In the present study we have analyzed the LA function in a group of patients with a recent diagnosis of HH who have not received any specific treatment for this disease. They had no cardiovascular symptoms and Fe overload was documented by biochemical methods, MRI and liver biopsy. Despite not observing differences in LA size and volumetric parameters, we have found a significant decrease in longitudinal strain during the reservoir and conduit phases, with an increase in the stiffness index, with which we can infer an incipient compromise of atrial myocardial function.
The indexed LA volume is more robust as a predictor of events than the anteroposterior diameter or the LA area. Current guidelines propose its measurement, and a value greater than 34 mL/m2 is associated with higher mortality, heart failure, atrial fibrillation, and ischemic stroke. Its value also correlates with other markers of ventricular diastolic dysfunction such as the E/e' ratio, and represents the impact over time of the increase in LV filling pressures (9). However, various techniques for studying myocardial function that could prove to be more sensitive have been developed. The study of myocardial deformation carried out using the speckle tracking technique has shown high feasibility and low interobserver variability. It has been increasingly used in the evaluation of myocardial function, mainly of the left ventricle, and in recent years its use has spread to the right ventricle, and to both atria. The method is based on monitoring the acoustic markers (speckles) of the myocardium during the cardiac cycle. It has the advantage of being angle independent, and the limitation of requiring adequate acoustic windows, which are not always possible. Its analysis has shown prognostic value in numerous clinical scenarios: coronary disease, heart failure, valvular disease, cardiomyopathy, and cardio oncology, among others (5, 13).
In the presence of Fe overload, this metal enters the myocyte through L-type calcium channels. The left ventricle is the most compromised heart chamber, and then in decreasing order are the right ventricle, the left and the right atrium (14). Intracellular Fe is found as ferritin, hemosiderin, and free form. The latter represents the most active form, which leads to the formation of toxic free radicals through the Fenton reaction. When the antioxidant capacity is exceeded, intracellular alterations occur at the level of the plasma membrane, proteins and nucleic acids that result in various degrees of dysfunction. On the other hand, there are alterations in the entry of calcium into the cell, which also contributes to alterations in systolic and diastolic function. It has been postulated that diastolic dysfunction is usually the earliest affectation of myocardial function in this pathology (8). In the LV, the subepicardial myocardium is mainly involved, so it is expected that in the analysis of contractile mechanics, radial and circumferential strain will be initially affected and therefore cardiac torsion, as observed by different studies, including ours (15–18).
In secondary hemochromatosis, Fe overload levels are usually much higher, and clinical cardiac involvement is also more frequent, but a significant correlation between serum ferritin levels and myocardial Fe concentration or the presence of cardiomyopathy has not always been observed, which makes us suppose that there are other immunoinflammatory and/or genetic mechanisms involved. Different studies have shown an early compromise of diastolic function in young patients with beta thalassemia and marked Fe overload (ferritin > 2000 ng/mL). Kostopoulo et al observed an increase in LA size and a decrease in the active and passive ejection fraction of the left atrium compared with a control population (19), and in the same sense, a decrease in atrial strain has been observed during the reservoir phase (20). The compromise of the LA function could occur both as a consequence of the increase in its afterload due to the increased LV rigidity, as well as its intrinsic compromise by Fe deposits in the atrial myocardium.
In HH, the clinical impact from the cardiovascular point of view is limited, when compared to forms secondary to repeated blood transfusions, where the Fe overload is much higher. However, subclinical compromise has been observed in both diastolic and systolic function in these patients, especially when more sensitive study techniques such as tissue Doppler or two-dimensional strain are used. Shizukuda Y et al studied 43 patients with HH, of whom half were recently diagnosed, and the others were under treatment by phlebotomies. Both groups were asymptomatic and were compared with a control population. No differences were observed in diastolic and systolic function between both groups by Doppler evaluation. However, patients with HH presented greater LA contraction force, which was assumed to be an early subclinical alteration of diastolic function in this group. There was no correlation with the serum concentrations of the Fe parameters, nor were there significant differences between the HH groups that had or did not have treatment for the disease (21). More recently, Byrne et al evaluated 25 patients with a recent diagnosis of HH and evaluated systolic function by analyzing LV radial strain and diastolic function through LA contraction force. After one year of treatment with phlebotomies, they observed a significant increase in radial strain (36.4 ± 21.3% vs 52.7 ± 18.9%, p = 0.015) and an improvement in diastolic function (5.6 kdynes vs 4.4 kdynes, p = 0.001). Unlike the previous work, in this case a difference was observed in cardiac function with the treatment, perhaps due to a longer time between both analyzes, and to the fact that patients were compared with themselves (4).
In our work we have found a moderate correlation between the LASr and the LV e'SR. Some research suggests that the E/ e'SR ratio could be a superior parameter to the classic tissue Doppler E/e' ratio in terms of prognostic value and a better correlation with LV filling pressures. Therefore, we could infer that the e' wave measured by strain rate could behave as an even more sensitive marker of diastolic alteration (22).
Other interesting information is the higher stiffness index in HH patients. It is defined as the pressure required to achieve a determined increase in volume in the LA (12). This easily obtained parameter has been postulated as an earlier marker of atrial function compromise and diastolic dysfunction, as well as being associated with follow-up events such as the appearance of atrial fibrillation and the occurrence of embolisms. It has been shown that the alteration of this index is even earlier than the increase in atrial volume, classically used as a prognostic variable (23–25). In a recent study by Porpáczy et al in a patient with systemic sclerosis, stiffness index is the variable that best correlates with serum levels of NT-pro-BNP, surpassing isolated LASr and LA volume (26).
We have not observed a correlation between various LA function parameters and the Fe metabolism profile. But the body excess of this metal, by the previously described mechanisms, generates reactive oxygen species, which would be the main determinants of cell dysfunction and death. It has been shown that patients with HH have elevated blood markers of oxidative stress, regardless of whether or not they are undergoing phlebotomy treatment, and that these correlate significantly with diastolic tissue velocities. Shizukuda et al observed a significant relationship between the velocities of the tissue Doppler e' wave and the levels of erythrocyte glutathione and malondialdehyde (27).
Although cardiac magnetic resonance imaging did not show pathological values of Fe overload, cardiac involvement cannot be ruled out. A recent study using the T1 mapping technique shows that up to two thirds of patients with systemic iron overload, with T2* greater than 20 ms, could have myocardial deposits of this metal, which is why some researchers are already proposing T1 mapping as a complement to T2* in the evaluation of these patients (28).
Among the limitations of our work are the lack of measurement of serum oxidative stress parameters and markers of myocardial dysfunction such as natriuretic peptides. However, in another research carried out by members of our team, not yet published, a significant decrease in serum levels of coenzyme Q10 (a powerful endogenous antioxidant) has been shown in patients with HH.