Vertebrates changed the structure and function of their hearts in order to adapt to the living environment over the course of evolution. Since adaptation from aquatic to terrestrial life requires more oxygen and energy, vertebrates developed a pulmonary circulation and septated the heart into venous and arterial compartments, allowing the supply of oxygenated blood to peripheral tissues [1]. The formation of the interventricular septum (IVS) initiates at around the fifth week of embryonic development; it involves the sequential fusion of three independent septa: muscular, outlet, and inlet [2]. Cardiac ventricular septation, besides its great intrinsic interest to evolutionary biologists, is also crucial to the physiologist and the clinician. IVS function is important in the healthy heart. IVS contributes to normal left and right ventricular (LV and RV respectively) function, not only via its position and movement, but also through the regulation of RV and LV interaction (ventricular interdependence) [3]. On the other hand, the IVS may become abnormal either from disease of the IVS itself (congenital anomalies, coronary artery disease, cardiomyopathy, hypertension, conduction abnormalities, tumors, etc.) or as a result of abnormalities that involve other structures of the heart that induce abnormal hemodynamics in the IVS (atrial septal defect, valvular heart disease, open heart surgery, etc.) [4].

2. IVS Structure

Traditionally, gross cardiac anatomy has been described mainly based on the findings in the dissection suite. However, imaging with echocardiography, cardiac computed tomography (CCT), and cardiac magnetic resonance (CMR), have fundamentally advanced the understanding of cardiac anatomy in the 21st century [5]. Additionally, CMR is unique for its tissue characterization capabilities, and for the identification of myocardial scar, fibrosis, edema, and inflammation. Diffusion tensor cardiovascular magnetic resonance (DT-CMR) is a noninvasive technique that has been increasingly used to unravel human cardiovascular microstructure in vivo. Finally, it is noteworthy that the IVS thickness prenatally assessed using ultrasound imaging may be a useful diagnostic marker of fetal macrosomia, a common condition affecting approximately 10% of fetuses, and potentially leading to serious complications in both mother and child [6]. The IVS is composed of a muscular and a membranous component. The muscular IVS component arises from the endocardial surface of the common ventricle, and has a normal thickness of approximately 9 mm in women and 10 mm in men [7]. The comparatively diminutive membranous component, the fibrous component of the IVS, is found between the outflow tracts of the LV and RV [8]. Animal studies that examined the transmural features of the IVS reported that the myofiber angle shifted from a longitudinal orientation on the LV-side to a circumferential orientation in the midwall, and then back to a longitudinal orientation on the RV-side of the septum. The main transmural change in the septum was related to the orientation of the myofibers (anisotropy), but not to the mechanical properties or tissue composition [9]. Blood supply to the IVS is predominantly derived from penetrating arteries entering from the left anterior descending artery, whereas branches from the posterior descending artery supply only the posterior third of the IVS [10]. The IVS is a site of collateral circulatory channels in the human heart. The middle cardiac vein, which empties into the coronary sinus, is responsible for draining the IVS [11]. Cardiac function is controlled by the autonomic nervous system, which consists of the parasympathetic and sympathetic divisions. In addition to the complex integration that occurs in the central nervous system, there is local intracardiac neural regulation brought about by a network of ganglionated plexuses consisting of a large number of intracardiac ganglia, and gathered in specific heart regions including the atria, the sinoatrial and atrioventricular nodes, the IVS, and both ventricles [12]. The IVS accommodates important parts of the cardiac conduction system. The atrioventricular node is located at the apex of the Koch triangle, whereas the bundle of His divides at the juncture of the fibrous and muscular boundaries of the IVS into the left and right bundle branches (LBB and RBB, respectively). The LBB subsequently divides into anterior and posterior fascicles, which course towards the anterior and posterior papillary muscles of the LV, whereas the RBB courses down the right side of IVS near the endocardium in its upper third, deeper in the muscular portion of the IVS in the middle third, and then again near the endocardium in its lower third [13]. Both ventricles contribute to IVS formation [14]. Cardiomyocyte helical architecture is present as early as the midgestational period [15], whereas cardiomyocyte transformation affecting the IVS initiates in the early postnatal period, whereby the RV origin of the IVS is reduced from 50% in the perinatal period to 25% later in life [15]. A highly echogenic zone seen in the IVS during cardiac ultrasound coursing from base to apex corresponds to the position of the circumferentially orientated cardiomyocytes.

