Author + information
- Received April 22, 2015
- Accepted May 21, 2015
- Published online March 1, 2016.
- Omar Niss, MDa,∗ (, )
- Charles T. Quinn, MD, MSa,b,
- Adam Lane, PhDb,c,
- Joshua Daily, MDd,
- Philip R. Khoury, MSd,
- Nihal Bakeer, MDa,b,
- Thomas R. Kimball, MDd,
- Jeffrey A. Towbin, MDd,
- Punam Malik, MDa,b,e and
- Michael D. Taylor, MD, PhDd
- aDivision of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- bCancer and Blood Disease Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- cDivision of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- dDivision of Cardiology, Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- eDivision of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
- ↵∗Reprint requests and correspondence:
Dr. Omar Niss, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229.
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.
Sickle cell disease (SCD) refers to a group of inherited blood disorders caused by abnormal hemoglobin, sickle hemoglobin (HbS), that polymerizes on deoxygenation. With newborn screening and comprehensive care, most children with SCD who are born in developed countries survive into adulthood, albeit with significantly shortened life expectancy. Cardiopulmonary complications are the most common causes of death in adults with SCD (1). Heart chamber dilation, diastolic dysfunction, and elevated pulmonary arterial pressures (PAPs) are commonly reported findings in SCD, but a unifying pathophysiologic explanation has not been recognized.
Many studies have characterized the pulmonary hypertension (PH) in patients with SCD, thereby advancing the concept that increased PAP results from pulmonary vascular endothelial dysfunction (2–4). Mildly increased PAP occurs in ∼30% of adults and children with SCD when estimated by an increased (>2.5 m/s) tricuspid regurgitant jet velocity (TRV) on echocardiography (2,5,6). However, the gold standard for the diagnosis of PH, right-sided heart catheterization (RHC), demonstrates that PH is less prevalent than TRV-based estimates would indicate. Only 30% of patients with increased TRV have PH confirmed by RHC. In addition, the degree of PH, which is often mild in patients with SCD, does not readily explain the full extent of cardiac morbidity and frequency of early mortality in SCD (7). Nevertheless, TRV, pulmonary pressure, and diastolic dysfunction are clearly associated with increased mortality and sudden death in SCD (2,7,8). The causes of cardiac-related death in the absence of apparently clinically significant PH have remained unclear.
Here we describe a consistent pattern of cardiac pathophysiology in children and adults with SCD at our institution, confirm this pattern in a comprehensive meta-analysis of the published cardiac literature in SCD, challenge the conventional wisdom about the cardiopulmonary pathophysiology of SCD, and propose an explanation for its association with sudden death. Specifically, we find that patients with SCD have a unique form of cardiomyopathy with superimposed restrictive and hyperdynamic physiology that has not been previously recognized. Similar to other forms of restrictive cardiomyopathy (RCM), the SCD-related cardiomyopathy with restrictive physiology can explain the mild elevations in TRV without the need to invoke pulmonary arterial endothelial dysfunction.
We conducted a combined retrospective and prospective study of patients with SCD who were treated at Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio and who underwent clinical screening echocardiography at steady state (no acute SCD events 3 weeks before or afterward), between 2007 and 2010 with similar protocols. Of 134 patients age 3 to 22 years, 102 had homozygous SCD (HbSS), 21 had sickle hemoglobin C disease (HbSC), 2 had sickle-β0-thalassemia, and 9 had sickle-β+-thalassemia. Laboratory data were also obtained at the time of echocardiography. The Institutional Review Board approved this research protocol and waived the requirement for written informed consent.
Transthoracic echocardiography was performed using 2-dimensional, M-mode, pulse-wave Doppler, color-flow Doppler, and tissue Doppler imaging with a GE Vivid 7 (GE Healthcare, Milwaukee, Wisconsin) ultrasound system. Images and views were acquired according to American Society of Echocardiography standards. Pulsed-wave Doppler imaging was used to measure mitral valve inflow velocity peak at early filling (E) and late filling (A) in a standard manner. Tissue Doppler imaging was used to determine mitral valve annular velocities in early (e′) and late diastole (a′) at both the septal (septal e′) and lateral (lateral e′) annulus. Details of echocardiographic measurement and methods are described in the Online Appendix.
