beating engine of our life. It can stand the heaviest proofs, bare the most difficult situations and face the worst diseases. Unfortunately, the heart loses its morphogenic potential at the end of its development. In the adult heart, new mitoses, though present, are not enough to sustain a regenerative capacity of the organ. The pluripotential cells that contribute to the embryological development of the heart are definitively differentiated at its end and this process becomes irreversible. This means that the adult heart will work in the set-up present at the end of its embryological development and that the pathological changes will have to be counteracted using only the final structure of the heart. Therefore the heart can only keep the memory of its development and not retrace its various passages. This makes the organ we see an excellent final product to be stored jealously and to be known at our best in order to be able to treat its various pathological states. The complex structure of myocardial tissue is at the base of its physiology, and we must keep this in mind in everyday clinical practice.The heart is truly a multidimensional organ.Its physiological function is based on several different parameters and characteristics: histology, tissutal disposition, endoplasmatic reticulum, myocardial coronary and sinusoidal circulation, conduction system and electrical sequential activation, intra-ventricular synchronization, chamber geometry and volume, fiber orientation, opposite rotation of apex and base generating torsion, elliptical shape, systo-diastolic alternation, filling pressure and volumes, afterload pressure, electrolytes exchange, metabolic needs etc. Each one of these parameters is a tile of the complex puzzle of heart function. Different heart diseases can alter one or more of these parameters, developing several functional and clinical pictures, whose therapy must take into account all the parameters involved. If we try to address singularly each of the normal parameter, we cannot be able to succeed in the treatment of the disease because all parameters are tightly interlaced. When a disease damages the heart, it damages a set of interconnected anatomical structures that have knock-on effects on various functional parameters: a multidimensional organ needs a multidimensional, contemporary treatment.Many examples support this close, multidimensional interconnection.Even only the change in heart rate modifies the pattern and the timing of endoventricular flow vortex, increasing or decreasing its kinetic energy and its position relative to the mitral valve .The two opposite movements of apical and basal regions generating torsion have a turnaround point of twist to untwist motion pattern located coincidentally at the papillary muscle level, with three rotation patterns: counterclockwise rotation, clockwise rotation, and counterclockwise to clockwise rotation. The exact level at which this happens in each heart is important for the interaction with mitral valve function .Preservation of the LV systolic torsional profile may be a helpful predictor for post-mitral surgery survival and reverse remodeling in patients with non-ischemic secondary mitral regurgitation with narrow QRS, and patients who received resynchronization prior to mitral surgery had poor post-surgery survival, whereas those who received resynchronization at the time of mitral surgery had better survival ,101.A new design of artificial heart has been proposed which mimics global left ventricular wall deformation patterns in terms of circumferential and longitudinal contraction, as well as torsion: it will likely result in more physiological intracavitary blood flow patterns and higher efficiency .cardiomyopathy as a disease of the heart muscle as a whole, but in terms of fibermyopathy with reference to its intrinsic structure. In this perspective, perhaps many of the clinical results reported in literature will have to be reinterpreted, in a more comprehensive and correct view of what we treat interventionally, surgically and pharmacologically every day.A new concept, a new vision of the heart can arise from the knowledge we have today: we should no longer be thinking in terms of How many studies on mitral repair take into account the turnaround point of twist to untwist motion pattern? How many pharmacological studies care of fibers’ disposition to judge the medical effect? How large are end-systolic volumes in heart failure studies that select patients with 30% ejection fraction ? The morI entrust the conclusion to the words of the final remarks of Pettigrew’s Physiology of Circulation Lecture: “The scheme of the course and direction of the fibers as summed up, while it greatly facilitates the comprehension of the general principle involved in the ultimate structure of the ventricles, harmonizes in the most perfect manner with all that is at present known of the heart’s movements—those movements apparently so simple, and yet so difficult of analysis. How far I have been right in doing so, time and advanced Physiology will determine”.instrumento mirabile that each of us owns.As scientists, we should keep on studying and applying the complex structure of the heart remembering each of its constituent elements, to better understand, appreciate and care of this


The relationship between the surface electrocardiogram (ECG) T wave to intracardiac repolarization is poorly understood.TW).The purpose of this study was to examine the association between intracardiac ventricular repolarization and the T wave on the body surface ECG  were studied. Decapolar electrophysiological catheters were placed in the right ventricle (RV) and lateral left ventricle (LV) to record in an apicobasal orientation and in the lateral LV branch of the coronary sinus (CS) for transmural recording. Each catheter  was sequentially paced using an S1–S2 restitution protocol. Intracardiac repolarization time and apicobasal, RV–LV, and transmural repolarization dispersion were correlated with the SECG1, V2, and V3 SECGTW, with sensitivity of 0.89, 0.91, and 0.84 and specificity of 0.67, 0.68, and 0.65, respectively. LV basal endocardial, epicardial, and mid-endocardial repolarization occurred on the upslope of leads V6 and I, with sensitivity of 0.79 and 0.8 and specificity of 0.66 and 0.67, respectively. Differences between the end of the upslope in V1, V2, and V3 vs V6 strongly correlated with right to left dispersion of repolarization . Poor association between the T wave and apicobasal and transmural dispersion of repolarization was seen.RV endocardial repolarization occurred on the upslope of lead VTW reflects regional repolarization differences between right and left heart. These findings have important implications for accurately identifying biomarkers of arrhythmogenic risk in disease.The precordial SECG TW) is poorly understood. Several markers of repolarization, including QT interval,TW is thought to represent a far-field recording displaying a summary of repolarization of the entire heart.TW markers represent within the heart.10The relationship between intracardiac repolarization of the intact human heart and the surface electrogram T wave  with structurally normal hearts undergoing diagnostic electrophysiological study were enrolled. The study was approved by the local ethics committee and conformed to the Declaration of Helsinki. All patients gave informed consent.epi) via the lateral cardiac vein of the coronary sinus (CS) for recording transmurally across the LV wall  and RT were measured at the minimum of the first derivative, min(dV/dt), of the signal within the depolarization phase and at the maximum of the first derivative, max(dV/dt), of the signal during the T wave, respectively , SECG markers  were ass markers . All 12 