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�%C&0s&�$R�*���*&%�*?&%dZZ� ZZZZZ�%�%� ZZZs&ZZZZ���������������������������������������������������������������������*ZZZZZZZZZ�	�:	TITLE:	Cardiovascular system abnormalities in sickle cell anaemia: clinical findings in steady state adult Nigerian patients.
AUTHORS:	*N.I. Oguanobi. MBBS, MSc, FWACP, FMCP. 
*B.J.C. Onwubere. MBBS, Dip.(Cardiol.), FWACP, FMCP. 
*E. C. Ejim. MBBS, FMCP.
**O.G. Ibegbulam. MBBS, FWACP
*S.O. Ike. MBBS, FMCP.
**O. Agwu. MBBS. 
ADDRESS:	*Department of Medicine, **Department of Haematology, University of Nigeria Teaching Hospital Enugu, Nigeria.

RUNNING TITLE: Clinical findings in steady state adult sickle cell anaemia.
Correspondence:	Dr. Nelson I Oguanobi
Department of Medicine, Federal Medical Centre, Asaba. Delta state. Nigeria.
Email:		nelifyik@yahoo.com
Abstract.
Aim and objective:
This study was aimed at examining the cardiovascular clinical features in steady state adult Nigerian sickle cell anaemia patients.
Method:
 	The study subjects were drawn from adult patients (age e"18 years), attending the adult sickle cell clinics who had haemoglobin genotype SS on haemoglobin electrophoresis and were in steady state. Age and sex matched normal subjects served as controls. All subjects were evaluated for symptomatology of cardiovascular disease with the aid of a questionnaire and then clinically examined to evaluate their cardiovascular status at rest. 
Result:
Significant increase in pulse rate was found in the study subjects (87.68 EMBED Equation.3 8.91/minute) compared with the controls (72.13 EMBED Equation.3 6.79/minute); {p < 0.05,}. The mean systolic blood pressure was comparable in the two groups. However the patients had significantly lower diastolic blood pressure, lower mean arterial blood pressure, as well as a higher pulse pressure than the control subjects. Abnormal physical findings found in the study group include loud pulmonary component of the second heart sound (83.3%), displaced cardiac apex (70.0%) and active precordium (43.3%) and radiologic evidence of cardiomegaly (cardiothoracic ratio {CTR} > 0.5) 86.67%. 
Conclusion:
	The haemodynamic response to chronic anaemia in sickle cell anaemia results in significant cardiovascular dysfunction.
Key words
Cardiovascular system abnormalities, sickle cell anaemia, clinical findings.










Introduction
	Cardiovascular system abnormalities are prominent features of sickle cell anaemia, and these have been thought to result from the cardiovascular effect of chronic anaemia seen in sickle cell disease1 as well as vascular occlusion by sickled red blood cells and micro-vascular sludging2. The effect of chronic anaemia and intravascular sickling combine to present significant findings on examination of the cardiovascular system3. Signs reflecting hyperdynamic circulatory states are found. Sinus tachycardia occurred in 27% of steady state adult patients studied by Uzzoy4. Heart rates were significantly higher in patients with history of dyspnoea or fatigue than in asymptomatic patients5.  In a study in Kenya of 52 sickle cell anaemia patients the mean heart rate was significantly lower in patients with haemoglobin level of 8.0-9.9 g/dl compared with patients with lower haemoglobin levels indicating that it is related to the cardiovascular response to anaemia6.  The blood pressure is typically low in sickle cell anaemia and fails to show the age related rise common in normal population7,8.  A thrill in the suprasternal notch was noted in 15(45%) by Ng et al9 and was significantly more common in children with low haemoglobin levels. Accentuation of the pulmonary component of the second heart sound is common and does not seem to correlate with the presence of pulmonary hypertension10. These signs probably result from a pulmonary artery dilatation as a consequence of increased pulmonary blood flow, palpated more readily because of a thin chest wall11 . Mid diastolic flow murmurs, particularly mitral were noted in 36% of children by Ng et al and were significantly more frequent in patients with low haemoglobin levels9. Patients without audible murmurs tend to be those without cardiomegaly and with high haemoglobin levels.
Most of the previous studies on clinical features in sickle cell anaemia were carried out on children between the ages of 2-17years. However with the continual development of better supportive care for patients with sickle cell anaemia, and the resultant increase in life span there could be a change in the pattern of cardiac manifestation in sickle cell anaemia over the years.
	This study was aimed at examining the cardiovascular clinical features in steady state adult Nigerian sickle cell anaemia patients.










