CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Vandana Sachdev, MD*,
Roberto F. Machado, MD,
William C. Blackwelder, PhD,
Gregory J. Kato, MD and
Mark T. Gladwin, MD
* Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892 (Email: sachdevv{at}nhlbi.nih.gov).
We appreciate the important information presented by Dr. Ntim and colleagues in reference to our report on diastolic dysfunction in sickle cell disease (SCD) patients. They suggest that renal insufficiency in our cohort may have been underestimated by using absolute serum creatinine levels instead of creatinine clearance. We have found in our sickle cell patient cohort that absolute creatinine levels correlate well with estimated creatinine clearance using the Modification of Diet in Renal Disease (MDRD) study equation and Cockgroft-Galt (CG) formulas (Spearman 
= –0.91, p < 0.0001 and = –0.71, p < 0.0001, respectively). Indeed, renal disease characterized by any of these measures is an important risk factor in the SCD population, and we reported in our initial study (1) that, "besides the tricuspid regurgitant jet velocity, the only significant univariate correlate of the risk of death was the creatinine level (p = 0.007)." In the present study (2), we found a good correlation between the creatinine level and the E/A ratio ( = –0.46; p < 0.0001); however, the E/A ratio remained significantly associated with mortality after adjustment for log10 creatinine. Similarly, when we adjusted for the MDRD GFR and CG GFR, the E/A ratio remained significantly associated with mortality (p = 0.0001 and p = 0.0002, respectively).
Although our study shows evidence of diastolic dysfunction in the SCD population, the etiology of this is likely to be multifactorial and may include relative systemic hypertension, microvascular vaso-occlusive disease, and iron overload. The presence of iron in the myocardium can be detected by advanced imaging techniques, including tissue Doppler echocardiography (3) and magnetic resonance imaging (4). We certainly agree that more accurate population-based measures of iron burden would be of great value to this field of research.
Dr. Ntim and colleagues cite reports of narcotic use being associated with prolonged QT and arrhythmic events. This is an interesting observation that requires follow-up, because the proximate cause of death in many SCD patients remains unknown. This being said, it is important to note that many of our patients with severe pulmonary hypertension and high hemolytic rate manifest a low frequency of vaso-occlusive crisis and many rarely use narcotics. This is consistent with the observation that patients with hemolytic anemia secondary to thalassemia and other hereditary hemolytic conditions develop pulmonary hypertension but do not have hemoglobin S or vaso-occlusive pain crises. We have suggested a paradigm in which hemolytic anemia leads to distinct complications associated with low nitric oxide bioavailability and vasculopathy, including priapism, cutaneous leg ulcerations, sudden death, and pulmonary hypertension (5). In contrast, high steady-state hemoglobin and leukocytosis are risk factors for frequency of vaso-occlusive pain crisis, acute chest syndrome, and increased narcotic usage.
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References
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- Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease N Engl J Med 2004;350:886-895.[Abstract/Free Full Text]
- Sachdev V, Machado RF, Shizukuda Y, et al. Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease J Am Coll Cardiol 2007;49:472-479.[Abstract/Free Full Text]
- Vogel M, Anderson LJ, Holden S, Deanfield JE, Pennell DJ, Walker JM. Tissue Doppler echocardiography in patients with thalassaemia detects early myocardial dysfunction related to myocardial iron overload Eur Heart J 2003;24:113-119.[Abstract/Free Full Text]
- Voskaridou E, Douskou M, Terpos E, et al. Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease Br J Haematol 2004;126:736-742.[CrossRef][ISI][Medline]
- Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes Blood Rev 2007;21:37-47.[CrossRef][ISI][Medline]
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