The Interventricular Septum: Structure, Function, Dysfunction, and Diseases

Vertebrates developed pulmonary circulation and septated the heart into venous and arterial compartments, as the adaptation from aquatic to terrestrial life requires more oxygen and energy. The interventricular septum (IVS) accommodates the ventricular portion of the conduction system and contributes to the mechanical function of both ventricles. Conditions or diseases that affect IVS structure and function (e.g., hypertrophy, defects, other) may lead to ventricular pump failure and/or ventricular arrhythmias with grave consequences. IVS structure and function can be evaluated today using current imaging techniques. Effective therapies can be provided in most cases, although definitions of underlying etiologies may not always be easy, particularly in the elderly due to overlap between genetic and acquired causes of IVS hypertrophy, the most common being IVS abnormality. In this review, state-of-the-art information regarding IVS morphology, physiology, physiopathology, and disease is presented.


Introduction
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].
In this review, an update on adult IVS morphology, physiology, physiopathology, and disease is provided.
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].

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].

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]. 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. Experimental 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].

Hypertrophic Cardiomyopathy
HCM is characterized by increased LV wall thickness in the absence of abnormal loading conditions, such as arterial hypertension or aortic valve stenosis, that can stimulate this magnitude of IVS hypertrophy. HCM is a common inherited cardiovascular disease with a prevalence of one in 200-500 adults in the general population [36].
HCM has been increasingly recognized as having a complex genetic etiology [37]. Most HCM patients remain asymptomatic or mildly symptomatic throughout life, whereas others have dyspnea, exercise intolerance, chest pain, palpitations, presyncope, syncope, and sudden cardiac death (SCD). SCD may be the initial presentation [38].
HCM diagnosis is confirmed usually with echocardiography or CMR ( Figure 1) [39]. Any segment of the LV can be involved, although HCM is classically asymmetric and mainly involves the IVS. RV dysfunction is often observed in HCM. The main histological features of HCM are cardiomyocyte disarray and fibrosis [40]. Mutations in cardiac β-myosin account for 35% of genetically based HCM. The majority of variants causing HCM increase the proportion of active myosin which consequently leads to amplified force production in systole (hypercontractility) and diastole (diastolic dysfunction) [41]. It has been proposed that the molecular basis of this hypercontractility in HCM can be described by three perspectives: (a) changes in the fundamental parameters of the actin-activated β-cardiac myosin chemo-mechanical ATPase cycle; (b) an increase in the number of functionally accessible heads in the sarcomere for interaction with actin; and (c) HCM mutations and small-molecule effectors leading to changes in load dependence and power output of cardiac contraction [42]. It is noteworthy that a recently discovered energy conserving state of myosin, the super relaxed state, is pivotal to modulating force production and energy use within the sarcomere [43]; this can be disrupted by HCM cardiac myosin mutations [44]. One of the most well recognized functional abnormalities in HCM is the dynamic LV outflow tract (LVOT) obstruction occurring in 60-70% of patients at rest, or with physiologic provocation [45]. "Athlete's Heart" may overlap with some features of HCM, and the distinction between physiological versus pathological changes in athletes is imperative [46].

Basal Septal Hypertrophy (Upper Septal Hypertrophy or 'Sigmoid Septum')
Basal septal hypertrophy (BSH) may be present in approximately 20-25% of patients with hypertension [47] or aortic stenosis [48], and is associated with a decrease in the regional myocardial deformation of the basal-IVS ( Figure 2) [49]. In some patients, BSH may increase the risk of dynamic LVOT obstruction even in the absence of underlying hypertrophic obstructive cardiomyopathy [50]. Based on the above, BSH has been proposed as an early imaging biomarker of risk for the progression of hypertensive disease to heart failure [51]. However, the precise definition of the underlying BSH etiology is not always easy, especially in the elderly, where there is overlap between genetic and acquired causes of IVS hypertrophy [52].

Basal Septal Hypertrophy (Upper Septal Hypertrophy or 'Sigmoid Septum')
Basal septal hypertrophy (BSH) may be present in approximately 20-25% of patients with hypertension [47] or aortic stenosis [48], and is associated with a decrease in the regional myocardial deformation of the basal-IVS ( Figure 2) [49]. In some patients, BSH may increase the risk of dynamic LVOT obstruction even in the absence of underlying hypertrophic obstructive cardiomyopathy [50]. Based on the above, BSH has been proposed as an early imaging biomarker of risk for the progression of hypertensive disease to heart failure [51]. However, the precise definition of the underlying BSH etiology is not always easy, especially in the elderly, where there is overlap between genetic and acquired causes of IVS hypertrophy [52].

