Implications for New Integrated Treatments

There are several fields in which the impact of these new concepts is presumed to be of importance.

In the assessment of systolic ventricular function, the angle between the descendant fibers and the ascendant ones seems to be crucial for efficient systolic function [12, 13]. In a similar way that a wider helical angle of a screw is more efficient for . . . the wider the angle between the descendant fibers and the ascendant ones, the more efficient are the torsion dynamics and ejection. In dilated cardiomyopathy, the more horizontal angle of the fibers due to ventricular remodelling favors the subsequent impairment of cardiac function; therefore, in the surgical treatment of heart failure, not only the size of the ventricle but also the fiber angle should be taken into account. The near-future possibility of imaging myocardial fiber dynamics online, through resonance tensor diffusion imaging or other imaging means, opens the way to research and the development of more adequate surgical strategies to compensate for cardiac dysfunction.

Over the past 20 years, the noninvasive evaluation of diastolic function has mainly relied on echo-Doppler analysis of how blood volume enters the ventricle, which largely depends on its loading conditions. One approach is to evaluate the degree of ventricular untwist that occurs during diastole [14], either by speckle tracking echocardiography [10] or by velocity vector imaging, a new ultrasound technique that is angle-independent and thus provides an avenue to evaluate the short-axis mechanics of the left ventricle [15]. Sampling of the descendant myo-cardial band segment responsible for systole and of the ascendant band responsible for diastole has recently been performed by Vannan and colleagues [16]. The results revealed that normal and hypertensive patients disclosed a similar peak twist velocity (1.9 +/- 0.2 versus 2.3 +/- 0.2 cm/s), whereas untwist was significantly less in hypertensive patients (1.7 +/- 0.1 versus 1.1 +/- 0.1 cm/s), suggesting that early diastolic dysfunction can be ascribed to the generation of less force by the ascendant segment. This finding may have important implications in terms of the early diagnosis of diastolic dysfunction and therapy. In this respect, the anatomy of the band may explain why diastolic dysfunction occurs before systolic alteration of function.

Furthermore, in surgery for heart failure, it seems appropriate, once the helical conformation of the ventricle is known, to plan surgery in such a way as to spare the helical ventricular anatomy. In an initial study by Torrent-Guasp and colleagues [1] and Ballester et al. [3], four theoretical possibilities of surgically reducing left ventricular volume without impairing the helical structure of the ventricles were considered. The most logical approach seems to be to spare the apical loop (small volume and the true motor of the ventricle) and reduce the basal loop; however, new initiatives are needed to convert these theoretical possibilities into practical surgical approaches.

In resynchronization therapy, an explanation of why some patients respond to device implantation whereas others fail to improve is not forthcoming. The issue is not that the left ventricle should contract simultaneously with (most of the indexes developed are aimed at the detection of this phenomenon); rather, what is crucial is the sequence of contraction of the descendant and ascendant segments. In fact, knowledge of the natural sequence of electromechanical ventricular activation [4, 17] should open the way to study the effects of selective stimulation of the band segments on ventricular function, and should provide a rationale for ventricular pacing protocols. In this respect, two recent studies using microcrystals selectively placed in the descendant and ascendant segments of the band have shown the hemodynamic disruption caused by right or left ventricular pacing [18]. This disruption is not solved by atrio-biventricular pacing, which compares less favorably (QRS complex, systolic and diastolic function, and cardiac index) with a more physiologic high septal pacing. With the latter mode of stimulation, the dynamics between descendant and ascendant segments are close to normal [19]. In the same way, the cardiac cycle should be explained in the light of the new anatomy and function and should include the twist and untwist motion and its relationship with the mechanical and acoustic events. Especially important is a description of muscular movements during isovolumic contraction and relaxation. The paradigmatic change in ventricular anatomy and function will prompt research in every field of cardiology.

Several studies show that cardiac resynchronization therapy induces a reduction in cardiac sympathetic nerve activity in responders that parallels an improvement in left ventricular ejection fraction, whereas nonresponders do not show any significant changes [20, 21]. Typically, imaging with (123)I-metaiodobenzylguanidine (MIBG) is used for the assessment of cardiac sympathetic activity. When cardiac sympathetic activity is analyzed before and after cardiac resynchronization therapy, and these findings are examined in relation to treatment response, improvement in cardiac sympathetic activity correlates with a positive response to resynchroniza-tion. Lower MIBG uptake before therapy is usually associated with nonresponse to resynchronization. Therefore, the assessment of cardiac sympathetic activity could be helpful in selecting patients for cardiac resynchronization. However, about a third of patients who receive cardiac resynchronization therapy do not improve. It seems that coupling cardiac MIBG studies with functional assessment, taking into account the newly discovered complex mechanics of ventricular activation, could improve the selection of candidates and the assessment of cardiac resynchronization.

