Increased Heart Rate and Steady State Among Sickle Cell Patients Seen in Sokoto, North-West Nigeria

Greener Journal of Human Physiology and Anatomy

Vol. 3(1), pp. 01-10, 2021

ISSN: 2354-2314

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Increased Heart Rate and Steady State Among Sickle Cell Patients Seen in Sokoto, North-West Nigeria

¹Michael I. Ikedue; ²Frank B.O. Mojiminiyi; ³Muhammad A. Ndakotsu; ⁴Simeon A. Isezuo; ⁵Adamu J. Bamaiyi

¹MSc, Department of Physiology. Usmanu Danfodiyo University, Sokoto, Nigeria.

²PhD, Professor, Department of Physiology, Usmanu Danfodiyo University, Sokoto, Nigeria.

³MBBS, FMCPath, Associate Professor of Haematology and Consultant Haematologist Haematology Department, Usmanu Danfodiyo University, Sokoto, Nigeria.

⁴MBBS, FMCP, Professor of Medicine and Consultant Cardiologist, Internal Medicine Department, Usmanu Danfodiyo University, Sokoto, Nigeria.

⁵MBBS, PhD, Senior Lecturer, Department of Physiology, Usmanu Danfodiyo University, Sokoto, Nigeria.

ARTICLE INFO

ABSTRACT

Article No.: 071021064

Type: Research

Background: Sickle cell anaemia (SCA) remains a major cause of morbidity and mortality among patients homozygous for the traits. However, some patients homozygous for the disease do not have vaso-occlusive crisis as much as others, and the reason for this is not yet clear.

Objectives: The present study aimed to assess haemodynamic and haematological parameters among adult SCA patients (with crisis or in steady state) attending clinics and compared same with normal adults.

Methods: One hundred and six consenting consecutive subjects were recruited under the groups; Steady (n = 53) or Crisis (n = 53) and compared the results with 40 apparently healthy genotype AA adults.

Results: We report that, the steady group, has significantly less Packed cell volume (PCV) compared to the normal group (27.39 ±4.36% Vs 33.44 ±1.80%, p <0.00005), but showed higher values of PCV compared to the crisis group (27.39 ±4.36% Vs 25.67 ± 4.23%, p <0.0422). The steady group compared to the crisis group, also demonstrated enhanced heart rate (HR) (84.19 ± 16.53 bpm Vs 78.96 ± 15.90 bpm, p = 0.019) and longer QTc (429.00 ± 37. 33 Vs 416.15 ±35.10, p = 0.0060).

Conclusions: Enhanced HR, rate pressure product (RPP) and optimum systolic phase of the cardiac cycle (QTc) in the steady state sub-group, may result in better ventricular functions and cardiac output. Therefore, whole blood or intravenous fluid infusion in SCA patients may improve the chronotropic and inotropic properties of the heart, enhance tissue perfusion and oxygen delivery that will help reduce crisis in the patients.

Accepted: 15/07/2021

Published: 31/07/2021

*Corresponding Author

Dr Adamu Jibril Bamaiyi

E-mail: adamu,jibril @udusok.edu,ng; abamaiyi@ yahoo.com

Phone: +2348030925695

Keywords: Sickle cell anaemia; Homozygous trait; Vaso-occlusive crisis; Steady state; Heart rate; Whole blood; Intravenous infusion; Cardiac output; Inotropic; Chronotropic

ABBREVIATIONS

BMI = Body Mass Index, SBP= Systolic Blood Pressure, PP= Pulse Pressure, HR = Heart Rate, PRP = pressure reference point, HbSS = Sickled cell haemoglobin, SO₂ = Percentage Oxygen Saturation, PCV = Packed Cell Volume, VOC = Vaso-occlusive crisis, P-R = P-R interval, QT = QT interval, QTc= QT corrected for heart rate, ISC = Irreversible sickled cell, RPP = Rate pressure product, SCA = Sickle cell anaemia, ECG = Electrocardiogram, UDUTH = Usmanu Danfodiyo University Teaching Hospital, AHA = American Heart Association, LAE = Left atrial enlargement, RAE = Right atrial enlargement, LVH = Left ventricular hypertrophy, RVH = Right ventricular hypertrophy, BBB = Bundle branch block, Na-EDTA = Sodium - ethylene diaminetetra acetic acid, HIV= Human immunodeficiency virus, Kg = Kilogramme, cm = Centimetre, m² = squared metres,

