Cardiomyopathy With Restrictive Physiology in Sickle Cell Disease

Abstract

Objectives: The aim of this study was to identify a unifying cardiac pathophysiology that explains the cardiac pathological features in sickle cell disease (SCD).

Background: Cardiopulmonary complications, the leading cause of adult death in SCD, are associated with heart chamber dilation, diastolic dysfunction, elevated tricuspid regurgitant jet velocity (TRV), and pulmonary hypertension. However, no unifying cardiac pathophysiology has been identified to explain these findings.

Methods: In a 2-part study, we first examined patients with SCD who underwent screening echocardiography during steady state at our institution. We then conducted a meta-analysis of cardiac studies in SCD.

Results: In the 134 patients with SCD studied (median age 11 years), significant enlargement of the left atrial volume was present (z-score 3.1, p = 0.002), shortening fraction was normal (37.6 ± 4.7%), and lateral and septal ratios of mitral velocity to early diastolic velocity of the mitral annulus (E/e') were severely abnormal in 8% and 14% of patients, respectively, indicating impaired diastolic function. Both TRV and lateral E/e' correlated with enlarged left atrial volume in SCD (p = 0.003 and p = 0.006, respectively). Meta-analysis of 68 studies confirmed significant left atrial diameter enlargement in patients with SCD compared with controls, evidence of diastolic dysfunction and enlarged left ventricular end-diastolic dimension with normal shortening fraction. The majority of patients with catheter-confirmed pulmonary hypertension had mild pulmonary venous hypertension consistent with restrictive cardiac physiology.

Conclusions: Patients with SCD have a unique form of cardiomyopathy with restrictive physiology that is superimposed on hyperdynamic physiology and is characterized by diastolic dysfunction, left atrial dilation, and normal systolic function. This combination results in mild, secondary, pulmonary venous hypertension and elevated TRV. Sudden death is common in other forms of restrictive cardiomyopathy. Our finding of this unique restrictive cardiomyopathy may explain the increased mortality rates and sudden death seen in patients with SCD with mildly elevated TRV.

Keywords: cardiomyopathy; pulmonary hypertension; restrictive physiology; sickle cell disease.

Figure 1. The Prevalence of Low Lateral e′ and Septal e′ Increases with Age

The percentage of SCD with low lateral and septal e′ (z-score<−1) in the age groups: 1–5 years, 6–9 years, 10–13 years, 14–18 years and older than 18 years of age.

Figure 2. LAV Association with TRV and Lateral E/e′

The regression of (A) TRV and LAV z-score, and (B) lateral E/e′ and LAV z-score. Dashed lines represent 95-percent confidence interval.

Figure 3. Meta-analysis Summarizing the TRV, PH, LAD, SF and LVED in SCD Patients

(A) Mean TRV values for SCD patients in different studies with weighted mean TRV and 95-percent confidence interval for the included studies. (B) The percentage of SCD patients with RHC-confirmed PH, PAH and PVH in patients that had TRV≥2.5 m/sec. Data are pooled from four different studies. (C) The mean difference between LAD in SCD and control groups in different studies, and the weighted mean difference with 95-percent confidence interval. (D) The mean SF for SCD population in different studies with weighted mean SF and 95-percent confidence interval. (E) The mean difference between LVED in SCD group and control group in different studies and the weighted mean difference with 95-percent confidence interval. Weighted mean and weighted mean difference values in plots A, C, D and E were calculated using a random-effects model. Each point represents mean value spanned by its 95-percent confidence interval.