Stem-cell, tissue-engineering, and regenerative sciences are currently undergoing vigorous laboratory studies and early clinical trials [22]. In the field of car-diothoracic surgery, such studies may lead to new therapeutic approaches, such as stem-cell implantation to repair damaged myocardium and improve cardiac function, a procedure known as cellular cardiomyoplasty; tissue-engineered cardiac valves and conduits constructed using autologous cells populated on biodegradable scaffolds, which will require neither anticoagulation therapy nor repeated replacements to adapt to the growing infant or child recipient; and regeneration of tissues and organs such as the limbs and heart. Therefore, cell transplantation may preserve or even restore contractile function to infarcted hearts. A typical human infarct involves the loss of approximately 1 billion cardiomyocytes, and, therefore, many investigators have sought to identify endogenous or exogenous stem cells with the capacity to differentiate into committed cardiomyocytes and repopulate the lost myocardium. As a result of these efforts, dozens of stem cell types have been reported to have cardiac potential. These include pluripotent embryonic stem cells, as well various adult stem cells resident in compartments including bone marrow, peripheral tissues, and the heart itself. Some of these cardiogenic progenitors have been reported to contribute replacement muscle through endogenous reparative processes or via cell transplantation in preclinical cardiac injury models. However, considerable disagreement exists regarding the efficiency and even the reality of cardiac differentiation by many of these stem cell types, making these issues a continuing source of controversy in the field.

As for stem cell injections, these are random and may distort the described architecture of the heart. Furthermore, assuming that cells are injected into the area of infarction and scar, they will be exposed to a hostile collagenous environment devoid of vascularization. In fact, up to 75% of the injected cells, no matter what their origin, die within 48 h of injection. It should therefore be a prominent goal of cardiac scientists to enhance viability and engraftment, an issue that has attracted increased attention lately. For instance, growth factors have been added to stem cell injections to improve the surrounding vascularization and donor cell viability. However, it seems that the eventual site of administration of these cells could be better decided on the basis of the knowledge of the new helical model of myocardial fiber distribution.

As more clinical trials utilizing stem cells emerge, it is imperative to establish the mechanisms by which stem cells confer benefit in cardiac diseases. Molecular imaging provides accurate noninvasive information about myocardial perfusion and contractile function and viability, which enables the assessment of the clinical benefits of stem cell therapy. In addition, molecular imaging has provided more specific tracers targeting cellular and subcellular biologic events, which are expected to shed more light upon the mechanisms of cell therapy. Sodium iodide symporter gene transfer has been employed for the sequential detection and quantification of reporter gene expression in the transplanted heart [23]. In future, gene therapy may develop in combination with stem/progenitor cell transplantation therapy [24].

Heart transplantation remains as the treatment of choice for patients with endstage heart failure without other medical or surgical options. During heart transplantation, the allograft becomes completely denervated. Lack of autonomic nerve supply is associated with major physiologic limitations. The inability to perceive pain does not allow symptomatic recognition of accelerated allograft vasculopathy, and heart transplant patients often develop acute ischemic events or left ventricular dysfuction or die suddenly. In addition, denervation of the sinus node does not allow either adequate acceleration of heart rate during stress or efficient increase in cardiac output. Reinnervation in transplanted hearts is functionally important, as patients with reinnervation have longer exercise times and an enhanced contractile response to exercise compared with patients with denervated transplanted hearts. Sympathetic reinnervation, measured by the regional distribution and intensity of myocardial MIBG uptake, increases with time after transplantation [25, 26]. Early vasculopathy may inhibit the process of sympathetic reinnervation of the transplanted heart. Fluorodeoxyglucose (FDG) positron emission tomography (PET) studies in heart transplant patients show marked enhancement of FDG uptake in the heart at 1 month of transplantation, which decreases over time, suggesting persistent ischemia/reperfusion damage after surgery. Ammonia PET studies after adenosine infusion provide a very sensitive means for the detection and evaluation of gtaft vasculopathy. Early detection of graft vasculopathy is important because it may respond to more aggressive immunosuppression [27]. In addition, cardiac-efferent adrenergic signals play an important role in modulating myocardial blood flow during activation of the sympathetic nervous system. The relationship between reinnervation status and graft vasculopathy deserves further investigation and may help to characterize subsets of transplant patients with different clinical outcomes. The restoration of sympathetic innervation is associated with improved response of the heart rate and contractile function to exercise, indicating the functional importance of reinnervation in transplanted hearts.

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