**8.2 Improving our understanding of the biomechanics of cardiac electromechanical coupling and the contribution of spatial orientation of the ventricular muscle band to cardiac pumping functions**

Perceiving heart pumping functions as a simple contraction of the bulletshaped left ventricle is thought nowadays as a misunderstanding which contributes significantly to delaying the successful progress of electrical device treatment for heart failure. The process of contraction and myocardial stretch need more investigation at the cellular, as well as, at gross myocardial fibers orientation level. At the cellular level, electrical activation will trigger mechanical contraction via an intracellular calcium-dependent process known as excitation-contraction coupling. Disturbance of the process of cardiac myocyte intracellular calcium handling is a common feature of heart failure. At the organ scale, pump dysfunction is the end result of mechanical alterations secondary to electrical dyssynchrony in heart failure subjects. A reverse coupling between cardiac mechanics and electrophysiology is also well established. It is commonly referred to as *cardiac mechanoelectric feedback* and is thought to be an important contributor to the increased risk of arrhythmia during pathological conditions that alter regional cardiac wall mechanics, including heart failure. The roles of stretch-activated ion channels and mechanisms that are independent of ionic currents need more investigation. We in the CRT community, are in high demand for new multicellular tissue-scale model systems and experiments to obtain a better understanding of how interactions between electrophysiological and mechanical processes at the cell scale affect ventricular electromechanical interactions at the organ scale in the normal and diseased heart [86]. At a gross level, many observations demand serious investigations considering proper understanding of the mechanics of heart pumping and the true contribution of the spatial orientation of the ventricular muscle band to cardiac pumping functions. Without this knowledge, our understanding and interpretation of ventricular activation and dyssynchrony will be deficient. The existence of right and left ventricles as a continuous muscle band has been proposed [87–90]. The muscle band is organized in special spatial orientation as a helix formed by basal and apical loops. Both ventricular contraction and relaxation controlling the ejection and the filling of ventricles are thought to be affected by this unique arrangement [91, 92]. A deeper investigation of this spatial fibers orientation and the contribution of its activation sequence to cardiac pumping functions in health and disease will improve our therapeutic measures for proper resynchronization of dyssynchronized ventricles. Sengupta PP et al, elaborated in this direction and describe LV as a complex structure in which myofibers are arranged in the form of a left-handed helix in the subepicardium and of a right-handed helix in the subendocardium, while the mid-wall is consisting of circumferential fibers. This type of fibers arrangement allows for myocardial deformation in multiple planes and explains the complexity of the ventricular dyssynchrony process (**Figure 3**) [94]. During LV systole, there is apical counterclockwise rotation and basal clockwise rotation around the LV long axis. During LV diastole, there is Untwisting of the subendocardial layers that occurs during diastole and contribute to diastolic suctioning. Simultaneously, the LV shortens in systole and lengthens in diastole. At this level of understanding, we are confident that the extent of LV mechanical dysfunction is never a matter of one direction of motion or deformation. Future research for resynchronization therapy must consider this basic understanding.

#### **Figure 3.**

*Twist mechanics of the left ventricle. A period of left ventricular isovolumic contraction (IVC) follows electrical and mechanical activation in the apical subendocardial region, during which (A), the subendocardial myofibers (right-handed helix) shorten with stretching of the subepicardial myofibres (left-handed helix) resulting in clockwise rotation of the apex and counterclockwise rotation of the base. Simultaneous shortening of the subendocardial and subepicardial layers is occurring during ejection (B). The larger arm of the moment of the subepicardial fibers dominates the direction of twist, causing counterclockwise and clockwise rotation of the apex and base, respectively. During isovolumic relaxation (IVR) (C). Subepicardial fibers lengthen from base to apex and subendocardial fibers lengthen from apex to base. In diastole, there is relaxation in both layers, with minimum untwisting (D). Illustration is from Sengupta PP [93].*

#### **8.3 Endocardial left ventricular pacing**

Challenges of transvenous LV lead implantation including limitations of coronary sinus (CS) anatomy, high LV pacing threshold, and/or phrenic nerve capture, have led to serious efforts to look for better alternatives [94]. As compared to standard epicardial LV pacing, pacing the LV endocardium reflects a more rapid and physiological activation of the left ventricle. Shetty AK et al have identified greater acute hemodynamic improvements with endocardial versus conventional LV pacing [95]. Subjects who demonstrated CRT non-response or known to have LV lead technical difficulties were evaluated in the alternate site cardiac resynchronization study. Endocardial LV lead placement was found to be safe and reported clinical and echocardiographic improvement in two-third of subjects [96]. An important drawback of this new trend of an implant is the need for anticoagulation and the reported few cases of thromboembolic events despite anticoagulation. The endocardial wireless stimulation for CRT (EBR Systems, Sunnyvale, CA, USA) incorporates a pacing system using a small ultrasound-responsive leadless electrode placed onto the LV endocardial surface [97]. The safety and performance of electrodes implanted in the left ventricle study is coming up with encouraging results. A total of 35 patients who had failed conventional CRT implant, underwent successful implant in 97% of the sample [93]. At 6 months, approximately two-thirds of patients demonstrated LV reverse remodeling with improved LVEF ≥5%. LV endocardial pacing seems to be a revolution creator in CRT practice in the present and future.
