In compiling the data from the 27 articles, it was possible to observe that the main cardiopulmonary changes described in sickle cell patients were: PH, acute thoracic syndrome (ATS), restrictive and obstructive respiratory dysfunctions, wheezing in children, increased tricuspid regurgitation velocity (TRV), enlargement of the left ventricle (LV) and left atrium (LA) and diastolic dysfunction with normal systolic function. It was also possible to observe that PH and ACS are among the most important causes of morbidity and mortality in patients with SCA.
Pulmonary complications in SCA
PH can be diagnosed through right cardiac catheterization, an invasive method that is the gold standard for diagnosis and non-invasively by measuring the TRV with diagnostic confirmation defined as a TRV ≥ 2.5 m/s. Caughey et al demonstrated that most studied patients with suspected PH had elevated TRV and 59% had values > 3.0 m/s. A higher PH detection rate was observed by measuring TRV, highlighting a greater possibility of false-positive results with this method[11,13,14].
Dham et al found that children with SCA had significantly higher TRV, systolic, diastolic and mean pulmonary artery pressures than controls. The highest frequency of pediatric patients with ACS and PH found was in the age group of 5-7 years. The high prevalence of PH among younger children is an uncommon finding as this complication is known to progress with age. TRV values ≥ 2.5 m/s were shown to be correlated with a history of acute chest syndrome and previous transfusions. Elevated left atrial pressure and right ventricular stroke volume were predictors of TRV in a multivariate regression model. Higher TRV was also associated with increased left ventricular and atrium chambers and higher levels of B-type natriuretic peptide, lactate dehydrogenase (LDH), amino aspartate transferase (AST), erythropoietin, urea, creatinine and reticulocytes. Another clinical finding reported in the studies found was the presence of the second heart sound with greater intensity. This change was statistically associated with PH in children with ACS and individuals with this clinical finding demonstrated a 3.4 times greater chance of having PH[12,13,17-20].
However, PVR and Hb levels were indirectly related to the increase in TRV. For every 1.0 g/dL increase in Hb, TRV decreased by 13%. The data found suggested that most adult patients with ACS and suspected PH had normal PVR. Caughey et al demonstrated that the mean PVR index was significantly higher in patients with suspected PH than in those without PH although they were still below the cutoff point for elevated PVR. Only 2 individuals with suspected PH (6%) with TRV values between 3.0 and 3.9 m/s, respectively, had a high PVR index[14,15].
The pathogenesis of PH in patients with SCD is complex. The compensatory state of high CO due to chronic anemia may contribute to increased pulmonary arterial pressure (PAP) in the presence of normal PVR. PH as a manifestation of left ventricular dilatation and eccentric hypertrophy may be significant in some patients. Hemolysis is also believed to play an important role leading to nitric oxide depletion, endothelin-1 release and platelet activation. Ultimately, they result in vasculopathy characterized by endothelial dysfunction, increased vascular tone, inflammation, hypercoagulability and vascular remodeling.
The strong and independent associations of TRV with the velocity-time integral of the right ventricular outflow tract and the left atrial pressure index support the importance of high CO in the pathogenesis of PH in this population. A possible role for hemolysis is suggested by the negative correlation of TRV with Hb and reticulocyte counts. Circulating erythropoietin concentrations reflect the degree of tissue hypoxia and the association of a higher level of erythropoietin with higher TRV may serve as a marker of the degree of tissue hypoxia which appears to be associated with the development of PH in other conditions[12,16,17].
ATS was reported in the study by Vichinsky et al in which more than two-thirds of participants with SCA had a history of ACS with multiple episodes. The cause of ACS was established in 38% of the episodes with infections and pulmonary emboli (bone marrow, fatty or thrombotic) being the main ones reported. Of the 27 different pathogens identified, Chlamydia pneumoniae was the most prevalent followed by Mycoplasma pneumoniae.
Maioli et al and Cuervo et al showed that the pulmonary function test in patients with ACS can identify different elements related to the evolutionary stage of the disease, including restrictive ventilatory dysfunction, observed in patients with SCA, regardless of a previous history of SCA. However, a history of 2 or more episodes of AST makes this clinical manifestation the most important risk factor for chronic lung damage and consequently, characteristic ventilatory changes. MacLean et al and Cuervo et al also reported that obstructive pulmonary abnormalities occur first followed by the development of restrictive abnormalities which become more prominent with increasing age in children and adolescents with SCA. A history of asthma or wheezing, bronchopulmonary dysplasia, cystic fibrosis, bronchiolitis and a higher concentration of LDH were associated with obstructive pulmonary disease reflecting lower TFP values. It was also observed that low forced expiratory volume in 1 s (FEV1%) was considered an independent predictor of early death in adults with SCA, with a decrease in FEV1% being associated with an increase in the measurement of TRV[23,24].
