Sickle cell disease is one of the most prevalent genetic diseases worldwide; affecting 1/400 individuals of African descent as well as people of Arab, Indian and Hispanic descents.1-3 Abnormalities of cardiovascular function have increasingly been documented in sickle cell disease patients. Reports from several clinical studies in recent times have drawn attention to some ‘emerging’ cardiac pathologies in sickle cell disease and their potentially negative impact on cardiovascular function in these patients. Among these include myocardial infarction without coronary artery disease, pulmonary hypertension and cor pulmonale.4-7 Moreover, sudden unexpected death has become increasingly recognised as an important clinical feature of both the homozygous and heterozygous sickling syndromes; although the exact nature and its cause has remained unexplained.8-10
The emergence of cardiac complications in sickle cell disease patients could be attributed to the increasing life expectancy observed in these patients. Recent data indicates that 86 to 90% of patients survive to beyond 20 years of age.11 With the continued development of improved management and supportive care for patients with sickle cell anaemia and the resultant increase in life span, the spectrum of cardiac dysfunction is likely to enlarge in the future.
The mechanism underlying cardiac dysfunction in sickle cell anaemia has been extensively studied and multiple mechanisms have been proposed. In addition to the impaired microvascular circulation from intravascular plugs of sickled erythrocytes, other contributory factors include: extensive fibromuscular dysplastic narrowing of small cardiac arteries, non-inflammatory focal degeneration and apoptosis, platelet abnormalities or similar stimuli for endothelial and smooth muscle proliferation.12-14 The hyperkinetic circulation as a result of chronic anaemia contributes to eccentric ventricular hypertrophy and cardiomegaly, and the severity of cardiac chamber dilatation progresses with increasing anaemia.5,15 Despite myocardial remodelling/hypertrophy, the patients have increased myocardial wall stress as well as impaired ventricular relaxation.16
Data from clinical studies evaluating left ventricular systolic function using load-independent measures of myocardial contractility have revealed significant systolic dysfunction in sickle cell anaemia patients.17,18 The development of left ventricular systolic and/or diastolic dysfunction in sickle cell anaemia is associated with increased morbidity and mortality.19 There is a large body of evidence showing that diastolic dysfunction in sickle cell disease contributes to pulmonary hypertension and represents an independent predictor of mortality in these patients.19
It has been recognised that ischaemic phenomena associated with sickle cell anaemia could elicit morphological and functional abnormalities in the cardiac conducting system, resulting in paroxysmal arrhythmia and could further worsen the ventricular dysfunction.5 Such electrical instability induced by myocardial ischaemia has been postulated to be the cause of sudden cardiac death in patients with sickle cell disease.5,10
In the presence of left ventricular diastolic dysfunction, atrial fibrillation and indeed any form of arrhythmia causes significant cardiac decompensation. Atrial fibrillation in sickle cell disease is believed to be due to increase in atrial size with accompanying advanced atrial remodelling and profound global electrophysiological changes in refractoriness. Additional factors affecting atrial refractoriness include autonomic impairment, scars, and changes in the cellular membrane function.20 Several non-invasive electrocardiographic indicators have been investigated to predict the occurrence of arrhythmia in left ventricular diastolic dysfunction. On a 12-lead surface electrocardiogram, P-wave dispersion, because of its relationship to the non-homogenous and interrupted conduction of sinus impulses both intra- and interatrially, is recognised as a non-invasive marker of risk of atrial fibrillation.21
In the light of this, one pertinent question needs to be addressed: what is the clinical utility of P-wave dispersion in sickle cell anaemia? A step towards unravelling this puzzle would involve the examination of the relationship between P-wave dispersion and measures of left ventricular function in sickle cell anaemia patients, and the comparison of the indices with those of appropriately matched controls. In this connection, the article in this issue, ‘P-wave dispersion: relationship to left ventricular function in sickle cell anaemia’ is of relevance. The authors showed that P-wave duration and P-wave dispersion were significantly increased in sickle cell anaemia and that P-wave dispersion had a negative correlation with indices of left ventricular diastolic function. This novel study provides an interesting insight into the potential value of this simple electrocardiographic tool in the evaluation of ventricular function in sickle cell anaemia. This is especially useful in resource-limited areas of developing countries where access to modern investigative modalities is lacking. Major challenges in the use of this tool are the difficulty in standardisation of methods and the lack of acceptable normal limits of P-wave dispersion in the general population.
It is expected that this pilot study will stimulate further research efforts to determine the diagnostic/normal cut-off values, and specificity and sensitivity, as well as the long-term prognostic significance of increased P-wave dispersion in sickle cell disease.