ectively . The actectively . DispersTW was analyzed for time of onset of the T wave (Ton), peak of the T wave (Tpeak), and end of the T wave (Tend), in every ECG lead in every patient , using a 2-way mixed model of absolute agreement. The relationship between the upslope of the T wave on the SECG, regardless of polarity, and regional intracardiac RT was assessed using sensitivity and specificity analysis. The relationship between the dispersion of repolarization and measures within the ECG T wave were assessed using ICC and R2 of linear regression. P ≤.05 was considered statistically significant. Statistical analysis was performed using R statistical computing software (version 3.2.2).Comparisons between measured intracardiac RT and SECG markers were assessed using a paired TW depend on the repolarization sequence within the myocardium  have low-amplitude or negative EGMTW. During LV pacing at the basal endocardium  and a positive amplitude in the LV leads (V5–V6). This again corresponds to the pattern of regional intracardiac repolarization . Moderate agreement was demonstrated between V6 and the LV base endocardially  and epicardially .The limb leads on the SECGentation . SupplemTW always preceded intracardiac RT , whereas the latest Tend in the SECGTW always followed RT .Independently of the pacing site, the earliest Ton in the SECGThe proportion of sites that repolarized before T peak on the SECG showed significant heterogeneity between the LV and RV, based on the location of the pacing site. During RV pacing, a greater proportion of RV sites repolarized before T peak, whereas LV sites repolarized after T peak . During TW in leads V1 and V6, in a single beat in 1 patient during pacing from the RV, LV endocardium, and LV epicardium. Consistency between the morphology and polarity of regional EGMTW and the most proximal SECGTW is confirmed. Furthermore, local repolarization within each cardiac region consistently occurred during the upslope of the most proximal SECGTW:•TW in V1, whereas late LV repolarization occurred within the upslope of SECGTW in V6 , sensitivity and specificity decreased, and the limb leads showed generally poor sensitivity and specificity for repolarization moments in the RV. LV basal endocardial, epicardial, and mid-endocardial regions displayed the opposite phenomenon, with sensitivity of 0.79 and 0.8, and specificity of 0.66 and 0.67 in leads V6 and I, respectively, but with decreasing sensitivity and specificity from leads V5 to V1, and poor sensitivity and specificity in the rest of the limb leads. Finally, LV apical RTs showed poor sensitivity and specificity to the upslope of the SECG, with only aVR showing sensitivity of 0.76 but with poor specificity of 0.52.Statistical analysis in all patients, cycle lengths, and pacing sites confirmed this observation . RV endoTW upslope across all leads, and the difference between the start and end of the SECGTW in all leads to dispersion of repolarization in the major anatomic axes.TpTe has previously been reported as a marker of dispersion of repolarization, transmurally in the wedge preparationTW upslope in lead V1 vs V6 , lead V2 vs V6 , lead V3 vs V6 , V1 vs aVL , V2 vs aVL , and V3 vs aVL  . No strong correlations existed between the difference between the end SECGTW upslopes and apicobasal  or transmural dispersion of repolarization .A strong correlation was seen between right to left dispersion of repolarization and the difference between the end of the SECGP <.001) , regardl4, V5, V6, or lead II on the SECG and dispersion of repolarization in the transmural , apicobasal , or right to left orientations   . Additioeasures)  in the rTW in the intact human heart. The main findings are as follows: (1) the amplitude/polarity of the T wave on the precordial leads reflects the polarity of the unipolar signal recorded on the underlying nearby myocardium; (2) local RTs in the RV occur along the upslope of the SECGTW in leads V1, V2, and V3, whereas local repolarization in the LV occurs during the SECGTW upslope in leads V5, V6, and I; (3) the difference between the end of the T-wave upslope time in V1 minus V6 provides a good representation of right to left dispersion of repolarization; (4) no strong markers for apicobasal or transmural repolarization differences were seen on the SECG; and (5) TpTe did not correlate with dispersion of repolarization in the right to left, apicobasal, or transmural axis.This is the first study to provide direct correlation between local repolarization in the major anatomic axis and SECGTW are related the local repolarization component of the underlying myocardium.TW is more positive when the repolarization of local tissue is early, biphasic in intermediate RTs, and negative in late depolarizing sites where the rest of the heart has repolarized.TW. Our data using the well-validated Wyatt methodTW mirrored the polarity of the T wave in the underlying myocardium, with V5 and V6 matching the polarity of sites measured in the LV(1, V2, and V3 matched the polarity of sites measured in the RV (TW polarity and the apex of the LV may highlight that the precordial SECG fails to extend inferiorly enough to cover the local repolarization of the LV apex and the overlap with the RV apex.The polarity and upslope of the contact EGMin the LV, whereasn the RV . The T w1–V3 showed good sensitivity to all measured RV repolarization, whereas the upslope of V5–V6 and I showed good sensitivity to transmural LV basal and LV mid-myocardial repolarization (TW, but our data do not support this. Regardless of the transmural gradient (6, and this did not alter its polarity. This is perhaps due to the differences between experimental studies and our intact whole human heart studies, in which the influence of the far-field or global myocardial muscle mass has a greater influence on the SECGTW.The upslope of Vrization . These fgradient  and 4C, 1, V2, and V3 vs V6/aVL provide excellent correlation to right to left dispersion of repolarization (TW as a measure of dispersion of repolarization.TW represents local regional repolarization of the nearby underlying myocardium. Thus, if the SECG T wave is negative, TpTe may reflect a local repolarization component; however, if the T wave is positive, it may represent a difference between the end of a regional repolarization component and the far-field or late repolarization regions within the heart. This may explain Our data show that differences between the end of the upslope in Vrization , regardlrization . This isTW reflect global dispersion of repolarization within the porcine heart, in which apicobasal differences predominate. In the intact human heart, however, differences in repolarization between the thin RV and the large muscle mass of the LV may predominate, reflecting species differences.There was no strong relationship to apicobasal dispersion of repolarization and SECG markers . PreviouData were confined to multielectrode unipolar contact catheter recordings in the human heart as opposed to global mapping. This was because it was not possible to use global mapping systems in patients admitted for a minimally invasive human study. In addition, although great care was taken to transmurally oppose the catheters, true transmural recordings like those of wedge preparations or plunge electrode recordings were not possible. We did not assess global measures of TpTe as assessed in some other studies; therefore, comparisons with these studies are not possible.1–V3 vs V6/aVL represent right to left dispersion of repolarization. Further assessment of the consistency of this marker in structurally abnormal intact human hearts and its role in risk prediction is needed. There was no correlation between TpTe and dispersion of repolarization in the intact human heart.The upslope of the T wave in the precordial leads on the surface ECG represents regional repolarization within the underlying RV and LV. Differences between the end of the upslope in V