Throughout life, patients with SCA have the lung parenchyma subject to episodes of ischemia during vaso-occlusion crises. These events sometimes lead to necrosis and subsequent regeneration with formation of fibrotic tissue. These pathophysiological mechanisms can occur during ACS or in the course of a vaso-occlusive chest crisis so that with advancing age, the lung parenchyma starts to present more fibrotic tissue contributing to the onset of the restrictive change which justifies the increase in the percentage of restrictive disorders from the age of 25 onwards. An association between restrictive changes and increased left ventricular size was also observed. LV dilation can reduce lung volume due to pulmonary congestion and the direct effect of heart compression on the lung parenchyma. In obstructive changes, they reported that increased capillary blood volume and hemolysis may contribute to increased airway obstruction in children with SCA[11,23-28].
Other pulmonary alterations associated with SCA have been described: Mosaic attenuation pattern on computed tomography (CT) associated with increased TRV, decreased hemoglobin levels and reduced respiratory muscle strength in a ground-glass pattern. Furthermore, it has been reported that children with sickle cell have more frequent wheezing compared to children without SCA and that leukocytosis is considered a risk factor for early decline in pediatric lung volumes[11,29,30]. Several mechanisms may be involved in the decrease in respiratory muscle strength in these patients: Shallow breathing due to chest pain, vaso-occlusion that affects muscle performance and chest cavity deformities resulting from successive bone infarctions. The results of the study by Maioli et al suggested that the partial collapse of airway spaces after inspiration, due to respiratory muscle weakness, may explain the matte pattern in the CT of these patients. The association between elevated TRV and the appearance of a mosaic attenuation pattern on CT is indicative of occlusive vascular disease and small airway obstructive disease.
The finding of wheezing on pulmonary auscultation also supports the appearance of obstructive disease. However, the mechanisms by which leukocytes can affect lung volumes are not clear. Leukocytes are able to adhere to blood vessel walls and obstruct the lumen. They also stimulate the vascular endothelium resulting in a cascade of events that lead to tissue damage and an inflammatory reaction that further favors the phenomenon of vaso-occlusion[29,30].
Cardiac complications in SCA
The most reported cardiac alteration indicated is an enlargement of the LV and atrium and prolongation of the corrected QT (QTc) interval on the electrocardiogram. Patients with SCA also had diastolic dysfunction with increasing age (with preservation of systolic function) and, in some cases, systolic dysfunction[31,32]. The pattern of diastolic dysfunction, left atrial dilation and normal systolic function observed in these patients is consistent with an aspect of restrictive cardiomyopathy. Elevated TRV is correlated with increased PAP, being the result of pulmonary arterial endothelial dysfunction due to intravascular hemolysis. However, restrictive physiology also increases PAP and TRV secondary to increased LA pressure[31,33].
Diastolic dysfunction may also result from a combination of myocardial fibrosis, microvascular occlusions by sickle cells, ischemic events, cardiomyocyte loss and oxidative stress. Niss et al reported that individuals with advanced fibrosis had concomitant diastolic dysfunction. These progressive myocardial injuries promote dilatation and increased pressure in the LA and a slight increase in retrograde pulmonary venous pressure[33,34]. The increase in LV is mainly due to hyperdynamic circulation related to anemia. In addition, abnormal loading conditions associated with anemia also lead to its dilation and consequent increase in stroke volume. Other factors, including iron overload, immunogenic factors, damage to the microcirculation from vaso-occlusive crisis and associated valvular disease may contribute to the remodeling process and cardiac dysfunction[31,33,34].
Indik et al reported that prolongation of the QTc interval on the electrocardiogram was present in 39% of men and 27% of women with SCA and associated with higher values of TRV. A QTc interval greater than 450 ms in men and 470 ms in women was associated with a higher risk of death. Thus, the presence of multiple vaso-occlusive episodes throughout life may also contribute to QTc interval prolongation, coronary microvascular dysfunction and increase the risk of sudden death in SCD.
The studies compiled herein showed an important frequency of pulmonary and cardiac impairment in patients with SCA. The treatments now available have contributed to increase the life expectancy of patients. The increase in the average age of patients may imply an increase in the prevalence of cardiopulmonary alterations, in addition to other comorbidities associated with the disease. This scenario suggests the need to improve specialized and early care for these patients, especially with a view to early diagnosis of dysfunctions and monitoring of cardiopulmonary function from childhood, aiming to promote a decrease in the worsening of cases of pulmonary and cardiac dysfunction, contributing to improvement of the cardiopulmonary function of these patients and above all, allow guarantees of a better quality and expansion of life expectancy for this population.