Systematic review for meta-analysis
MEDLINE, PubMed, Ovid, and Google Scholar databases were searched for the following terms: sickle cell disease, sickle cell anemia, and sickle cell in combination with each of the following: heart, cardiac, pulmonary hypertension, echocardiography, echocardiogram, cardiac MRI, cardiac MR, CMR, cardiomyopathy, catheterization, and hemodynamic. Articles that contained 2-dimensional, M-mode echocardiographic, Doppler, tissue Doppler, cardiac catheterization, or cardiac magnetic resonance (CMR) data in patients with SCD were retrieved for full text review. Studies that lacked quantitative data (mean, SD, or number of observations) in both SCD and control groups were excluded from the final quantitative analysis. However, these excluded articles were reviewed separately. An overview of the selection process is shown in Online Figure S1.
Continuous and categorical variables were expressed as mean ± SD. Student t tests were used to compare continuous variables, and chi-square tests were used for categorical variables across groups. Variables were assessed for normality by using the Shapiro-Wilk test. Associations between approximately normally distributed continuous variables were calculated using the Pearson correlation coefficient; otherwise, Spearman rank correlation coefficients were used. Significance of echocardiographic z-scores was estimated using area under the standard normal distribution curve tables for each z-score value.
For the meta-analysis, Cochran’s Q test was used to detect heterogeneity, and I2 was used to estimate the amount of heterogeneity among studies (9). The 95% confidence intervals (CIs) for individual studies and random-effects weighted mean (WM) and weighted mean difference (WMD) were determined using relevant quantiles of the standard normal distribution. Because of the degree of heterogeneity among studies, statistical significance was determined on the basis of the results of the random-effects approach (10). All statistical analyses were performed using Prism 6.0 (GraphPad Software, Inc., La Jolla, California) and Excel (Microsoft, Inc., Redmond, Washington). Differences were considered statistically significant at p <0.05.
Local patient-related characteristics
The characteristics of 134 patients with SCD, mainly children and young adults, are shown in Online Table 1. The median age was 11 years (range 3 to 22 years). Twenty-six patients (19%) were ≥18 years old. Most (76%) had HbSS.
Patients with SCD have left atrial enlargement
Echocardiographic findings are shown in Table 1. Left atrial volume (LAV) index, left atrial diameter (LAD), left ventricular end-diastolic diameter (LVED), posterior wall thickness, interventricular septal diameter, and indexed left ventricular mass (LVMi) were numerically higher in patients with SCD compared with normal values for age and body size. However, only LAV and LAD were significantly enlarged, with an average z-score of 3.1 (p = 0.002) and 2.19 (p = 0.02), respectively. The 2 most common abnormalities were left atrial (LA) enlargement (62%) and high LVMi (57%).
The LAD was disproportionately enlarged compared with other M-mode chamber measurements. One hundred twenty-four patients (92.5%) had higher LAD z-scores than LVED z-scores. No patient had mitral regurgitation.
Mean TRV was 2.16 ± 0.3 m/s in 96 patients with measurable TRV. Thirteen patients (13.5%) had TRV ≥2.5 m/s, all of whom had HbSS. None had a TRV ≥3 m/s. All had normal systolic function (mean shortening fraction [SF] = 37.6%). Taken together, these data show that young patients with SCD (median age 11 years) have significant and disproportionate LA dilation with normal systolic function. Most (86.5%) do not have increased TRV.
Patients with SCD have diastolic dysfunction
The mitral valve annular velocity e′ correlates with left ventricular (LV) relaxation (11). In our cohort, we observed a strong trend toward low lateral and septal e′, consistent with diastolic dysfunction. Notably, lower lateral and septal e′ values were most prevalent in older patients with SCD; this finding is the opposite of that seen in normal pediatric patients, in whom lateral and septal e′ values increase with increasing age (12). In children, the decreasing lateral and septal e′ values with increasing age suggest that diastolic function worsens with age (Figure 1).
