Right-to-Left Shunts Are Unexpectedly Common in Adults with HbSS
Authors: Hambley Bryan Christopher , Rahman Rania Abdul , O'Riordan Mary Ann , Langer Nathan , Rotz Seth , Smith Aaron , Schilz Robert , Ginwalla Mahazarin , Little Jane A. 
Published: October 2019

Abstract
INTRODUCTION:
Patients with homozygous sickle cell anemia (SCA) have frequent cardiopulmonary complications. The clinical prevalence and consequences of intracardiac or intrapulmonary right-to-left shunts in SCA are unknown. Here we report a retrospective examination of this complication, and clinical and laboratory correlates at clinical baseline, in an adult population with SCA. These shunts may be of particular relevance, due to the susceptibility of these patients to thrombosis and the role that desaturated hemoglobin plays in the underlying pathophysiology of this disease.
METHODS:
This single-institution study included 153 patients with homozygous HbSS, who are followed at Case-UH Medical Center, Cleveland. Clinical and laboratory data were gathered on patients who underwent an echocardiogram with bubble contrast. Echocardiograms were reviewed to confirm the presence, characteristics, and degree of a right-to-left shunt. Immediate (intracardiac) or delayed (intrapulmonary) shunts were identified; the latter were quantitated as <5, 5-15, or >15 bubbles visualized in the left heart. Continuous variables were described, using mean ± standard deviation (SD) and nominal variables were described as N (%). The relationship between clinical characteristics and echo results was determined using linear regression. All analyses were undertaken using SAS v9.4 The SAS Institute, Cary, NC. n.b. Compound heterozygous sickle cell disease patients showed this complication rarely, and were not examined systematically.
RESULTS:
82/153 (53.6%) of studied SCA patients were female. Mean (SD) age in years was 32.2 (11.8). 90 (58.8%) patients had an echo with bubble study. In our population, 27 (17.6%) patients had an intracardiac shunt, 41 (26.8%) had an intrapulmonary shunt, and 22 (14.4%) had no shunt present; 63 (41.2%) patients did not have a bubble study.
Mean (SD) LDH was 523.3 (318.1) for those with intracardiac shunts and 570.5 (205.4) for those with intrapulmonary shunts. Mean (SD) LDH for all shunt patients combined was 551.3 (255.9). Mean LDH (SD) for patients either with no shunt or no contrast echocardiogram was 415.5 (193.0).
In a combined analysis, patients with shunts (N=68) showed a statistically higher baseline mean LDH when compared to a mean LDH of patients with either a negative bubble study or no bubble study (N=85), (551.3 vs 415.5, p<0.001).
No difference was seen in prevalence of clinical outcomes of acute chest syndrome or stroke between groups. Laboratory markers of disease activity, such as absolute reticulocyte count or baseline hemoglobin were not different in shunt versus non-shunt patients.
8 patients had <5 bubbles in the left atrium or ventricle, 7 had 5-15 and 25 >15 bubbles. There was no evidence that this had an effect at clinical baseline, but the impact of such shunts during crises or multi-organ failure has not yet been assessed. A small number of individuals with shunts showed significant oxygen desaturation with exercise, but these were not statistically distinct from other groups.
CONCLUSIONS:
68 patients with HbSS, or almost half of the adult SCA population, had right-to-left shunting on echocardiograms, either intracardiac or intrapulmonary, when evaluated at clinical baseline. These patients had significantly higher LDH than did patients with no bubble study or a negative bubble study, when evaluated in a combined post hoc analysis. The pathophysiology of these shunts is not known, but these have the potential to delay reoxygenation of sickle hemoglobin at clinical baseline and to facilitate right-to-left passage of fat or thrombotic emboli during clinical exacerbation.
We are currently evaluating the potential impact of these shunts in patients with HbSS prospectively, both at baseline and during clinical exacerbation.

Disclosures
Schilz: Genetech: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Actelion: Consultancy, Speakers Bureau; United Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Arena: Research Funding; Eiger: Research Funding.