Surgical repair or replacement of the mitral valve is currently the only recommended therapy for severe primary mitral regurgitation. The chronic elevation of wall stress caused by the resulting volume overload leads to structural remodelling of the muscular, vascular and extracellular matrix components of the myocardium. These changes are initially compensatory but in the long term have detrimental effects, which ultimately result in heart failure. Understanding the changes that occur in the myocardium due to volume overload at the molecular and cellular level may lead to medical interventions, which potentially could delay or prevent the adverse left ventricular remodelling associated with primary mitral regurgitation. The pathophysiological changes involved in left ventricular remodelling in response to chronic primary mitral regurgitation and the evidence for potential medical therapy, in particular beta–adrenergic blockers, are the focus of this review. Mitral regurgitation (MR) is caused by failure of adequate coaptation of the anterior and posterior mitral leaflets duringleft ventricular contraction, resulting in various degrees ofregurgitation of blood from the left ventricle (LV) into the leftatrium (LA). The result of this regurgitation is twofold. Firstly,there is a reduction in forward stroke volume (FSV) into theaorta, with subsequent reduction in perfusion. Secondly, there isan increase in LA blood volume during ventricular systole, whichresults in an increase in left ventricular preload, the so-called‘volume overloaded’ state.MR is classified as either primary (organic) or secondary , and acute or chronic.4Current therapy for patients with severe chronic primary MR, as recommended by the European Society of Cardiology guidelines,5Although there have been several recent reviews focusing on ventricular remodelling in ischaemic heart disease, hypertensive heart disease and aortic stenosis, there have been few recent reviews on pathological left ventricular remodelling in patients with primary MR.Primary MR may present acutely, as a slowly progressive disease, or as chronic progressive MR with sudden deterioration related to acute changes in mitral valve anatomy such as a ruptured cord. Acute MR is usually a medical emergency requiring emergent surgery and is not the focus of this review.Patients with chronic primary MR are often asymptomatic for long periods of time before presenting at a late stage in heart failure. During this period, there is development of progressive left ventricular dysfunction as the LV is remodelled in an attempt to produce an adequate forward stroke volume.12Alterations in the global structure of the LV in response to primary MR have been reviewed in detail previously.18Eccentric hypertrophy normalises afterload, as estimated by mean systolic stress, compared to patients with aortic regurgitation, leading to a period of so-called ‘compensation’.21There is no clear explanation for this phenomenon but it has been proposed that the lower systolic load in the case of MR may result in a reduced hypertrophic response at a time when there is a marked demand for an increased stroke volume.24Chronic increases in wall stress are detrimental to the myocardium, resulting in activation of a number of complex inflammatory and apoptotic pathways, in a similar manner to heart failure from other causes. Ultimately, there is myocyte loss and sliding displacement of cardiomyocytes, or cell slippage, caused by disruption of the myocardial extracellular matrix (ECM)–integrin linkages.25Various lines of evidence point to time-dependent changes in the up- and downregulation of remodelling pathways in chronic primary MR.Myocardial mechanoreception is currently poorly understood.30The contraction–relaxation cycle of the myocyte depends on coordinated interaction between the thin actin filament and the thick myosin filament within the myocyte sarcomere.40Titin complexes with a number of potential ‘signalosomes’ , including the Z-disclocalised protein MLP (muscle LIM protein), which has been shown to be responsible for hypertrophy and cardiomyopathy in MLP-deficient animals.Pathological volume overload-induced mechanical stretch has a number of other effects on the cardiomyocyte. For example, in in vitro39ROS play an important role in signal transduction and physiological regulation in vascular and myocardial cells. However, under pathological conditions, such as excessive myocyte stretch or excessive inflammatory signals, ROS have been shown to activate maladaptive remodelling signal-transduction pathways.53ROS are increased in patients with congestive heart failure,56Tumour necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) are produced by all nucleated cells, including cardiac myocytes.61Chronic elevation of cytokines has an effect on left ventricular remodelling by blunting of β-adrenergic signallingCytokines are elevated in patients with heart failure,56As the LV becomes dilated and dysfunctional, there is an increase in inflammatory pathway gene expression,26 which is supported by clinical work in patients with severe chronic primary MRApoptosis is activated by several extracellular death signals, including myocyte stretch,Myocyte arrangement and myocardial integrity is highly organised to enable the continuously moving myocardium to produce coordinated contraction, resulting in stroke volume.91The ECM is a highly dynamic part of the myocardium that changes depending on the degree and type of mechanical stress, neurohormonal activation, inflammation and oxidative stress. These stressors on the ECM result in changes in the expression and activation of the proteins responsible for ECM turnover and, ultimately, alterations in collagen deposition and degradation.MMPs are a heterogeous family of enzymes responsible for the proteolysis of various protein-based extracellular substances. They include the collagenases , stromelysins (MMP-3 and MMP-10) and the gelatinases (MMP- 2 and MMP-9). They are expressed and secreted into the extracellular space by a variety of cells, including cardiac myocytes, cardiac fibroblasts and macrophages.97TIMPs are low-molecular-weight proteins that bind to the catalytic domain of active MMPs, preventing substrate binding. There are four species of TIMPs with overlapping functions within the myocardium, which are not restricted to MMP inhibition. Other pleomorphic effects have been described. For example, TIMP-2 increases collagen production by fibroblasts, whereas TIMP-3 is responsible for fibroblast apoptosis.98Biological and/or mechanical stimuli trigger various signal transduction pathways, resulting in the production of MMP transcription factors and the secretion of these enzymes into the ECM.108Cytokines, such as TNFα and IL-1, have been found to increase MMP expression,112TGF-β stimulation induces maturation of fibroblasts to myofibroblasts and enhances ECM protein synthesis via induction of TIMP expression and inhibition of certain MMP expression.In response to different haemodynamic overloads (pressure versus volume), the ECM undergoes different patterns of remodelling.113There appears to be a time-dependent increase and decrease in MMP activity during the evolution of left ventricular remodelling in response to primary MR .26,117 M128MMP gene expression in dogs with isolated MR has confirmed that, at four months, there was down-regulation of a number of non-collagen genes important in ECM structure, down-regulation of pro-fibrotic connective tissue growth factor and plasminogen activator, and down-regulation of numerous genes in the TGF-β pathway.129Over