A restrictive pattern of diastolic function was observed despite the young age of these patients (Table 2). There was a general trend toward increasing E-wave and E/A ratio in patients with SCD, whereas 24 patients (18%) and 4 patients (3%) had severely abnormal E and E/A ratio values, respectively, consistent with restrictive diastolic dysfunction. In addition, the E/e′ ratio, which correlates with LV filling pressure (13) and is reported to be abnormal in SCD (4–6), was also severely abnormal in 10 patients (8%) and 18 patients (14%) for lateral and septal E/e′ values, respectively (Table 2). Together, the pattern of diastolic dysfunction, LA dilation, and normal systolic function observed in young patients with SCD is most consistent with cardiomyopathy with restrictive physiology (14).
Patients with SCD with increased tricuspid regurgitant jet velocity have restrictive physiology
High TRV correlates with increased PAP and increased mortality in adults with SCD (2), postulated to be the result of pulmonary arterial endothelial dysfunction secondary to intravascular hemolysis (15). However, restrictive physiology also increases PAP and TRV secondary to increased LA pressure (16). To determine the relationship between diastolic function and TRV in this population, we compared 2 subgroups on the basis of TRV. Patients with SCD with TRV ≥2.5 m/s in our cohort had significantly larger left atrium than patients with TRV <2.5 m/s (p = 0.03 for LAV and p = 0.002 for LAD) (Table 3). They also had a higher A-wave z-score, which reflects the LA-LV pressure gradient during late diastole and is affected by LV compliance and LA contraction (11). The group with TRV ≥2.5 m/s also had significantly higher lateral E/e′ and lower septal e′/a′ ratios. Septal e′/a′ ratio has been reported to be abnormal and an independent predictor of mortality in SCD (7). The group with TRV ≥2.5 m/s had numerically higher reticulocytes, leukocytes, platelets, lactate dehydrogenase, and bilirubin levels and lower hemoglobin concentrations, but these differences were not statistically significant. Although systolic function was normal in both groups, the echocardiographic estimate of LV filling pressure, lateral E/e′, was significantly associated with TRV and LAV z-score but not with LVED z-score or LVMi (Figures 2A and 2B, Online Figure 2, Online Table 2); this finding indicates that patients with TRV ≥ 2.5 m/s have features of restrictive physiology.
Next, we examined whether the association among LAV, diastolic dysfunction, and TRV is also observed with LVED or LVMi, which are directly related to anemia (17,18). As anticipated, LAV z-score, LVED z-score, and LVMi were associated with the degree of anemia, reticulocyte count, lactate dehydrogenase, and bilirubin values (Table 4). However, high TRV and the diastolic measures E and lateral E/e′ were associated only with LAV z-score and not with LVED z-score or LVMi (Table 4, Figures 2A and 2B). Together, the association of TRV, LAV, and diastolic dysfunction strongly suggests distinct SCD-related cardiomyopathy with restrictive physiology superimposed on anemia-related high-output cardiac physiology. Although it is unlikely, chronic anemia may be contributing to the degree of LA enlargement; however, in the typical patient with significant anemia, a dilated left ventricle is common (because of the high-output state), but LA dilation without mitral regurgitation is rare.
Meta-analysis data support cardiomyopathy with restrictive physiology in SCD
To corroborate our findings, we conducted a meta-analysis of the published echocardiographic, CMR, and cardiac catheterization data in patients with SCD. We identified 108 manuscripts for full text review, of which 68 manuscripts were included. Details of meta-analysis article selection and the list of the studies included are provided in Online Figure 1 and in the Online References.
The WM TRV in patients with SCD in 12 studies was 2.34 m/s (95% confidence interval [CI]: 2.25 to 2.42 m/s) (Figure 3A) (Online Ref. 8,16,22,27,32–39). Although TRV was associated with PH in SCD, the validity of using TRV as a surrogate measure for PH was not supported by hemodynamic data in some reports (3,19,20). RHC is the gold standard to diagnose PH. In 4 studies that performed RHC on almost all patients with SCD with TRV ≥2.5 m/s, only 53 of 173 patients (31%) had confirmed PH (mean PAP ≥25 mm Hg) (Figure 3B) (Online Ref. 38,64–66). Thirty-two of these 53 patients with PH (60%) had pulmonary venous hypertension (PVH) defined by pulmonary capillary wedge pressure >15 mm Hg, whereas 40% had pulmonary arterial hypertension (PAH).