INTRODUCTION

Sickle cell anaemia (SCA) is still the largest hereditary haemoglobinopathy in the world (1, 2). With Africa, especially Nigeria having the highest burden globally (2-4). And in terms of mortality, about 10% - 14% of the patients do not live beyond 20 years (5) and by the fifth decade of life about half of their population might have died (5). However, not all SCA patients come down with complications or crisis, even though there is no any preferential treatment given to them. Indeed, there is still ambiguity as to the factors that are responsible for this polymorphism among SCA patients (6). In this regard, the electrocardiography of SCA patients have been documented, and some cardiovascular abnormalities in SCA have been reported (5-7). Nevertheless, data is almost non-existent on the haemodynamic features in the SCA category of patients with crisis compared with those without crisis (6, 8).

Hypoxia is also a pathophysiological feature of vaso-occlusive crisis (VOC) in SCA patients (1). Therefore, the rate and volume of blood delivered to the tissue may explain the VOC tendencies in the patients. In the presence of optimum systolic functions, increased HR will result in improved cardiac output and oxygen delivery to tissues will be better. In the present study therefore, we assess in addition to the haematological parameters, some tissues oxygen delivery indices and haemodynamic parameters including blood pressure, heart rate and electrocardiographic features in the patients with crisis, using pulse oximeter and electrocardiograph respectively. The results were compared with those who do not have crisis (steady state) and compared same with normal AA genotype group. The haemodynamic factors that might be conferring crisis-free advantage on the steady state patients, but not the other group were noted.

Subjects, Materials and Methods

Ethical approval with reference UDUTH/HREC/2016/No.428 for the study was obtained from the Ethical Committee of the Usmanu Danfodiyo University Teaching Hospital (UDUTH), Sokoto. Informed consent was obtained from all participants. And the research complied with regulations concerning human research, as enshrined in the Helsinki declaration (9).

It was a cross sectional study that assessed the ECG patterns, blood pressure and some blood parameters of adult SCA patients. This study was carried out in the Hematology outpatient clinic of (UDUTH), Sokoto, North-Western Nigeria. A total of 106 sickle cell anemia (SCA) patients of both sexes were recruited, comprising; a group with crisis (n=53), the group with steady state (n=53), and they were compared with 40 normal (genotype AA) subjects sourced from the hospital environment. The normal subjects were also selected randomly among medical and nursing students, hospital workers and members of the local community who served as controls.

Inclusion criteria

Only SCA patients older than 18 years, confirmed by HbSS genotype by Hb electrophoresis were included in the study. Apparently healthy adults from the same environment were recruited as the normal group.

Exclusion criteria

Excluded in the study sample are, patients with reported leukemia, renal disease, HIV infection, congenital or acquired heart disease, pregnancy, severe anaemia, excessive use of alcohol (more than 16 g daily) (10), and significant use of tobacco.

Definitions

Crisis sub-group: Individuals homozygous for the SCA traits, who had vaso-occlusive crisis (VOC) within the last 4 weeks (11)

Steady sub-group: Individuals homozygous for the SCA traits but had no VOC in the last 4 weeks (11)

Normal group: Apparently healthy individuals who are homozygous for AA genotype

Anthropometric measurements

The weights (Kg) and heights (cm) of participants were measured by standard procedures and the body mass index (BMI, kg/m²) derived from the corresponding weights and heights.

Blood Pressures

Standard procedures were followed in measuring brachial blood pressure, using Accuson mercury sphygmomanometer with an appropriate cuff on the left or right arm. The average of five readings were taken as the Systolic and diastolic blood pressures, respectively at 1^st and 5^th Korotkoff sounds, in sitting position after 5 minutes of rest with the arm at pressure reference point (PRP) and readings taken to the nearest 2mmHg (12).

Radial pulse rate was assessed using standard procedures.