Methodology
     The study was carried out in the adult out patient sickle cell clinics and the cardiac center of the University of Nigeria Teaching Hospital (UNTH) Enugu, Nigeria. The study subjects were drawn from adult patients (age e"18 years)12, attending the adult sickle cell clinics of the UNTH Enugu, who had haemoglobin genotype SS on haemoglobin electrophoresis, were in steady state and consented to participate in the study.
Steady state is defined as absence of any crisis or blood transfusion in the preceding four weeks, absence of any symptoms or signs attributable to acute illness. A total  of sixty two sickle cell anaemia patients and sixty two age and sex matched normal controls were studied. All subjects were evaluated for symptomatology of cardiovascular disease with the aid of a questionnaire and then clinically examined to evaluate their cardiovascular status at rest. The weight and height of each subject were recorded and the surface area determined from a standard formula13. All the patients had posterior � anterior chest X-ray examination. 
Data were presented as means � standard deviation for continuous variables and as proportions for categorical variables. Comparison of continuous variables between groups were made with independent Student�s  t-test. For discrete variables distribution between groups were compared with Chi- square test and Fishers exact test as appropriate (where an expected cell is less than 5). In order to examine the effect of anaemia on the variables, the subjects were classified based on the haematocrit values into four classes in accordance with the World Health Organization classification of anaemia as follows:- Class 1; normal (haematocrit e" 36%), Class 2; mild anaemia (haematocrit 30-35.9%), Class 3; moderate anaemia (haematocrit 21 - 29.9%), Class 4; severe anaemia (haematocrit 18-20.9%)14. Inter-class differences in clinical parameters in the patients were compared by one-way analysis of variance and post hoc multiple comparison of mean using the Tukey�s honestly significant difference test. All statistical analyses were carried out using the Statistical Packages for Social Sciences (SPSS Inc. Chicago Illinois) software version 11.0. Statistical tests with probability values less than 0.05 were considered statistically significant.











Results
Age and gender distribution 
A total of sixty two sickle cell anaemia patients (31 males, 31 females) and sixty two normal controls matched for age and sex were studied. All the patients were homozygous for the sickle cell gene on haemoglobin electrophoresis, while all the controls had haemoglobin genotype AA. The age and sex distribution of the subjects are shown in table 1. The mean ages for patients and controls were 28.27�5.58 ( range 18 - 44) and 28.37�5.91 (range 18 � 45 ) years respectively. There were no statistically significant age and gender differences in patients and controls. 
Anthropometric data and physiologic variables
	The study subjects had statistically significant lower mean values than controls in the measurement of height, weight, body mass index, and body surface area.{P( 0.001} (table 1). Significant increase in pulse rate was found in the study subjects (87.68 EMBED Equation.3 8.91) compared with the controls (72.13 EMBED Equation.3 6.79); {p < 0.05,}. The mean systolic blood pressure was comparable in the two groups. However the patients had significantly lower diastolic blood pressure (64.87EMBED Equation.38.95; 76.88 EMBED Equation.3 6.18 mmHg), lower mean arterial blood pressure (81.18 EMBED Equation.3 12.65; 91.71 EMBED Equation.3 5.47mmHg), as well as a higher pulse pressure than the control subjects ( 54.63 EMBED Equation.3 12.87; 44.31 EMBED Equation.3 10.91 mmHg), {table 2}.   

Haematocrit values in patients and controls
	The mean haematocrit values were 24.07�3.10%; (range 20 � 31.3% )  for the patients and 38.65�1.97%;(range 30 - 42%) for the controls. The mean haematocrit values was significantly lower in patients than controls (t= 30.589; P= 0.001 ).
	The patients and controls were categorized into four groups based on the haematocrit values (table 3). Fifteen percent of the patients and 18.33% of the controls had haematocrit values between 30 and 35.9%.  Sixty seven percent of the patients had haematocrit values between 21 and 29.9%, while 81.67% of the controls had haemotocrit values above 36%.
Clinical findings 
Clinical findings in patients and controls	
 	Abnormal physical findings found in the subjects are summarized in table 4. Notable features in the study group include loud pulmonary component of the second heart sound (83.3%), displaced cardiac apex (70.0%) and active precordium (43.3%). 
Clinical findings in patients based on the haematocrit level 
��������� Comparison of the clinical findings in sickle cell anaemia patients with the degree of anaemia showed significant association of leg oedema, right ventricular heave  and increased cardiothoracic ratio with the degree of anaemia, (Table 5).