Ventricular Septal Defects
Ventricular septal defect (VSD) accounts for 10% of congenital heart defects in adults [53]. VSD in the adult can also occur as an acquired condition, such as a complication after acute myocardial infarction (MI) (see below), surgical or transcatheter aortic valve replacement [54], septal myectomy for HCM [55], erosion of a strut of a bioprosthetic mitral valve [56], or from stress (Takotsubo) cardiomyopathy [57]. VSDs vary in size, ranging from small defects without hemodynamical significance, to large communications leading to complications in early childhood [58]. A decrease in shunt size or even spontaneous closure of VSDs is common during early childhood. Depending on size and physiology, clinical presentation and findings vary considerably. Small defects typically cause a loud pansystolic murmur often associated with a palpable thrill, whereas in large defects with ventricular pressure equalization, no murmur is audible. Patients with elevated pulmonary vascular resistance and shunt reversal show signs of central cyanosis with clubbing of hands and feet.

Septal Infarction
Isolated septal MI is uncommon and may be due to occlusion of the septal perforator branches that supply the anterior portion of the IVS and the bundle of His. Septal involvement in MI is usually due to occlusions of the LAD or dominant right coronary or dominant left-circumflex arteries, since all of these give rise to septal branches and may lead to IVS rupture [59]. Occasionally, IVS rupture may occur, establishing a communication between the two ventricles. In the era of early reperfusion therapy, however, post-MI VSD is a rare (<1% of MI patients) but potentially catastrophic complication [60]. Post-MI IVS rupture and VSD occur 3 to 8 days after a transmural acute MI.

Ventricular Septal Defects
Ventricular septal defect (VSD) accounts for 10% of congenital heart defects in adults [53]. VSD in the adult can also occur as an acquired condition, such as a complication after acute myocardial infarction (MI) (see below), surgical or transcatheter aortic valve replacement [54], septal myectomy for HCM [55], erosion of a strut of a bioprosthetic mitral valve [56], or from stress (Takotsubo) cardiomyopathy [57]. VSDs vary in size, ranging from small defects without hemodynamical significance, to large communications leading to complications in early childhood [58]. A decrease in shunt size or even spontaneous closure of VSDs is common during early childhood. Depending on size and physiology, clinical presentation and findings vary considerably. Small defects typically cause a loud pansystolic murmur often associated with a palpable thrill, whereas in large defects with ventricular pressure equalization, no murmur is audible. Patients with elevated pulmonary vascular resistance and shunt reversal show signs of central cyanosis with clubbing of hands and feet.

Septal Infarction
Isolated septal MI is uncommon and may be due to occlusion of the septal perforator branches that supply the anterior portion of the IVS and the bundle of His. Septal involvement in MI is usually due to occlusions of the LAD or dominant right coronary or dominant left-circumflex arteries, since all of these give rise to septal branches and may lead to IVS rupture [59]. Occasionally, IVS rupture may occur, establishing a communication between the two ventricles. In the era of early reperfusion therapy, however, post-MI VSD is a rare (<1% of MI patients) but potentially catastrophic complication [60]. Post-MI IVS rupture and VSD occur 3 to 8 days after a transmural acute MI.

Ventricular Arrhythmias and Conduction Abnormalities
The IVS is important as part of the ventricular tachycardia (VT) substrate in several conditions such as idiopathic VT [61] as well as in VT, as a result of ischemic heart disease (IHD) [62], HCM [63] and dilated cardiomyopathy (DCM) [64]. Further, patients with ischemic heart disease may develop heart block due to ischemia or infarction of the atrioventricular conducting pathway. The atrioventricular node artery is a major contributor to the arterial supply of the atrioventricular conducting pathway, and is an important vessel in the pathogenesis of heart block. It is noteworthy that in a study in which the terminal ramifications of this artery were evaluated by serial sectioning in 50 human hearts, the atrioventricular artery provided branches to the posterior IVS in all hearts (100%) and to the interatrial septum in 22 hearts (44%). The vessel supplied the atrioventricular node in 45 hearts (90%), whereas it supplied the penetrating bundle in 32 hearts (64%) [65].

Other
Less common pathologies affecting the IVS include aneurysm [66], diverticulum [67], and lipomatous hypertrophy [68]. Intramyocardial dissecting hematoma is a rare form of cardiac rupture that may occur following MI, chest trauma, or percutaneous intervention. It can develop in the LV free wall, RV, or IVS, and consists of blood infiltration into and through the myocardial wall ( Figure 3) [69]. 45 hearts (90%), whereas it supplied the penetrating bundle in 32 hearts (64%) [65].