Electrocardiography

Dr. Lee model electrocardiography machine (made in China) at a paper speed of 25mm/s and standardized at 0.1mv/mm was used. The recommendation of the American Heart Association (AHA) (12), were adopted using the standard resting 12 lead ECG. Atrial and ventricular rates, rhythm, P-wave, P-R interval, QRS duration, abnormality and axis in frontal plane directed to the region between -30⁰ to 105⁰ were taken as normal axis. Similarly, QT and QTc intervals were retrieved and recorded. Right atrial enlargement (RAE), defined as the presence of peaked P-wave with amplitude of 2.5mm or more in lead II, III and avF or as P-pulmonale were sought for. Left atrial enlargement (LAE), defined as the presence of notched P with duration of 0.12 seconds or more or defined as P-terminal force in V1 equal or more negative than 0.04 mm.sec or as P-mitrale were sought for. Biatrial enlargement was considered when both RAE and LAE parameters occurred together in same patient. The presence of Left ventricular hypertrophy (LVH) were defined as per Sokolow-lyon criteria (13) as S-wave in V1 + R-wave in V5 or V6 > 35mm or as defined by Araoye criteria S-wave in V2 + R-wave in V5 or V6 >35mm in female or > 40mm in male (13). But, after the presence of bundle branch blocks (BBB) were excluded (14, 15). Right ventricular hypertrophy (RVH) was defined as per dominant R-wave (a) R wave in V1 ≥ 7mm (b) R/S ratio ≥1 in V1 or alternatively R/S ratio in V5 or V6 <1 (c) R wave in V1+S wave in V5 or V6 > 10.5mm (d) qR complex in V1. Combined ventricular hypertrophy defined as meeting the criteria for both LVH and RVH.

Determination of Packed Cell Volume (PCV)

Each subject’s venous blood was collected by venipucture as described by (16). Three millilitres (mls) of blood was drawn from a peripheral vein of either upper limb because of their prominence and accessibility using 5 mls syringe and 21G needles (17) and transferred into Sodium - ethylene diaminetetra acetic acid (Na-EDTA) tubes. The PCV was determined using microhaematocrit method. Two-third of the capillary tube was filled with blood sealed at one end using plasticine, then placed appropriately in the microheamatocrit centrifuge and allowed to revolve at 10000 rev/min for 5 minutes. Subsequently, the tube was placed on a microhaematocrit reader for proper PCV estimation.

Determination of percentage of irreversibly sickled cells (ISCs)

A thin blood film was made using wedge technique, allowed to air-dry and labeled. The film was flooded with Leishman stain and allowed for 2 minutes, then diluted with equal volume of buffered distilled water and left for about 8 minutes, after which the stain was washed off completely with distilled water. Following other standard procedures, the percentages of irreversibly sickled cells were calculated by counting 100 cells in various fields on the slide with normal and sickled cells counted. The percentage of ISCs was calculated using the following formula;

Determination of percentage of oxygen saturation

Oxygen saturation was determined using the pulse oximeter (PC – 60B1, USA) by appropriately placing the participant’s index finger in the sensor of the oximeter (18, 19) and the readings were recorded.

Statistical analysis

Database storage and analysis was done using IBM SPSS (version 23.0) package. Exploratory data analysis was performed to detect incorrect entries and normality was examined using Shapiro-Wilk test. Data were presented as mean ± standard deviations (mean ± SD) for continuous variables and tables were used in presenting data. Multiple regression analysis was used to determine β-coefficients for confounding factors and confidence intervals (CI) of quantitative variables. Where linear relationships are sought between two factors, the slope of the relations using the equation for linear regression, with the corresponding squared-R determined, using Microsoft excel software. Single factor ANOVA were also used in assessing the difference in mean among the groups, also using Microsoft excel software. The level of statistical significance (α) for the test was set at P<0.05

RESULTS

The mean ages of the groups; Normal, Steady and Crisis were respectively 21.38±2.31, 20.92±2.71, 21.47±2.80 and were not significantly different (p=0.6907). However, the normal group, compared to the steady and crisis groups, had higher PCV (33.44 ±1.80, Vs 27.39 ±4.36 and 25.67 ±4.23, P<0.0001) and SO₂(98.20 ±0.88 Vs 95.15 ±3.25 and 95.89 ±3.55, P<0.0001). Refer figures 3a and 3b. But the normal group had no irreversibly sickled cells (ISC) compared to the SCA steady and crisis groups, 9.76±4.22 and 10.37±5.01, respectively. See figure 3c.