3. IVS Function

During systole the IVS thickens and moves towards the LV after the onset of electrical depolarization followed by a brief ‘shudder’ at end systole, whereas during diastole it returns to its original thickness and position [16]. The IVS sides are significantly softer than their corresponding ventricular free walls, and the collagen content is less than that of the ventricular walls [9]. Moreover, at low strains, there is similar anisotropic behavior between the two sides, whereas at high strains, both sides are isotropic. Normal septal position and twisting are essential for ventricular function, whereas the functional interaction between the RV and LV via IVS has been termed ‘‘ventricular interdependence” ^[3][17][3,17].

3.1. Ventricular Interdependence

Ventricular interdependence describes the influence that each ventricle has to the other as a result of the shared IVS [18], the encircling of the two ventricles by common myocardial fibers, and the pericardial constrain [19]. An intact pericardium enhances ventricular diastolic interdependence but has negligible effect on ventricular systolic interdependence, which is affected by IVS and free wall properties [20]. The RV contributes significantly to the normal cardiac output response to exercise, as demonstrated by the 30–40% decrease in maximum oxygen uptake in young patients with Fontan physiology compared with healthy controls [21]. Ventricular interdependence has also been implicated in the development of RV remodeling in untreated asymptomatic mild hypertensive patients, and has been attributed to changes in IVS structure [22].

3.2. Abnormal IVS Motion

Abnormal, paradoxical septal motion (PSM), is a type of motion abnormality where the IVS movement is atypical for the particular phase of the cardiac cycle. The most common cause of PSM is left bundle branch block (LBBB) due to periods of asynchrony in contraction, ejection, end-systole, and end-diastole between RV and LV, in addition to decreased regional ejection fraction (EF) of the IVS. The LBBB usually results in two types of PSM, namely septal flash and apical rocking, which are interrelated ^[23][24][23,24]. Septal flash refers to a leftward motion of the IVS associated with a marked pre-ejection shortening; this is mainly due to active IVS contraction, which is followed by immediate re-lengthening (rebound stretch) resulting from contractions in late-activated remote myocardium and subsequent paradoxical rightward IVS motion [25]. Apical rocking, in turn, is characterized by a short septal motion of the apex caused by the contraction of the IVS early in systole, and a subsequent long motion to the lateral side during ejection resulting from the late lateral contraction caused by the LBBB [23]. IVS ischemia/infarction is another common cause of abnormal septal motion. Experi-mental studies have demonstrated that following septal artery ligation, IVS shortening is immediately replaced by systolic lengthening [26]; eventually, IVS hypokinesia or akinesia develop. The cardiogenic shock, which is frequently due to acute myocardial infarction (AMI), depends on AMI extent and its complications, the most important being mitral regurgitation, IVS rupture, and rupture of the LV free wall [27]. Diastolic and systolic ventricular interactions are negatively affected in pulmonary arterial hypertension (PAH) and result in PSM. In the early stages of PAH, a rapid leftward IVS motion occurs during early LV diastole which is most likely due to prolonged RV myocardial activation [28]. Severe PAH results in RV failure with RV eccentric remodeling and contractile dysfunction, and has an important impact on the geometry, structure, and function of the LV. RV volume and pressure increases cause mechanical IVS flattening and shifting towards the LV, leading to LV compression visualized by paradoxical IVS motion, a “D-shaped” LV, and an increased LV eccentricity index [29]. RV systolic and biventricular diastolic dysfunction result in a reduction of cardiac output and coronary blood flow, both of which may exacerbate congestion [30]. A common cause of PSM is constrictive pericarditis, which is characterized by dissociation of intrathoracic from intracardiac diastolic pressures; it exaggerates diastolic ventricular interdependence due to the fixed volume in the pericardial sack resulting from the thickened, fibrotic, and/or calcified non-compliant pericardium [31]. With inspiration, the RV cannot expand to accommodate increased venous return and encroaches into the LV space, via a shift of the IVS; this results in decreased LV filling and output. The preferential filling of the right heart chambers during inspiration subsequently gives way to preferential left heart filling with expiration, when increased intrathoracic pressure decreases systemic venous return to the right heart, restores the filling gradient between the pulmonary veins and left heart chambers, and shifts the IVS towards the RV [32]. PSM may also occur after uncomplicated cardiac surgery resulting from an increase in RV transverse shortening (free wall to septal fibers), in order to compensate for the reduced RV longitudinal shortening [33], atrial septal defect (ASD) to accommodate the increased RV volume [34], and mitral stenosis reflecting an abnormal transseptal gradient [35].