time, there are characteristic changes in the MMP/TIMP ratio, enabling the ventricle to initially increase compliance in the acute and compensated phases of MR. However, at some point (the ‘transition’ point) there is excessive degradation of the ECM, leading to the decompensated and dilated LV.27Patients with chronic primary MR demonstrate LV systolic dysfunction even before a reduction in LVEF occurs.140Long-term increases in myocardial angiotensin II levels increase local TGF-β, with the resultant increases in activation of genes involved in ECM production via nuclear translocation of NFκB.143Three types of β-adrenergic receptors (β-ARs) are known to exist in the myocardium: β1, β2 and β3, with an approximate ratio of 80:17:3.148The β-adrenergic receptor system plays an important role in the pathogenesis of myocardial remodelling and heart failure.In patients with systolic heart failure (HF), several studies in the last three decades show that â1-receptor density80Chronic β1-AR activation causes a number of detrimental effects, ultimately resulting in changes in the ECM and cell loss from necrosis and apoptosis,158Most β-adrenergic blockers are antagonistic to β-ARs  by occupying the receptor and preventing signal transduction via G-protein activation. Importantly, there is an up-regulation of β1-AR expression and improvements in receptor sensitivity, resulting in reversal of cardiac remodelling.There are other important differences between carvedilol and other beta-blockers. For example, metoprolol upregulates cardioprotective β3-AR expression, whereas carvedilol does not.168Clinical support for β-adrenergic receptor blocker therapy in patients with heart failure is well known,171Several mechanisms for the improvement in outcomes with β1-receptor blockade have been proposed,178Since MR leads to a reduction in forward stroke volume, it is hypothesised that the adrenergic system is activated to maintain systemic blood pressure and perfusion, and blockade of the adrenergic system should limit adverse left ventricular remodelling. There is evidence that chronic primary MR results in excessive activation of the sympathetic nervous system, with increases in myocardial catecholamine levels,179Tallaj et al.159At present there is no proven medical therapy for chronic primary MR. Surgery is the mainstay of treatment for severe MR1 but carries peri-operative risk, and patients are potentially subjected to a life-time risk of anticoagulation if they undergo mitral valve replacement. Many patients in the developing world are from poor and rural backgrounds where access to regular medication and regular anti-coagulation assessment is difficult. A medication that could limit or even reverse left ventricular dysfunction associated with the volume-loaded state of chronic severe MR would be extremely beneficial to these patients, even if only to delay the need for surgical intervention. This would especially be true in women of child-bearing age. Warfarin is teratogenic and many women with prosthetic valves have complicated pregnancies related to the teratogenic effects of warfarin or the risks related to bleeding during pregnancy.Persistent, and often worsened, postoperative left ventricular dysfunction is a major cause of morbidity and mortality in these patients,2, as assessed by echocardiography, should promptly be considered for cardiac surgery. Barbieri et al.191Current guidelinesHow these patients should be managed in the interim is unclear but it is important that patients are not left untreated until irreversible left ventricular remodelling has taken place. In resource–limited hospitals, patients who do not need emergency surgery often wait several months before they undergo surgery, by which time there has been progressive advancement of ventricular remodelling, leading to permanent impairment of function. Medical therapy that could reverse or at least attenuate LV remodelling may improve outcomes in these patients.To date, there is little evidence to support medical therapy in the treatment of patients with organic valve disease,There is some clinical evidence to support the concept that β–AR blockade may attenuate remodelling in patients with primary MR . Stewart197A retrospective observational study involving 895 patients in California showed that participants on β1–AR blocker therapy with severe MR and normal left ventricular function had a significantly lowered mortality hazard, regardless of the presence of hypertension or coronary artery disease.By contrast, there are several pre–clinical and clinical studies demonstrating that beta–blocker therapy actually worsens left ventricular dimensions and function in chronic primary MR (Table 1).Similarly, in a four–month dog model, extended–release metoprolol succinate failed to attenuate the adverse global left ventricular remodelling and ECM loss, but did preserve cardiomyocyte function.A retrospective echocardiographic study in 134 human subjects with moderate–to–severe MR (67% degenerative and 20% ‘non–specific thickening’) found that patients exposed to beta–adrenergic blockade developed worsening of their ejection fraction over a mean of 20 months of follow up.196At the present time, there are no recommendations regarding medical therapy in chronic primary MR. Afterload reduction has not consistently been shown to improve long–term outcomes.Firstly, the studies have been performed in different experimental models and at different stages in the evolution of MR–related left ventricular remodelling. Many of the experiments performed thus far have been in animal models with controlled formation of volume overload showing that early introduction of beta–blocker therapyEarly after the development of MR there is a marked increase in inflammatory and neurohormonal response to the acute volume overload.Secondly, various beta–adrenergic agents have been tested under different circumstances. Compared to the impressive beneficial results in heart failure patients with the mixed adrenergic blocker, carvedilol,200Thirdly, an important question is whether patients presenting in more advanced stages of left ventricular remodelling will respond to anti–remodelling therapy or whether the wall stresses determined by the Laplace law will outweigh any potential beta–blocker effect. In this regard, the findings of Pat et al. Left ventricular remodelling in response to the volume load created by chronic primary MR is a complex process that stems from excessive diastolic stretch of myocytes. Excessive stretch triggers activation of numerous signal transduction pathways, resulting in an initial adaptive remodelling process in the form of eccentric hypertrophy. However, chronic activation of these pathways results in abnormal increases in ROS, catecholamines, angiotensin II and inflammatory cytokines. This is followed by a transition to adverse remodelling involving cardiomyocyte apoptosis and interstitial collagen loss, common to all forms of heart failure.Limited data do not support the routine long–term use of afterload–reducing agents for the treatment of chronic primary MR. By contrast, there is pre–clinical data demonstrating that β–AR blockade reverses remodelling caused by the volume overload of chronic primary MR, and there are some recent clinical data to support this hypothesis. However, some studies demonstrated worsening left ventricular remodelling with betablocker therapy. Whether these contrasting outcomes are related to differences in beta–blockers, varying experimental models or differences in timing of therapy will need clarification. Ultimately, further studies are required to elucidate the exact mechanisms involved, and large randomised clinical trials are needed to clarify the role of these agents for patients with chronic primary MR.