Haemodynamic values of the study participants

The normal group had higher SBP compared to the SCA groups (122.9 ±10.4 mmHg Vs 106.8 ±12.23 mmHg, P<0.00005). The pulsatile component of the blood, pulse pressure (PP) was similarly higher in the normal group as compared to the SCA groups (49.2 ±1.1 mmHg Vs 42.6 ±13.5 mmHg, P<0.05). However, there was no any significant differences in both the SBP and PP between the SCA sub-groups. See table 1. But, the HR among the SCA sub-group in steady state is enhanced, compared to both the normal and the SCA sub-group that was in crisis state (84.2 ±16.5 bpm Vs 77.1 ±14.3 bpm, P=0.0050). Refer table 1. The corrected QT, (QTc) which represent the ventricular depolarization and repolarization of the electrical functions of the heart was also significantly higher among the steady sub-group, compared to the other groups (429.0 ±37.3ms Vs 411.3 ±38.2 ms, P=0.018). See figure 2c. There was however, no statistically significant differences among the groups, in the P-R interval, which represent the period of atrial depolarization among the groups (P = 0.1078). See figure 2a.

Table 1: Characteristics of the study populations

Parameter	Normal (n=40)	Steady (n=53)	Crisis (n=53)
Age ±SD (yrs)	21.4 ±2.3	20.9 ±2.7	21.5 ±2.8
BMI ±SD (Kg/M²)	24.3 ±0.6***	19.3 ±3.4	19.9 ±3.2
Height ±SD (cm)	158.4 ±7.0	160.5 ±8.8	161.0 ±9.3
SBP ±SD (mmHg)	122.9 ±10.4***	108.1 ±11.8	105.5 ±12.6
PP ±SD (mmHg)	49.2 ±1.1*	44.2 ±13.8	41.1 ±13.1
HR ±SD (bpm)	76.5 ±12.9	84.2 ±16.5*	79.0 ±15.9

*** p<0.00005. BMI = Body Mass Index

Ventricular chamber and walls characteristics of the study populations

The cardiac chamber or myocardial walls might be within normal ranges, as can be deduced from the ECG precordial results presented in table 2. And the results were not significantly different among the three groups.

Table 2: Precordial ECG results of the study groups

	Normal (n =40)	Steady (n =53)	Crisis (n =53)
SV1 (mm)	9.9 ± 5.0	9.6 ±4.9	7.8 ±4.6
RV6 (mm)	10.4 ±5.0	11.7 ±6.9	13.6 ±6.2
SV1 +RV6 (mm)	20.3 ±8.4	21.4 ±10.5	21.4 ±8.8
RV1 (mm)	2.5 ±1.8	2.2 ±1.7	2.2 ±1.8
RV1/SV1	0.3 ±0.2	0.3 ±0.3	0.3 ±0.3

Table 3: Correlations (standardized β-coefficients) of the haemodynamic parameters with patients’ level of arterial haemoglobin oxygen saturation, SO₂

	Normal (n =40)			Steady (n = 53)			Crisis (n = 53)
	β-coeff	CI	P-Value	β-coeff	CI	P-Value	β-coeff	CI	P-Value
HR	0.053	-0.021 – 0.029	0.768	0.359	0.13-0.115	0.016	-0.039	-0.083 – 0.065	0.803
SBP	0.032	-0.030 – 0.036	0.869	-0.125	-0.114–0.049	0.427	-0.089	-0.142 – 0.089	0.645
PP	-0.043	-0.056 – 0.044	0.817	-0.019	-0.083–0.044	0.543	0.063	-0.090 – 0.126	0.734
BMI	0.019	-0.073 – 0.082	0.912	0.324	0.027-0.534	0.031	-0.122	-0.874 - 0.273	0.477
PCV	0.353	0.007 – 0.385	0.041	0.381	0.069-0.448	0.009	0.171	-0.193 - 0.485	0.390
ISC	-	-	-	-0.229	-0.353– 0.031	0.099	-0.143	-0.387 - 0.178	0.459

HR = Heart Rate (bpm), SBP= Systolic Blood Pressure (mmHg), PP= Pulse Pressure (mmHg), BMI= Body Mass Index (Kg/m²), PCV = Packed Cell Volume (%), ISC = Irreversible Sickle Cell (%).