References
- 1.Ronald LN. Origins and dispersion of sickle cell gene. In: Embury SH, Hebbel RP, Mohandes N, Steinberg MH, editors. Sickle Cell Disease: Basic Principles and Practice. 4th edn. New York: Raven Press; 1994. pp. 353–377. [Google Scholar]
- 2.Hickman M, Modell B, Green Gross P. Mapping the prevalence of sickle cell and thalassaemia in England: Estimating and validating ethnicspecific rates. Br J Haematol. 1999;104:860–867. doi: 10.1046/j.1365-2141.1999.01275.x. [DOI] [PubMed] [Google Scholar]
- 3.Serjeant GR, Serjeant BE, Forbes M, Hayes RJ, Higgs DR, Lehman H. Haemoglobin gene frequencies in the Jamaican population: a study of 100,000 newborns. Br J Haematol. 1986;64:253–262. doi: 10.1111/j.1365-2141.1986.tb04117.x. [DOI] [PubMed] [Google Scholar]
- 4.Mc Cormick WK. Massive nonatherosclerotic myocardial infarction in sickle cell anaemia. Am J Forensic Med Pathol. 1988;9:151–154. doi: 10.1097/00000433-198806000-00012. [DOI] [PubMed] [Google Scholar]
- 5.Gerry J, Bukley B, Hutchins G. Clinicopathological analysis of cardiac dysfunction in 52 patients with sickle cell anaemia. Am J Cardiol. 1978;42:211–216. doi: 10.1016/0002-9149(78)90902-5. [DOI] [PubMed] [Google Scholar]
- 6.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. doi: 10.1056/NEJMoa035477. [DOI] [PubMed] [Google Scholar]
- 7.Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale in the sickle haemoglobinopathies. Am J Med. 1982;73:814–821. doi: 10.1016/0002-9343(82)90763-x. [DOI] [PubMed] [Google Scholar]
- 8.Kart JA, Coffey SE, Estella E, Robinowitz M, Posey DM, Virmani R. Comparison of sudden death syndromes with and without sickle cell trait. Blood. 1989;74(suppl 1):62. [Google Scholar]
- 9.Liesner RT, Vandenberghe EA. Sudden death in sickle cell disease. J R Soc Med. 1993;86:484–485. doi: 10.1177/014107689308600822. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.James TN, Riddick L, Massing GK. Sickle cells and sudden death: morphologic abnormalities of the cardiac conducting system. J Lab Clin Med. 1994;124:507–520. [PubMed] [Google Scholar]
- 11.Platt OS, Brambilla OJ, Rosse WF. et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Eng J Med. 1994;330:1639–1644. doi: 10.1056/NEJM199406093302303. [DOI] [PubMed] [Google Scholar]
- 12.Keiden AJ, Sowter MC, Johnson CS, Noguchi CT, Girling AJ, Steven SME, Stuart J. Effect of polymerization tendency on haematological, rheological and clinical parameters in sickle cell anaemia. Br J Haematol. 1989;71:551–557. doi: 10.1111/j.1365-2141.1989.tb06316.x. [DOI] [PubMed] [Google Scholar]
- 13.James TN. Morphological characteristics and functional significance of focal fibromuscular dysplasia of small coronary arteries. Am J Cardiol. 1990;65:129–229. doi: 10.1016/0002-9149(90)90954-y. [DOI] [PubMed] [Google Scholar]
- 14.Frenette PS. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Haematol. 2002;9:101–106. doi: 10.1097/00062752-200203000-00003. [DOI] [PubMed] [Google Scholar]
- 15.Balfour IC, Covitz W, Davis H, Rao PS, Strong WB, Alpert BS. Cardiac size and function in children with sickle cell anaemia. Am Heart J. 1984;108:345–350. doi: 10.1016/0002-8703(84)90623-9. [DOI] [PubMed] [Google Scholar]
- 16.Adebayo RA, Balogun MO, Akinola NO, Akintomide AO, Asaleye C.M. Non-invasive assessment of cardiac function in patients with sickle cell anaemia. Trop Cardiol. 2004;30(120):51–55. [Google Scholar]
- 17.Colan SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress – velocity of fibre shortening relation: a load-independent index of myocardial contractility. J Am Coll Cardiol. 1984;4:4715–4724. doi: 10.1016/s0735-1097(84)80397-6. [DOI] [PubMed] [Google Scholar]
- 18.Lamers L, Ensing G, Pignatelli R, Goldberg C, Bezoid L, Ayres N, Gajarski R. Evaluation of left ventricular function in paediatric sickle cell anaemia patients using the end-systolic wall stress-velocity of circumferential fibre shorthening relationship. J Am Coll Cardiol. 2006;47:2283–2288. doi: 10.1016/j.jacc.2006.03.005. [DOI] [PubMed] [Google Scholar]
- 19.Sachdev N, Machido RF, Shizukuda Y, Rao YN, Sidenko S, Ernest I. 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. doi: 10.1016/j.jacc.2006.09.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Connes P, Martin C, Barthelemy JC, Monchanin G, Atchou G, Forsuh A. et al. Nocturnal autonomic nervous system activity impairment in sickle cell trait carriers. Clin Physiol Funct Imaging. 2006;26:87–91. doi: 10.1111/j.1475-097X.2006.00655.x. [DOI] [PubMed] [Google Scholar]
- 21.Dilaveris PE, Gialafos EJ, Andrikopoulos GK, Richter DJ, Papanikolaou V, Poralis K, Gialafos JE. Clinical and electrocardographic predictors of recurrent atrial fibrillation. Pacing Clin Electrophysiol. 2000;23:352–358. doi: 10.1111/j.1540-8159.2000.tb06761.x. [DOI] [PubMed] [Google Scholar]