The effect of eccentric (ECC) resistance exercise (RE) on myocardial mechanics is currently unknown.This study investigated ECC RE at varying intensities on left ventricular (LV) function using LV strain (ε), wall stress and haemodynamic parameters. Twenty-four healthy male volunteers completed ECC leg extensions at 20%, 50% and 80% of their ECC maximal voluntary contraction (MVC), whilst receiving echocardiograms. Global longitudinal ɛ, strain rate (SR), longitudinal tissue velocity, heart rate (HR), blood pressure (BP), mean arterial pressure (MAP), LV wall stress and rate pressure product (RPP) were assessed at baseline and during exercise.P < 0.01). Eccentric RE increased HR and peak late diastolic SR at all intensities compared to rest (P < 0.02).Left ventricular global ɛ, systolic SR and wall stress remained unchanged throughout. Systolic blood pressure (sBP), MAP and RPP increased at 80% and 50% intensities compared to rest (The findings suggest acute ECC RE may not alter main parameters of LV function, supporting future potential for wider clinical use. However, future studies must investigate the impact of multiple repetitions and training on LV function. In clinical practice, the current trans-thoracic echocardiogram evaluates LV cavity size and wall thickness to assess structural components; whilst valve health, inflow velocity and ejection fraction are investigated to understand function  RE, such as isometric and eccentric (ECC) have been investigated. Isometric exercise can prevent or delay significant muscle mass and strength reductions . It is hypothesised that there will be no significant difference in Global longitudinal ε during ECC RE independent of intensity compared to baseline.Twenty-four recreationally active healthy males volunteered to participate in this study. General participant characteristics displayed in Table. This was a repeated-measures research design. Participants visited the laboratory in light training appropriate clothing, having refrained from alcohol, strenuous physical activity and caffeine for 24 h prior. Participants completed two visits, one preliminary and one main trial session separated by 5–7 days. During the preliminary visit, participants performed an ECC knee extension maximal voluntary contraction (MVC) using an isokinetic dynamometer and received body fat (BF) percentage measurements via air-displacement plethysmography. During the main trial visit, participants rested for a period of 5 min in the supine position and received a transthoracic echocardiogram at baseline and during ECC knee extensions at 20%, 50%, and 80% of the pre-determined ECC MVC. During each echocardiogram, heart rate (HR) and blood pressure (BP) were measured.−1. Three ECC MVC manoeuvres were performed and the highest peak force (N) was recorded (mean ECC MVC: 1141 ± 342 N). Two-minute rests separated each attempt. The session was terminated at the completion of a 3-min cycling cool down at 70 W.Participants’ height (cm) was recorded with shoes removed using a wall-mounted stadiometer . Resting BP measurements were acquired using an aneroid non-mercury sphygmomanometer  following standard guidelines by the American Heart Association (AHA) and the British Hypertension Society (BHS)  and sit inside the Bod Pod  for 3 min to obtain BF percentage. This was repeated 1 further time. Body fat was deemed reproducible only when body volume differences < 150 ml , 50% (mean: 571 ± 171 N) and 80% (mean: 913 ± 274 N) . A 3 lead ECG  was used continuously to monitor HR and track cardiac cycles for offline ε analysis. Heart rate was recorded as the peak HR occurring during the ECC contraction. Images were captured Fig.  Wharton. Image qAll ε analyses weres performed through semi-automated STI Fig.  Dandel , offlineN = 24) between rest and 20%, 50% and 80% exercise intensities in this repeated-measures test design. All relevant assumptions were met. Bonferroni post-hoc analysis identified where differences were situated. Global longitudinal ε coefficient of variation (CV) was calculated via pairwise analysis of reliability data following Hopkins  compared: HR, sBP, diastolic blood pressure (dBP), LV global longitudinal ε, LV SR, LV longitudinal tissue velocity, LV wall stress, MAP and RPP in all subjects  in comparison to rest (80%: 132 ± 13 vs 50%: 129 ± 14 vs rest: 118 ± 8 mmHg). Furthermore, there were significant increments (P = 0.004) in sBP between 20 and 50% intensity exercise (20%: 123 ± 12 vs 50%: 129 ± 14 mmHg). Moreover, a significant increase in dBP (P = 0.008) was found at 50% intensity ECC RE compared to rest (50%: 73 ± 11 vs rest: 67 ± 8 mmHg). In addition, both MAP and RPP displayed significant increments  at 50% and 80% intensities compared to rest .Eccentric RE stimulated a significant increase in HR  and peak early diastolic SR  were unchanged during ECC RE, whilst peak late diastolic SR increased significantly (P =  < 0.02) at all exercise intensities compared to rest (rest: 0.42 ± 0.11 vs 20%: 0.52 ± 0.15 vs 50%: 0.56 ± 0.21 vs 80%: 0.62 ± 0.33 s−1). No significant changes were observed in peak late diastolic myocardial velocity . However peak early diastolic velocity became less negative at 50% exercise intensity compared to rest . Finally, LV wall stress (P = 0.856) remained unchanged during ECC RE (rest: 130.38 ± 43.29 vs 20%: 127.27 ± 44.04 vs 50%: 129.62 ± 41.59 vs 80%: 127.66 ± 35.16 dyn cm−2).Progressive ECC RE did not significantly change P = 0.24; Fig. 5 The aim of this study was to investigate the effect of different intensities of ECC RE on LV longitudinal ɛ. ECC RE elicited positive chronotropic and haemodynamic responses without concomitant alterations in global longitudinal ɛ and systolic SR. The results of this study may suggest large muscle group single-repetition ECC RE transiently upregulates haemodynamic markers and HR responses, without augmenting LV systolic function. The lack of significant alterations in LV global longitudinal ɛ during ECC RE independent of intensity may support existing research which suggests ECC exercise stimulates reduced cardiovascular stress compared to traditional CON RE  and the intensity is markedly lower than commonly used in recreationally trained populations (Stefani et al. The haemodynamic responses discovered in this experiment coincide somewhat with the general cardiovascular responses understood to occur during a bout of exercise, although to a lesser amplitude. For instance, RE traditionally stimulates acute increases in HR, BP and arterial resistance which subsequently increases MAP and RPP (Stӧhr et al. Whilst the results of this study cannot confirm the potential of ECC RE as a clinical diagnostic tool or as a therapeutic strategy due to differences between the experimental protocol and common exercise practice, it provides novel information on the valuable topic of ventricular ε. This study also provides an insight into cardiovascular changes transiently occurring during brief exposure to an alternative exercise type and in addition, provides comparative data to other studies investigating transient CON and isometric changes. Finally, the results of this study may help work towards a future reference range of ventricular ε values in response to varied exercise modalities.There are several study limitations that require attention: first, the study sample encompassed only healthy recreationally active males between 18 and 35 years old; therefore, any potential implications for the wider population can only be speculated. In addition, the physiological responses observed during this study can only be described as transient modifications that take place during a single rep at each intensity. Physiological responses to multiple repetitions or training requires further investigation. Additionally, due to the nature of exercise ultrasonography and STI, image quality somewhat varied, through individual differences and torso movement. Although ~ 73% of all images ranked satisfactory or above using the study image quality scale; images of poorer quality existed and may impair analytical accuracy to an extent. Finally, LV ɛ investigations were limited to a single apical view due to the time constraints of imaging during muscular contractions. Therefore, changes may have occurred in other planes or within circumferential and radial ɛ that could not be captured during each recording.Results from this study exhibit LV global longitudinal systolic function is transiently unaffected during the performance of brief lower limb ECC RE irrespective of intensity, independent of haemodynamic and chronotropic augmentations. These outcomes may provide foundations for further investigations of the use of large muscle group ECC RE for diagnostic or therapeutic interventions. Future investigations should assess the LV functional responses to long-term ECC resistance training or during multiple repetitions using a larger cohort with potential comparison to clinical populations. The evaluation of LV radial, circumferential and twist mechanics during this unique exercise modality may also be justifiable.