In patients with RHC-confirmed PH, the WM values for mean PAP, systolic PAP, diastolic PAP, and pulmonary vascular resistance were 33.8 mm Hg (range 30 to 42 mm Hg), 41.9 mm Hg (range 41 to 58 mm Hg), 23.3 mm Hg (range 19 to 26 mm Hg), and 159.2 dyn·s/cm5 (range 137.6 to 300 dyn·s/cm5), respectively (Online Ref. 38,64–70). These hemodynamic values are remarkably lower than those seen in idiopathic PH (21). Despite the high prevalence of PVH among patients with catheter-confirmed PH, cardiac output was normal to high (WM 8.4 l/min [range 7.2 to 10.4 l/min]) in both PAH-affected and PVH-affected patients. Diastolic dysfunction, a common cause of PVH (22), was prevalent in 11% to 77% of patients with SCD, depending on the criteria used to define diastolic dysfunction in each study. Despite this variability, nearly all (24 of 26) studies found evidence of diastolic dysfunction in SCD (Online Table 3, Online Ref. 6–31), similar to our younger cohort.
LA enlargement was another common and concordant finding between our data and the meta-analysis. WMD of LAD between patients with SCD and controls in 10 studies was 0.57 cm (95% CI: 0.40 to 0.74 cm) (Figure 3C) (Online Ref. 9,12,13,21,23,30,35,41,43,44). Even in the studies excluded because they lacked quantitative data or used different measures for LA size, LA size was consistently larger in patients with SCD compared with controls (Online Ref. 6–8,16,22,24,26-28,31,40,42,45–47). LA dilation was also seen on electrocardiography (Online Ref. 13,26,52).
Systolic function was normal in the meta-analysis, with a WM SF of 36.7% (95% CI: 35.4% to 38.1%) (Figure 3D) (Online Ref. 10,12–14,16,18,19,23,24,29,42,46,47,49,52,58,62,63). A similar finding was observed in studies that used other systolic measures, ejection fraction, and stroke volume index (Online Figures 3 and 4). LVED was larger in patients with SCD than in controls in the meta-analysis. WMD for LVED was 0.46 cm (95% CI: 0.35 to 0.56 cm) (Figure 3E) (Online Ref. 6,8–10,12,13,21,23,24,28–30,41,43,52). The degree of LV enlargement in this meta-analysis was greater than measured in our younger cohort.
To address the heterogeneity in meta-analysis results we conducted a meta-regression using the following pre-defined variables: age, hemoglobin, date of publication, and origin of study (United States or international). These variables were significant in a multivariate model that combines all factors, but not univariately, for LAD and TRV. This model was not significant for LVED or SF. The p values for heterogeneity after accounting for these factors were 0.16 and 0.002 for WMD LAD and WM TRV, respectively, findings suggesting that other factors contribute the heterogeneity observed in TRV results (Online Figure 5).
In summary, our single-institution data and the meta-analysis support the existence of a unique form of cardiomyopathy with restrictive physiology in patients with SCD. As in other forms of RCM, the defining features are diastolic dysfunction, LA enlargement, and normal systolic function. The standard definition of RCM excludes ventricular dilation to differentiate it from dilated cardiomyopathy; therefore, the SCD-related cardiomyopathy with restrictive physiology does not meet the classic definition of RCM. However, in SCD the LV enlargement results from the anemia-related hyperdynamic circulation, and unlike in dilated cardiomyopathy in which systolic function is decreased, systolic function in SCD is normal. The standard definitions do not account for this distinction. The cardiomyopathy of SCD, therefore, is best characterized as restrictive physiology with superimposed hyperdynamic circulation. This RCM can explain the mild, secondary elevations in PAP and TRV observed in SCD, unlike the severely increased PAP seen in primary PAH. Other forms of RCM are associated with sudden death, especially in times of stress, despite normal or mildly elevated pulmonary pressure. As such, a unique SCD-related cardiomyopathy with restrictive physiology and superimposed hyperdynamic circulation is a unifying explanation for the echocardiographic findings, normal or mildly increased pulmonary pressures (and TRV), and the association with early, sudden death.