4. Treatment Modalities Targeting Diseases of the IVS

4.1. Cardiac Resynchronization Therapy (CRT)

CRT is an established treatment in selected patients with heart failure ^[36][75]. CRT in most cases is achieved by adding a LV pacing lead (lateral or posterolateral wall of the LV) to a standard pacemaker or defibrillator system that generally includes only an RV lead (RV apex) and—in cases of sinus rhythm—a right atrial lead ^[37][76]. The mechanisms of action of CRT in this setting include correction of IVS abnormal systolic motion and restoration of LV electrical and mechanical synchrony ^[38][77]. Circumferential contraction of IVS myocardial fibers is improved with CRT, and it is strongly correlated with an increase in aortic velocity time integral (VTI) and shortening of QRS duration ^[39][78]. Therefore, not surprisingly, CRT improves cardiac function and symptoms, as well as reduces morbidity and mortality in a specific group of heart failure patients with abnormal LVEF and QRS duration. Nevertheless, approximately 20–40% of the abovementioned patients may not respond to CRT (non-responders) ^[40][79].

4.2. Mavacamten

Mavacamten is a small molecule that belongs to the myosin modulators, a novel class of pharmaceutical agents that are being developed to treat patients with a range of cardio-myopathies. Myosin modulators are often classified as either “myosin activators” (omecamtiv, danicamtiv) or “myosin inhibitors” (mavacamten, aficamten) ^[41][80]. The therapeutic goal of these drugs is to target cardiac myosins directly to modulate contractility and cardiac power output, in order to alleviate symptoms that lead to heart failure and arrhythmias without changes in calcium signaling ^[42][81]. In the recently completed EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy), about one-third of patients on mavacamten, a myosin inhibitor that reduces myocardial contractility, achieved the primary end-point of subjective symptomatic improvement and increased functional capacity assessed by peak VO2 ^[43][82]. This beneficial effect has been attributed to mavacamten-induced decrease in LVOT gradients and resolution of mitral valve systolic anterior motion in most HCM patients ^[44][83].

4.3. Septal Reduction Therapy (SRT)

SRT reduces LVOT obstruction in patients with HCM and includes surgical IVS myectomy and transcoronary alcohol IVS ablation. The role of surgical IVS myectomy in HCM is well established. Transcoronary alcohol IVS ablation provides a less invasive approach to septal reduction in HCM. Both surgical IVS myectomy and transcoronary alcohol IVS ablation may improve HCM patients’ functional status, with low periprocedural mortality and excellent long-term survival ^[45][84]. As the results of these two treatment options seem to be comparable in experienced centers, selection depends on the anatomical findings, concomitant cardiac and non-cardiac morbidities, technical issues, the operator’s expertise and availability, and patient’s choice ^[46][85].