Right ventricular (RV) dysfunction is a known risk factor for increased mortality in cardiac surgery. However, the association between RV performance and ICU morbidity is largely unknown.We performed a single-centre, retrospective study including cardiac surgery patients equipped with a pulmonary artery catheter, enabling continuous right ventricular ejection fraction (RVEF) measurements. Primary endpoint of our study was ICU morbidity  in relation to RVEF. Patients were divided into three groups according to their RVEF; < 20%, 20–30%, and > 30%.p < 0.001), prolonged duration of mechanical ventilation , usage of inotropic drugs , and increase in creatinine .We included 1109 patients. Patients with a RVEF < 20% had a significantly longer stay in ICU, a longer duration of mechanical ventilation, higher fluid balance, a higher incidence of inotropic drug usage, and more increase in postoperative creatinine levels in comparison to the other subgroups. In a multivariate analysis, RVEF was independently associated with increased ICU length of stay  contains supplementary material, which is available to authorized users. Nowadays, a set of robust models for the prediction of perioperative mortality in cardiac surgery has been validated –3. HowevTo this end, we aimed to determine the prognostic value of postoperative RV function in relation to ICU morbidity. Subsequently, we investigated the additional value of individual components of the euroSCORE in a multivariate model.We performed a single-centre retrospective study in a tertiary teaching hospital with a closed-format ICU. We included all cardiac surgery patients equipped with a pulmonary artery catheter (PAC) and admitted to the intensive care unit in the postoperative phase between January 2011 and January 2015. Exclusion criteria for this retrospective analysis include isolated coronary artery bypass grafting (CABG) with a good LV function. According to our institutional protocol, a large proportion of patients are equipped with a PAC after induction of anaesthesia. The decision to insert a pulmonary artery catheter was protocol driven and was taken at the start of the surgical procedure by the attending cardio-anaesthesiologist. His/her decision is based upon predefined criteria, entirely restricted to the type of surgery. In practice, only patients with an anticipated uncomplicated CABG procedure were not included.The same cohort of patients has been used in a previous publication to clarify the association between RV performance post cardiac surgery and all-cause long-term mortality .The study was approved by the local ethical and scientific committee and the need for informed consent was waived in accordance with applicable laws.y (TEE). Prior to transfer to the ICU, the PAC was interfaced with a computerised monitoring system . The catheter is equipped with a thermal filament positioned 4 cm from the tip of the catheter. This thermal filament generates heat pulses in a random on-off pattern. The change in blood temperature is measured downstream throughout the entire respiratory cycle. Based on a repeating on-off signal, a relaxation waveform can be generated. The right ventricular ejection fraction can be computed by the exponential slope of this waveform curve and the continuous averaged heart rate. The longer it takes for the curve to reach baseline, the lower the ejection fraction. The random on-off pattern is repeated every 60 s and reflecting an average of the measurements taken over the last 5 to 10 min (time averaging) [2), and RVEF) started directly after ICU admission and were averaged over the first 24 h of ICU admission. Based upon the Gaussian distribution curve of the postoperative RVEF, patients were stratified into three predefined groups: Group 1: RVEF < 20%, group 2: RVEF 20–30%, group 3: RVEF > 30%.In case of postoperative PAC monitoring, patients were equipped with a 7.5 F CEDV-Pulmonary Artery Catheter , directly after induction of anaesthesia. During surgery, additional haemodynamic monitoring was performed by transesophageal echocardiographeraging) . This caAll patients were admitted to the ICU direct postoperatively. In our institution, by protocol, all postoperative cardiac surgery patients are admitted to the ICU on mechanical ventilation. No cases were extubated in the operating room.2O. Extubation was performed within 2 h of ICU admission in case the patient was haemodynamically stable and in absence of signs of  complications . All patients were discharged from the ICU on the first postoperative day, unless they had unstable and/or insufficient haemodynamic parameters, need for inotropes or vasopressor, signs of surgical complications , and/or signs of organ failure.Settings of mechanical ventilation were standardised according to local protocol, with a respiratory frequency of 20–30 times per minute, tidal volumes limited up to 6 ml/kg ideal bodyweight, and a postoperative end-expiratory pressure (PEEP) of 10 cm Hs) test. Bivariate logistic regression of the association between the RVEF and morbidity was performed using the backward likelihood ratio method. Markers of morbidity were transformed into dichotomous variables by using the 75th percentile as a cut off value.Statistical analysis was performed using the statistical package for social science . Data are described as median with interquartile range (IQR) unless stated otherwise. Kolmogorov-Smirnov test was used to test normal distribution. Differences between groups were performed with applicable non-parametric tests for unpaired data. Correlations were tested with the Spearman Rho  in relation to right ventricular ejection fraction.2).Secondary endpoints included the correlation between RVEF and different haemodynamic variables %), 747 patients to group 2 (RVEF 25 (23-27)%), and 146 to group 3 (RVEF 32 (30-34)%). Baseline characteristics are listed in Table p < 0.001, Fig. p < 0.001, Fig. p < 0.001), a higher incidence of inotropic drug usage (p < 0.001), and a larger increase in postoperative creatinine (p = 0.004)  had a significantly longer stay in ICU (p < 0.001), duration of mechanical ventilation , the use of inotropic drugs , and increase in creatinine  . The odds ratios are a decreased risk for every increase in RVEF per percentage in model 1, and in model 2, the odds ratios are an increased risk compared to the group with the best RVEF. .After multivariate analysis, RVEF as a continuous variable was independently associated with ICU LOS  had a significant higher PAP and EDVi. Furthermore, they had a significant lower cardiac index and SvO0% had a rs = − 0.187, p < 0.001), CVP and EDVi , and PAP and EDVi . In addition, there was no significant correlation between the CVP and RVEF  . Furthermore, both isolated poor LV and RV performance are also statistically associated with prolonged mechanical ventilation , we separated LV and RV performance into four groups: group 1: LVEF ≥30% and RVEF ≥20%, group 2: LVEF <30% and RVEF >20%. group 3: LVEF ≥ 30% and RVEF ≤20%, and group 4: LVEF <30% and RVEF ≤20%. Poor LV function was defined as an EF < 30%, and poor RV function as an EF < 20%. Isolated poor LV performance is statistically associated with the presence of prolonged ICU stay (p < 0.001).The second main confounder is most likely pulmonary artery pressure (which relates to COPD as well). In addition to the correlation coefficient Fig. , we sepaIn addition, 121/216 patient (56%) had a RVEF < 20% in the absence of a poor LV performance or pulmonary hypertension. Interestingly, the percentage of patients with a prolonged length of stay ICU and prolonged mechanical ventilation was not significantly different between those two subgroups.In this study, we aimed to evaluate the prognostic value of RV performance and to identify risk factors for ICU morbidity. There was a striking absence of association between well-known risk factors for mortality, such as left ventricular function and pulmonary artery pressure, and markers of ICU morbidity. With the exception of unstable angina, all variables of the euroSCORE model