There is a smaller, separate subgroup of patients with SCD (∼3% to 4%) who have PAH explained by primary pulmonary arterial vascular disease, evidenced, for example, by pulmonary arterial plexiform lesions on autopsy specimens (23), and plausibly explained by hemolysis-related endothelial dysfunction (15). However, it is not a parsimonious explanation for the broader constellation of features that is better explained by a unique SCD-related form of cardiomyopathy with restrictive physiology and secondary, mild elevations in pulmonary pressures resulting from PVH.
The use and applicability of adult diastolic heart failure grading guidelines (11) have not been validated in pediatrics. Indeed, many patients with overt RCM were missed when the current guidelines were used to classify their diastolic dysfunction (24). In addition, there is high discordance among different parameters and poor interobserver agreement in pediatric and adult studies (24,25). Different criteria are likely needed to diagnose and grade diastolic dysfunction in pediatrics. Although grade III/IV or “restrictive” diastolic dysfunction grades were not common in our study, abnormal diastolic function measures were prevalent in our cohort and in the meta-analysis. Diastolic dysfunction and LA enlargement with normal systolic function are seen in nearly every SCD study.
Diastolic dysfunction is an independent risk factor for early death in SCD (7,8). In our patients, diastolic dysfunction was associated with LA dilation, which was the most severely and disproportionately enlarged heart chamber. Our data are consistent with previous pediatric studies that showed LA dilation to be more common in young patients with SCD than enlargement of other chambers (26–29). This finding suggests that LA enlargement precedes enlargement of other chambers in SCD. In addition, LV dilation and LV hypertrophy are known adaptive responses to anemia (18), and these conditions worsen over time in SCD (17,28,30). Thus, LVED enlargement and LVH were more noticeable in meta-analysis results, compared with our data from a younger cohort of patients with SCD than in most studies in the meta-analysis. A recent publication described 4-chamber dilation, normal systolic function, and diastolic dysfunction in adults with SCD (31), contrasting with our data in a much younger cohort with milder anemia. With increasing age, LV dilation and LV hypertrophy are expected to worsen, resulting in progressive 4-chamber dilatation. In a recent meta-analysis of systolic function in SCD, LV systolic function was normal in patients with SCD, although they had progressive LV dilation over time (32). Together, our data and these studies (31,32) suggest that LA dilation precedes pan-chamber dilation. Indeed, it was these characteristics of our patient population that allowed us to identify the features of cardiomyopathy with restrictive physiology that would otherwise be masked by enlarged ventricles in older patients.
We observed a strong correlation between the features of SCD-related cardiomyopathy with restrictive physiology (LA enlargement and diastolic dysfunction) and TRV. The accuracy of defining PH using TRV in SCD has been challenged (3,19,20). Our meta-analysis also confirms these reports and shows that only 12% of patients with SCD with TRV ≥2.5 m/s have PAH. Importantly, most patients with catheter-confirmed PH were found to have PVH, which may be secondary to restrictive physiology. Recently, Sharma et al. (33) showed that pulmonary capillary wedge pressure overestimates PAH in SCD and that the real prevalence of PVH may even be higher in patients with SCD and PH. The typical RCM results in increased LA filling pressures, eventually causing PVH. This is another similarity between SCD-related cardiomyopathy with restrictive physiology and primary RCM (14,34). In addition, the strong association among TRV, LAV, and lateral E/e′, which was also noted in our systematic review (4–8,29), further supports that high TRV in SCD is best considered a marker of cardiomyopathy that predicts mortality and reduced exercise capacity (2,4,20), rather than primary pulmonary arterial pathophysiology.
Another notable similarity between patients with SCD and patients with primary RCM are the high incidences of cardiac mortality and sudden death, known characteristics of RCM, in which LA dilation has been correlated with worse outcome (35–37). Sudden death has been reported in about 30% of patients with SCD (38,39). The modestly elevated PAP and the mild PH do not directly explain the increased mortality and sudden death rates in SCD (1). Ischemic injuries to the conduction system, fibrosis, and extensive chamber dilation have been suggested as potential causes of for arrhythmia in RCM (36), and they could also be the causes of sudden cardiac death in SCD. Indeed, ischemic injury of the conduction system (40) and fibrotic and pulmonary vascular changes are also seen in autopsies in patients with primary RCM (35) and SCD (31,41,42).