Other
Less common pathologies affecting the IVS include aneurysm [66], diverticulum [67], and lipomatous hypertrophy [68]. Intramyocardial dissecting hematoma is a rare form of cardiac rupture that may occur following MI, chest trauma, or percutaneous intervention. It can develop in the LV free wall, RV, or IVS, and consists of blood infiltration into and through the myocardial wall ( Figure 3) [69].
. IVS abscess development usually occurs as an extension of infective endocarditis from cardiac valves and is associated with high mortality [70]. Cardiac tumours are some of the rarest primary tumours, while cardiac metastases are more common yet still relatively rare [71]. Seventy-five percent of primary cardiac tumours are benign and seldom involve the IVS. Fibromas and hemangiomas occasionally originate in the IVS and may mimic HCM (Figure 4) [72], whereas hamartomas of mature cardiac myocytes (HMCM) are hyperproliferative growth of mature cardiac cells, which are slow growing and solitary, usually present in young men in their mid-twenties in the ventricles and IVS; they may be asymptomatic. tively rare [71]. Seventy-five percent of primary cardiac tumours are benign and seldom involve the IVS. Fibromas and hemangiomas occasionally originate in the IVS and may mimic HCM (Figure 4) [72], whereas hamartomas of mature cardiac myocytes (HMCM) are hyperproliferative growth of mature cardiac cells, which are slow growing and solitary, usually present in young men in their mid-twenties in the ventricles and IVS; they may be asymptomatic. Cardiac thrombi may occur in 2-7% in patients with atrial fibrillation or LV dysfunction, with thrombus formation occurring at the IVS in approximately 11% of the cases [73]. IVS rupture as a mechanical complication of MI may lead to thrombus formation. Cardiac involvement including the IVS is rare in cystic hydatid disease (CYHD) [74]. Echocardiography is useful for the diagnosis, whereas CCT and CMR provide further information, such as the extent and anatomic relationships of the cysts ( Figure 5) [74].

Cardiac Resynchronization Therapy (CRT)
CRT is an established treatment in selected patients with heart failure [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 [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 [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 [78]. Therefore, not surprisingly, CRT improves cardiac function and symptoms, as well as reduces morbidity Cardiac thrombi may occur in 2-7% in patients with atrial fibrillation or LV dysfunction, with thrombus formation occurring at the IVS in approximately 11% of the cases [73]. IVS rupture as a mechanical complication of MI may lead to thrombus formation. Cardiac involvement including the IVS is rare in cystic hydatid disease (CYHD) [74]. Echocardiography is useful for the diagnosis, whereas CCT and CMR provide further information, such as the extent and anatomic relationships of the cysts ( Figure 5) [74].

Cardiac Resynchronization Therapy (CRT)
CRT is an established treatment in selected patients with heart failure [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 [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 [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 [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) [79].

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) [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 [81].
In the recently completed EXPLORER-HCM (Clinical Study to Evaluate Mavacamten  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 [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 [83].

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 [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 [85].

VSD Closure
VSD is the most common congenital heart defect. VSD creates a shunt between the RV and LV. Untreated medium or large VSDs lead to congestive heart failure [86]. Surgical closure remains the treatment of choice for most defects. However, transcatheter closure of muscular VSD has emerged as a safe and effective alternative [87]. Moreover, it has been recently demonstrated that transcatheter device closure of perimembranous VSD and intracristal VSD can be performed safely and successfully in selected patients with excellent medium-and long-term results [88]. Interestingly, repair of post-MI septal rupture with transcatheter defect closure emerges as a viable option [89].

IVS Ablation of VT
Ventricular arrhythmias originating from the LV summit and IVS account for 10-15% of ventricular arrhythmias. Managing those arrhythmias is a major challenge. Novel mapping and ablation strategies are needed in order to treat arrhythmias originating from these regions, given the current suboptimal long-term success rates with standard techniques [90]. In this regard, bipolar radiofrequency ablation has emerged as a promising technique for the treatment of septal VTs in patients with non-ischemic dilated cardiomyopathy [91]. However, it was recently reported that idiopathic ventricular fibrillation (IVF) in which a triggering premature ventricular complexes leading to the IVF episodes could not be identified, was successfully treated using posterior fascicle transection and empirical linear ablation of the mid-Purkinje potentials identified along the LV interventricular inferior septum [92].

Conclusions
The IVS plays a pivotal role in cardiac function as it contributes to the structure and function of both ventricles. Conditions or diseases that affect the IVS may lead to pump failure and/or ventricular arrhythmias with grave consequences (Figure 6). A detailed evaluation of the IVS is feasible with current noninvasive imaging modalities, and effective therapy can be implemented in most cases with IVS involvement. Definition of the underlying etiology may not always be easy, especially in the elderly there is overlap between genetic and acquired causes of IVS pathology, particularly in IVS hypertrophy, the most common abnormality. The rapid developments in medical science and technology are anticipated to help better define the mechanisms underlying IVS pathology and lead to accurate diagnoses, better management, and hopefully prevention at least in certain cases.

Conflicts of Interest:
The authors declare no conflict of interest.