did not independently predict ICU LOS or duration of mechanical ventilation in our population. On the other hand, the performance of the RV (which is not included in the euroSCORE or APACHE IV) was independently associated with markers of ICU morbidity. However, it must be stressed that the total package of easily obtainable variables in the euroSCORE and APACHE IV score is a robust and well-validated method to predict outcome.Over the last decades, mortality in cardiac surgery has decreased despite an increase in age and complexity of surgery , 17. At In addition, the euroSCORE and Parsonnet score were reported to be suitable as risk scores for ICU morbidity , 18, 22.Several studies addressed the contribution of RV performance on ICU morbidity and mortality in cardiac surgery. Among patients with hypotension, the majority of the non-survivors appeared to classify as isolated RV failure or biventricular failure. In contradiction, isolated LV dysfunction was associated with a significant better prognosis as compared to RV dysfunction , 24. In 2 and will overcome the above limitations. Furthermore, our data showed a significant correlation between TEE findings and PAC-derived RVEF. Despite all odds, recent data indicate a benefit of the use of PAC in the setting of cardiac surgery [A possible explanation for the absence of postoperative RV performance in predictive models is the fact that RV dysfunction may well be under-diagnosed. The complex anatomy of the RV makes it challenging to assess its function . Althoug surgery , 33.The lack of clinically relevant correlations between volumetric variables (RVEF/EDVi) and classical pressure variables, such as CVP and PAP, is an important observation in our study. Although an inconvenient truth, such observations are supported by physiological theory. First of all, pulmonary hypertension is a well-known risk factor for RV dysfunction, since it is the main determinant of RV afterload . HoweverPulmonary hypertension may not be the only contributing factor to RV failure in the postoperative setting; LV dysfunction, ischemia, and positive-pressure ventilation have been associated with RV performance as well , 37, 38.p = 0.084).In addition, CVP may not serve as a surrogate for RV performance either, reflecting the non-linear end-diastolic pressure-volume relation . At low Lastly, we observed an independent association between RVEF and a postoperative increase in creatinine. In addition, we also observed a significant correlation between rise in creatinine and CVP. This is in line with the current literature. Venous congestion has been reported to be the strongest haemodynamic determinant for worsening of renal function, independent of cardiac output . The curOur study has several limitations. Although the PAC used in our study allows for continuous assessment of RV performance, its use for this purpose may be a topic of debate. Alternatively, RV function may be determined by TEE-derived variables such as Tricuspid Annular Plane Systolic Excursion (TAPSE) and S′ , 45. HowIn our dataset, RVEF and unstable angina appeared to be independent risk factors for markers of ICU morbidity, such as length of ICU stay, duration of mechanical ventilation, and increased use of inotropic drugs. There was a striking absence of prognostic value for the individual components of the euroSCORE in relation to ICU morbidity. CVP and PAP cannot be used as surrogates for volumetric RV variables. Selection of high-risk cardiac surgery patients in terms of individual burden, costs, and use of ICU resources warrants further research in this field.Additional file 1:Table S1. Operation type. (DOCX 13 kb)


Repositioning of the heart during myocardial perfusion imaging (MPI) using Rubidium-82 (Rb-82) PET may occur when using regadenoson. Our aim was to determine the prevalence and the effect of correcting for this myocardial creep on myocardial blood flow (MBF) quantification.We retrospectively included 119 consecutive patients who underwent dynamic rest- and regadenoson-induced stress MPI using Rb-82 PET. The presence of myocardial creep was visually assessed in the dynamic stress PET series by identifying differences between the automatically drawn myocardium contour and the activity. Uncorrected and corrected stress MBFs were compared for the three vascular territories  and for the whole myocardium.P  < 0.001), in the whole myocardium from 2.7 to 2.6 mL/min/g (P  = 0.01), and increased in the LAD from 2.5 to 2.6 mL/min/g (P  = 0.03) and remained comparable in the LCX (P  = 0.3).Myocardial creep was observed in 52% of the patients during stress. Mean MBF values decreased after correction in the RCA from 4.0 to 2.7 mL/min/g  contains supplementary material, which is available to authorized users. The use of myocardial blood flow (MBF) quantification using Rubidium-82 (Rb-82) in myocardial perfusion imaging (MPI) with positron emission tomography (PET) is increasing rapidly.61, A2B, and A3 receptors, adenosine and dipyridamole are associated with undesirable short-term side-effects as general discomfort, chest pain, and hypotension, and more severe side-effects such as atrioventricular block or bronchospasm.2A receptors and is fast and better tolerated by patients.23A dynamic PET acquisition including the capture of the first-pass bolus of the activity is required for MBF quantification. Pharmacological vasodilators are generally used to induce stress, while the patient is lying inside the PET scanner.Despite the reduced patient motion when using regadenoson, in clinical practice, we frequently observe repositioning of the heart after administration of regadenoson. This so-called myocardial creep is presumably caused by an increasing respiration and lung volume and thereby the repositioning of the diaphragm and heart after induction of pharmacological stress.We retrospectively included 119 consecutive patients referred for MPI using Rb-82 PET/CT , who underwent dynamic rest- and pharmacological-induced stress using regadenoson. This study was retrospective and approval by the medical ethics committee was therefore not required according to Dutch law. Nevertheless, all patients provided written informed consent for the use of data for research purposes.All subjects were asked to abstain from caffeine-containing substances for 24 hours and to discontinue dipyridamole-containing medication for 48 hours before imaging. Prior to MPI, a low-dose CT scan was acquired during free-breathing to provide an attenuation map of the chest. This scan was made using a 5-mm slice thickness, 0.8 s rotation time, pitch of 0.97, collimation of 32x0.625 mm, tube voltage of 120 kV, and a tube current of 10 mA. Next, 740 MBq Rb-82 was administered intravenously with a flow rate of 50 mL/min using a Sr-82/Rb-82 generator . After the first elution, we induced pharmacological stress by administrating 400 µg (5 mL) of regadenoson over 10 seconds. After a 5 mL saline flush (NaCl 0.9%), we administered a second dose of 740 MBq Rb-82. We acquired seven-minute PET list-mode acquisitions after both Rb-82 administrations. Attenuation correction was applied to all data on the PET system after semiautomatic registration of CT and PET data. We reconstructed the dynamic datasets using 26 time frames  with default settings as recommended by the manufacturer using 3D iterative reconstruction using 2 iterations and 24 subsets, while correcting for decay, attenuation, scatter and random coincidences, and dead time effects. Neither time-of-flight information, nor a post-processing filter or resolution modeling was used. Static images were reconstructed from 2:30 to 7:00 minutes for both rest and stress scans.The reconstructed dynamic images were processed using Corridor4DM software (v2015.02.64). Myocardium contours were automatically detected in both rest and stress scans based on the static images. Furthermore, a region of interest (ROI) was manually placed at the location of the mitral valve to estimate the activity in the blood pool. The activity concentrations in the myocardium contour and ROI