Given the small number of patients studied, their wide age range, the comparatively high age of our first observation, other possible latent pathologies, and the time-variable impact of different balancing factors, we considered inappropriate any statistical re-elaboration of our results, which, morphologically evaluated, allowed a qualitative assessment, and subsequent pathophysiological deepening. Similarly, the microvascular factors, the common background of SCD, difficultly can be evaluated quantitatively. In every way, the primary role played by PAH in promoting RV damage and a consequent chain of adverse cardiac events is evident, so much to hypothesize the interfering action of other genes, still unknown [4]. Certainly, it acts as a link between micro-vascular and macro-cardiac factors.
Microvascular pathology
In the microvascular circulatory system, a chronic anemia causes peripheral vasodilatation and increases the circulating blood volume trough an activated renin-angiotensin-aldosterone system. As a result, blood viscosity and peripheral resistances decrease, while the speed of internal blood flow increases, as does the shear stress on the capillary walls, followed by an abnormal release of the von Willebrandor other coagulation factors [5–7]. Moreover, the increased intravascular lysis of SCD erythrocytes, activated leukocytes and platelets causes a large release of interleukins and generation of cell-derived particles [8]. All this, associated with reduction in nitric oxide bioavailability and increased release of nitrogen dioxide and endothelin-1 factor, favors diffuse micro-thromboses. This pathology electively affects the pulmonary micro-vessels, promoting their contraction, hypertrophy and proliferation of smooth muscle cells of the medial layer, and becoming a crucial component of PAH. In addition, left atrium hypertension, sometimes an early expression of increased LVEDP, can promote equivalent changes in the pulmonary venules [9, 10]. A further ubiquitous element is represented by increased tissue deposition of bioactive iron, which also involves the myocardial tissue [11].
Cardiac pathology
In addition to this complex chain of microvascular events, cardiac function is impaired by two other mechanisms, namely tachycardia and hyper-dynamic circulation, often together each other correlated. This firstly causes a proportional lengthening of RV myocardial fibers, useful within the limits of Frank-Starling law. However, beyond this physiological threshold, this process becomes disadvantageous, leading to RV large spherical remodeling, increasing RVEDV, enhancing its contraction in a horizontal or semi-horizontal plane, at the expense of the more physiological contraction along the longitudinal axis. Secondly, this causes a progressive RV concentric hypertrophy, attempting to balance its afterload [12–14]. Thirdly, within the pericardium, the increased RVEDV and internal tension, especially in the late diastolic and early systolic phases, hinders LV in increasing its diastolic compliance, promoted by the augmented circulating blood volume, so to simulate a restrictive cardiomyopathy with a paradoxically preserved ejection fraction. On 3-DE this effect is demonstrated by a D-shape of the interventricular septum (IVS). Fourthly, this negative anatomo-functional condition tilts the atrioventricular plane, mainly in its right part, promoting an abnormal systolic excursion of the tricuspid annulus, predisposing to a tricuspid valve insufficiency, and progressive RV-pulmonary artery uncoupling (Fig. 1) [15–18].
As a countermeasure, the impact of this negative hemodynamics activates a support from the LV to the RV through their interdependent anatomical structures. They consists of myocardial fibers, which continue from the inner RV walls, through the IVS, until the LV subepicardium [19–25]. From a functional point of view, in the absence of cardiac arrhythmias, this system can be compared to an electrical circuit with two derived secondary branches, to which, according to Newton's second law and Ohm's principle, energy is distributed in proportion to their capacity, in turn related with the total magnitude of their demand. This compensatory mechanism agrees with the ventricles common embryological origin from a single structure [26, 27]. However, despite all these protective mechanisms and benefits of medical treatment, the progressive PAH increases RV afterload and RVEDV (Table 2).
Table 2 Right ventricle sickle cell disease
Consequently, in the long term, the LV, already damaged by chronic anemia, abnormal tissue deposition of bioactive iron, increased inotropic state, and possible endothelial dysfunction in its coronary microvascular system, may become progressively insufficient, and in a vicious circle augment the resistance in the pulmonary micro-venules. This leads to an impending global heart failure. It can be considered 'RV-driven', given the great impact of the RV pathology, in particular its uncoupling with the pulmonary artery, where microvascular and endothelial lesions persist active (Fig. 2).