Abstract Background: The morbidity and mortality burden of cardiac complications, including diastolic dysfunction (DD), is significant in sickle cell disease (SCD) (Sachdev et al, 2007). Therefore, there is a pressing need to elucidate the underlying mechanisms for SCD-cardiac injury and to identify its early biomarkers. Myocardial ischemia/infarction is seen in SCD without obstructive coronary epicardial artery disease, suggesting a potential coronary microvasculature mechanism. Myocardial perfusion imaging (MPI) is widely used to noninvasively assess myocardial blood flow within the coronary microvasculature. MPI allows for the quantification of myocardial blood flow (at rest and during stress), and the coronary flow reserve (CFR) (defined as a ratio between myocardial blood flow at stress and rest) is a well-validated index used to assess microvasculature dysfunction in the absence of obstructive epicardial coronary disease. MPI using single-photon emission computed tomography (SPECT) and cardiac magnetic resonance imaging (CMR) has suggested impairment of coronary microvasculature blood flow in patients with SCD. However, these imaging modalities, unlike positron emission tomography (PET) with 13N ammonia, do not allow quantitative blood flow analysis (global and regional) and absolute quantification of CFR. Hence, 13N ammonia PET is more comprehensive than SPECT or CMR for detecting microvasculature disease with multi-vessel involvement, where the perfusion is globally and symmetrically reduced (thus limiting qualitative relativistic comparison), as is suspected in SCD. Furthermore, whether this microvascular ischemic injury drives the SCD-cardiac pathophysiology of DD remains to be studied. In this study, we hypothesized that microvasculature dysfunction, determined by decreased CFR, is associated with DD. Study Design: This is a non-therapeutic study (NCT05583721) conducted at St Jude Children's Research Hospital using a cross-sectional case-control design to compare CFR in SCD patients with DD (≥3 abnormal diastolic parameters) and without DD (≤2 abnormal diastolic parameters) and healthy controls, using 13N ammonia PET rest-stress MPI. Individuals aged 18-21 years with HbSS or HbSβ0 thalassemia are approached for participation. Participants with a history of vaso-occlusive crisis in the last 4 weeks, seizures, cardiac surgery, or cardiac disease (congenital heart disease, arrhythmia) are excluded. To control for SCD, age-matched healthy participants are enrolled. Healthy (non-SCD) participants are excluded if they have anemia of grade 2 or worse (per CTCAE v5.0; Hb 10 g/dl) or cardiac disease (as detailed for SCD participants). The enrollment goal is 20 healthy controls and a minimum of 20 SCD participants (10 with DD and 10 without DD), over a 24-month study period. The study visits include visit one, which involves screening labs and an EKG/echocardiogram, and visit two, which consists of a rest-stress PET MPI using 13N ammonia. The primary study aim is to compare the CFR among the three pre-defined groups: SCD patients with DD, SCD patients without DD, and healthy controls, using one-way ANOVA or Kruskal–Wallis. The secondary aim is to assess the association between abnormal CFR and the presence of abnormal diastolic parameters. We will group the participants based on their abnormal diastolic parameters into three groups: Group 1, with 0 or 1 variable abnormal; Group 2, with 2 variables abnormal; and Group 3, with≥3 diastolic variables abnormal. We will first summarize the mean and standard deviation of CFR values for each diastolic group. One-way ANOVA or the Kruskal-Wallis test will be used to explore whether there are any differences between the means of these three groups. To date, 8 participants (6 healthy controls and 2 individuals with SCD) have completed the study with no study-related complications. Conclusion: PET rest-stress MPI may provide a safe and sensitive screening tool for early SCD-related heart disease, enhancing clinical care by enabling the identification of at-risk patients and assessing the effects of early therapeutic interventions. This study will provide preliminary data necessary for a more comprehensive analysis to determine whether PET-based CFR is a clinically feasible and useful imaging biomarker that may serve as a potential early endpoint of the cardiac manifestations observed in SCD, particularly DD.
Rai et al. (Mon,) studied this question.