were measured in the 26 reconstructed time frames to calculate the time activity curves (TACs) for the left ventricle (LV), for the three vascular territories: left anterior descending (LAD), left circumflex (LCX) and right coronary (RCA) artery, and for the whole myocardium. The one-tissue compartment model of Lortie et al. based on a ROI methodology was used to calculate the MBF from the TACs using Corridor4DM.25The activity in the myocardium was visually compared with the drawn contours in all individual time frames to detect possible patient motion or myocardial creep. Myocardial creep was defined as gradual decreasing misalignment of the drawn myocardium contour with the activity present in the ventricle and/or myocardium, primarily in the inferior direction. This misalignment was at least one third of the width of the left ventricular myocardial wall and present in at least two time frames of which one had to include the first-pass phase: the filling of the LV. If myocardial creep was present, manual realignment of the contour to the activity in the myocardium was applied in each of the related time frames. Motion not fulfilling the requirements of myocardial creep, suggesting general patient motion, was manually corrected by realigning the myocardium contour to the activity. Patients were excluded when patient motion was present together with myocardial creep to prevent biased results due to overlapping motion. Furthermore, patients with an unreliable TAC were also excluded. Unreliable TACs were defined as TACs showing no clear LV peak.26To evaluate the influence of myocardial creep correction, both rest and stress MBFs were calculated for the original data and for the corrected data regarding the three vascular territories  and for the whole myocardium. Furthermore, the myocardial flow reserve (MFR), defined as the stress MBF divided by the rest MBF was calculated as well. A difference in MBF or MFR >10% between the corrected and uncorrected scans was considered to possibly influence diagnostic interpretation.Patient-specific parameters and characteristics were determined as percentage or mean ± standard deviation (SD) and compared with Chi-square and t-tests as appropriate, using SPSS Statistics version 22.0 (IBM Corporation). The MBF and MFR of the uncorrected and corrected data were compared using the Wilcoxon signed rank test. The level of statistical significance was set to 0.05 for all statistical analyses.Of the 119 patients, 11 (9%) were excluded due to the presence of both patient motion and myocardial creep in the stress data. An additional four patients (3%) were excluded due to unreliable TACs. An example of an unreliable TAC is shown in Figure P ≥ 0.10). Yet patients with myocardial creep were younger (64 years old) than patients without myocardial creep . Of the 54 patients with myocardial creep during stress, two patients also showed myocardial creep during the rest scan.The baseline characteristics of the remaining 104 patients are summarized in Table P < 0.001) and the mean MFR from 3.5 to 2.4 (P < 0.001). Moreover, the MBF of the RCA decreased in 91% (49/54) of the patients, and the MFR of the RCA decreased in 89% (48/54) of the patients, as shown in Figure P = 0.03) and for the MFR from 2.2 to 2.3 (P = 0.006), and for the whole myocardium, the mean MBF and MFR values decreased from 2.7 to 2.6 mL/min/g (P = 0.01) and from 2.4 to 2.3 (P = 0.03), respectively. No significant differences were found for the LCX territory in stress (P = 0.3) nor in the rest scans (P ≥ 0.11). In the 54 patients with myocardial creep, 45 (83%) had a change > 10% in MBF and 45 (83%) had a change > 10% in MFR in one of the territories or the whole myocardium.The uncorrected and corrected MBF and MFR measurements, in both rest and stress, for each of the three territorial segments and for the myocardium as a whole  are shown in Table In this study, we have demonstrated that a myocardial creep occurs in more than half of the patients during regadenoson-induced stress MPI using Rb-82 PET. Moreover, correction of this myocardial creep resulted in significantly lower MBF and MFR values for the RCA territory and may improve diagnostic accuracy. Besides the large impact on MBF and MFR values in the RCA territory, myocardial creep also resulted in significant differences in stress MBF and MFR values for the LAD and the whole myocardium. These differences can be explained by the anatomic position and direction of myocardial creep, as illustrated in Figure Multiple studies have reported the occurrence of myocardial creep, also known as non-returning motion of the heart, primarily occurring in the post-stress period during MPI using different pharmacological vasodilators.Multiple mechanisms are hypothesized in the literature to explain the occurrence of myocardial creep. Karacalioglu et al. hypothesised that myocardial creep is caused by gravity on the organs when patients switch from a standing to a lying position in the scanner. They reported that a five-minute bed rest on the scanner table significantly decreased the vertical motion of the heart.30Another mechanism previously described by Friedman et al. which is more likely to cause myocardial creep is that after administration of a pharmacological vasodilator, in our case regadenoson, lung volume increases which causes a repositioning of the diaphragm and heart.Several limitations of this study should be recognized. First, we were unable to determine the effect of myocardial creep correction on the diagnostic accuracy due to the lack of a reference standard. However, in some patients myocardial creep resulted in unrealistic high MBF values (>5 mL/min/g) which decreased after correction to realistic values. Hence, we assume that correcting for myocardial creep increases diagnostic reliability.Second, manual actions are required in the quantification process and for the myocardial creep correction which could have introduced additional operator variability. Although this operator variability might have introduced additional variance, the changes in stress MBF quantification were higher than the previously reported ± 10% test-re-test reproducibility errors when calculating the MBF using Rb-82 PET in MPI.Third, a high fraction of the patients had a normal MBF, possibly limiting generalization. However, in case of the poorly perfused tissue with myocardial creep, the influence of spillover from the LV is expected to be larger than that for the normal perfused tissue resulting in a relatively larger overestimation of the modeling parameter k1 and, hence, MBF.Finally, we only corrected the myocardial creep in the attenuation-corrected PET images. However, only the PET data acquired between 2:30 and 7:00 minutes were co-registered to the CT to create an attenuation map. As myocardial creep only occurs in the earlier time frames, misregistration and, hence, attenuation-correction artifacts may occur. This misregistration could result in altered MBF measurements.28If myocardial creep is present but remains uncorrected in clinical practice, the stress MBF and MFR of the RCA territory will be overestimated, as shown in Figure There are two practical ways to recognize myocardial creep in clinical practice. The first sign is an elevated time activity concentration of the RCA during the first-pass phase in the TAC in comparison with the LCX and LAD. As no activity is yet present in the myocardium, the whole activity measured in this phase is due to spillover and should therefore be constant across the three vascular territories, as shown in Figure Myocardial creep was seen in 52% of the patients who underwent regadenoson-induced stress Rb-82 PET. Correcting for myocardial creep significantly changed MBF measurements during stress and MFR quantification, especially in the RCA territory. As this may hamper diagnostic accuracy, detection and correction of myocardial creep seem necessary for reliable quantification when using regadenoson.Supplementary material 1 (PPTX 3170 kb)Below is the link to the electronic supplementary material.