The cause of diastolic dysfunction in SCD is not established. Myocardial fibrosis may be a potential mechanism underlying the restrictive physiology seen in SCD. CMR studies have been inconsistent in detecting the extent of fibrosis in SCD, and microscopic fibrosis, in particular, has not yet been well studied. Most studies have shown small degrees of LV focal fibrosis (31,43–45). Fibrosis was described in autopsy studies in SCD without atherosclerosis (40–42,46). In addition, multiple known profibrotic pathways and signals have been shown to be dysregulated in SCD (47–49). Polymorphisms in the profibrotic transforming growth factor-β signaling pathway genes have been associated with elevated TRV in SCD (50). This finding suggests that ventricular stiffness secondary to fibrosis may contribute to the underlying SCD-related cardiomyopathy with restrictive physiology.
We recognize the limitations of our study, including the absence of a control group and the lack of hemodynamic data by RHC. It is not ethical to perform this invasive procedure in asymptomatic children with SCD. It is difficult to find a reasonable number of control patients with the same degree of severe life-long anemia that is not confounded by cardiac iron overload or long-term transfusion therapy. In addition, the cross-sectional nature of the study does not permit tenable inference about the rate of progression of cardiomyopathy in SCD or the specific temporal sequence of events. Meta-analyses also have inherent limitations, which include the assumption that all studies were conducted under similar conditions and with the same level of expertise, as well as heterogeneity among different studies. In our analysis, results remained statistically significant after using a random effects approach. Some studies were excluded from analysis because of missing data; however, the results of the excluded studies were consistent with the quantitative analysis.
Children and adults with SCD develop a unique form of cardiomyopathy that is best characterized as restrictive physiology superimposed on a hyperdynamic state. Over time, the left ventricle enlarges and diastolic dysfunction progresses. This unique cardiomyopathy, like other forms of RCM, can explain the secondary, passive mild elevations in TRV and PAP and is consistent with the high rate of cardiopulmonary mortality and sudden death in SCD. Unraveling the causal mechanisms that produce this unique cardiomyopathy could identify therapies to decrease cardiopulmonary morbidity and early death in SCD.
COMPETENCY IN MEDICAL KNOWLEDGE 1: Patients with SCD are at risk of early death from cardiopulmonary causes. High TRV, diastolic dysfunction, and increased PAP are associated with increased mortality rates in SCD, but the pathophysiology behind these features is not known.
COMPETENCY IN MEDICAL KNOWLEDGE 2: Patients with SCD have features of RCM (diastolic dysfunction, LA enlargement, and normal systolic function) that can lead to PVH and elevated TRV.
TRANSLATIONAL OUTLOOK: More studies are needed to identify the mechanisms that lead to restrictive physiology in SCD. Understanding the pathophysiology of SCD-related cardiomyopathy with restrictive physiology can lead to targeted therapies that prevent or delay cardiac disease in SCD.
The authors thank Dr. Robert J. Fleck for the helpful discussions and comments and Ellen Skalski, RN, BS, BSN for helping in data collection.
For an expanded Methods section with references and supplemental figures and tables, please see the online version of this article.
This work was supported by NIH grant UO1-HL117709. Drs. Malik, Towbin, Quinn, Niss, Taylor, and Bakeer have received an Excellence in Hemoglobinopathies Research Award. Dr. Quinn has received research funding from Novartis, Amgen, MAST Therapeutics, and Eli Lilly. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Malik and Taylor are joint senior authors.
- Abbreviations and Acronyms
- mitral valve annular velocity in early diastole
- left atrial
- left atrial diameter
- left atrial volume
- left ventricular
- left ventricular end-diastolic diameter
- indexed left ventricular mass
- pulmonary arterial hypertension
- pulmonary arterial pressure
- pulmonary hypertension
- pulmonary venous hypertension
- restrictive cardiomyopathy
- right-sided heart catheterization
- sickle cell disease
- shortening fraction
- tricuspid regurgitant jet velocity
- weighted mean
- weighted mean difference
- Received April 22, 2015.
- Accepted May 21, 2015.
- American College of Cardiology Foundation
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