Diastolic Dysfunction Is Associated with Impaired Cardiopulmonary Exercise Performance in Sickle Cell Disease

Background:

Left ventricular diastolic dysfunction is associated with increased mortality in sickle cell disease (SCD). Diffuse myocardial fibrosis is common in patients with SCD and is associated with diastolic dysfunction. Measurement of functional capacity by cardiopulmonary exercise test (CPET) has prognostic value in several cardiac diseases. Exercise impairment is common in SCD, but the causes and correlates are not well understood. Diastolic dysfunction is associated with a shorter 6-minute walk distance in SCD, but the effect of diastolic dysfunction and myocardial fibrosis on CPET has not been studied before.

Methods:

As part of a prospective study to characterize the cardiomyopathy of SCD (NCT02410811), children and adults with SCD underwent cardiac MRI (CMR), echocardiography and cycle ergometer CPET. Diffuse myocardial fibrosis was assessed by CMR-based measurement of extracellular volume fraction (ECV) from pre- and post-gadolinium T1 maps. Cardiac chamber sizes and cardiac performance were evaluated using CMR, and diastolic parameters were measured by echocardiography. Patients were classified to have diastolic dysfunction if they had left atrial enlargement and abnormalities in two diastolic parameters (E/e' ratio and e'). The following measures were recorded during CPET: percent predicted VO2 at maximum exercise (VO2 max) and ventilation efficiency (VE/VCO2 slope at maximum exercise (VE/VCO2 max). Reduced exercise capacity was defined by VO2 max <80% and classified as mild (VO2max 60-80%) or moderate to severe (VO2 max <60%).

Results:

Fifteen patients with SCD have completed the study (age range 8-38 years). No adverse events were reported within one month of CPET. Only one patient did not reach maximum exercise due to muscular fatigue. Fourteen patients (93%) had reduced exercise capacity; four of them (28%) had mild impairment and 10 (71%) had moderate to severe impairment. Four patients had diastolic dysfunction and none had systolic dysfunction. Patients with diastolic dysfunction had lower exercise capacity compared to patients with normal diastolic function as measured by lower VO2 max (46.6 ± 5.9% vs 59.2 ± 11.5%; p=0.02). The z-score of the left ventricular lateral E/e' ratio, a diastolic measure that reflects left ventricular filling pressure, negatively correlated with the maximal exercise capacity VO2 max (r=-0.57, p=0.02) and positively with worse ventilation efficiency measured by VE/VCO2 max (r=0.61, p=0.01), indicating an association between diastolic dysfunction and worse exercise performance. We did not find an association between ECV and exercise capacity. Hemoglobin concentration was moderately associated with VO2 max (r=0.37) but this association was not statistically significance (p=0.09).

Conclusion:

Diastolic dysfunction is associated with poor exercise capacity assessed by CPET in patients with SCD. Myocardial diastolic dysfunction may be one of the causes of impaired exercise capacity in SCD. Strategies to prevent or delay the acquisition of diastolic dysfunction to improve exercise capacity and long-term outcomes in SCD should be explored.