Discussion
Abnormal cardiovascular physical findings demonstrated by this study in sickle cell anaemia were increased pulse rate, increased pulse pressure, displaced cardiac apex (cardiomegaly), raised JVP, leg oedema, left parasternal heave, loud pulmonary component of second heart sound, and expiratory splitting of second heart sound. 
Blood pressure and pulse pressure
 The brachial systolic blood pressure in sickle cell anaemia patients from this study was not significantly different from that of the controls but the diastolic blood pressure was found to be significantly lower in the patients than in the controls. The significantly lower diastolic blood pressure and increased pulse pressure noted in the patients in this study could be as a result of the haemodynamic effect of chronic anemia. However, increased pulse pressure has been shown to predict cardiac morbidity in studies carried out in diabetic and hypertensive patients15,16.    Its relevance in patients with sickle cell anaemia is yet to be explored.
Leg oedema and jugular venous pulsations.
���������� The finding of leg oedema and raised jugular venous pulsation in 6.67% and 21.7 percent respectively of the patients and none in the controls can be so striking as to suggest congestive heart failure. In many of the cases these signs represent systemic effects of chronic anaemia rather than true congestive heart failure.
��������� In one study, clinical evidence of congestive heart failure was found before death    in 17 patients ( 33%) out of 52 adult sickle cell patients . At autopsy, 7 had moderate to severe left ventricular hypertrophy associated with chronic renal failure and hypertension, 2 had right ventricular hypertrophy with organized pulmonary thrombosis, 2 had rheumatic mitral valve disease and only 2 patients had congestive cardiac failure17. 
It has been suggested that patients with congestive cardiac failure usually have severe coexisting disease secondarily affecting myocardial function rather than a cardiomyopathy specific for sickle cell anaemia17. Although the patients in this study did not have any clinical or biochemical finding suggestive of renal impairment, the possibility of background sickle cell nephropathy cannot be ruled out.  
Leg edema has been shown to precede leg ulcers in sickle cell anaemia18. The occurrence of leg ulcers in 13.33% of the patients in this study may contribute to the significant finding of leg edema in these patients. 
�Heart sounds 
The loud pulmonary component of the second heart heard in 83.3% of the patients may reflect increased flow in the pulmonary vascular bed which is readily auscultated because of their thin chest wall. Tress et al19, in Rio de Janeiro Brazil noted loud pulmonary component of the second heart sound in 75% of patients aged between 6 to 48 years. The slight difference compared with the present finding could be accounted for by the large numbers of relatively younger patients included in the latter study. Increased hemodynamic load in the patients would also explain the widely spit second heart sound heard in the patients.
Cardiomegaly 
��������� Cardiomegaly was found in 70% of patients by clinical assessment (displaced cardiac apex) and in 86.67% of patients by radiology (increased cardiothoracic ratio >0.5). Uzsoy4 found clinical evidence of cardiomegaly in 80% of patients while Ng et al found radiological evidence of cardiomegaly in 85% of patients aged 2 � 17 years9. Cardiomegaly is largely due to sustained increase in hemodynamic circulation with increased cardiac out put. A clinicopathological study in sickle cell patients reported finding of right and left ventricular dilatation in 64% and 44% of patients respectively and biventricular hypertrophy in 36% of patients17. 
The impact of Anaemia 
	The effect of chronic anaemia and the resultant increased volume load and increased cardiac output could, at least in part, explain some of the clinical findings in sickle cell anaemia in this study.  Increased pulse pressure, raised jugular venous pulsation, leg oedema, left parasternal heave and cardiomegaly were significantly found in sickle cell patients in this study.  Subdivision of the patients into three groups based on their haematocrit values identified significant differences in some of these parameters that would suggest progressive deterioration in heart function with increasing degree of anaemia.
	More studies are recommended using patients with chronic anaemia from other causes other than sickle cell anaemia as controls in order to evaluate the role of anaemia and/or sickling in the pathogenesis of the cardiac changes seen in sickle cell anaemia.  













References
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