Table 4: Correlations (standardized β-coefficients) of the hemodynamic parameters with patients corrected electrical systolic period, QTc

	Normal (n =40)			Steady (n = 53)			Crisis (n = 53)
	β-coeff	CI	P-Value	β-coeff	CI	P-Value	β-coeff	CI	P-Value
HR	0.595	0.910 – 2.818	0.000	0.369	0.116 – 1.551	0.024	0.417	0.320 – 1.520	0.004
SBP	-0.045	-1.431 – 1.080	0.778	-0.007	-1.163 – 1.119	0.969	-0.103	-1.234 – 0.650	0.535
PP	-0.195	-3.057 – 0.731	0.220	0.089	-0.650 -1.130	0.589	0.108	-0.579 -1.177	0.496
BMI	-0.060	-3.539 – 2.343	0.681	0.030	-3.224 – 3.877	0.854	-0.084	-4.438 – 2.465	0.567
PCV	0.040	-5.351 – 7.107	0.776	-0.007	-2.707 – 2.592	0.965	-0.394	-5.955 - -0.431	0.025
ISC	-	-	-	-0.019	-2.864 -2.515	0.897	-0.207	-3.737 – 0.858	0.213

Heart Rate (HR), Systolic Blood Pressure (SBP), Pulse Pressure (PP), Body Mass Index (BMI), Packed Cell Volume (PCV), Irreversible Sickle Cell (ISC)

Table 5: Correlations (standardized β-coefficients) of the haemodynamic parameters with patients’ electrical diastolic period, P-R interval

	Normal (n =40)				Steady (n = 53)			Crisis (n = 53)
		β-coeff	CI	P-Value	β-coeff	CI	P-Value	β-coeff	CI	P-Value
HR		-0.130	-1.133 – 0.532	0.468	-0.370	-1.548 - -0.227	0.010	-0.361	-1.378 - -0.106	0.023
SBP		0.046	-0.964 – 1.228	0.808	-0.036	-1.177 – 0.924	0.809	0.103	-0.735 – 1.281	0.587
PP		0.188	-0.823 – 2.484	0.314	0.201	-0.242 – 1.397	0.163	-0.148	-1.335 – 0.563	0.416
BMI		0.317	-0.213 – 4.921	0.071	-0.069	-4.071 -2.469	0.624	-0.233	-6.217 – 1.118	0.168
PCV		-0.077	-6.693 – 4.181	0.641	0.162	-0.960 -3.920	0.228	-0.025	-3.107 -2.731	0.897
ISC		-	-	-	0.352	0.864 – 5.818	0.009	0.026	-2.354 – 2.697	0.892

Heart Rate (HR), Systolic Blood Pressure (SBP), Pulse Pressure (PP), Body Mass Index (BMI), Packed Cell Volume (PCV), Irreversible Sickle Cell (ISC)

DISCUSSION

The main findings in the present study are; SCA patients have significantly lower BMI, systolic blood pressure, pulse pressure and PCV compared to the normal individuals. The normal group also showed better blood oxygen saturation compared to the SCA groups. Indeed, the steady sub-group of the SCA populations have higher PCV level compared to the crisis sub-group. Furthermore, the steady sub-group of SCA had significantly higher HR compared to both crisis sub-group and the normal group. Although, both sub-groups of the SCA had increased HR, the steady sub-group had significantly enhanced HR. In this regard, the steady sub-group of SCA showed significant relationship between the HR and SO₂, but this was not seen in the crisis sub-group. Indeed, the normal group, which had much lower HR showed no significant relationship between the HR and SO₂. Moreover, the sub-group in steady state showed significant relationship between PCV and SO_2,similar to what obtains in the normal population sampled. However, the sub-group with crisis displayed not any appreciable relationship between the PCV and SO₂. The normal and steady state sub-groups also demonstrated significantly higher heart rate-pressure product (RPP) compared to the sub-group with crisis. Furthermore, all the three sub-groups demonstrated significant relationship between its HR and corrected QT (QTc). There was also no evidence of ventricular chamber abnormalities (see table 2).

Heart rate and QTc

Although QT intervals beyond 429 ms is reported to be associated with all-cause mortality among cardiovascular disease patients (not SCA) (20, 21), a study (6) indicated that most SCA patients may be having borderline or prolonged QT interval without clinical symptoms. Nevertheless, cardiovascular adjustments require that in anemia, typical of SCA patients (24, 25), that there will be upregulation of the HR to improve cardiac output (CO) in order to meet the tissue needs (26). Increased HR is an important component of the CO which is compensatorily improved according to the body need (27-29). However, a study, (30) observed that substantially high HR is associated with SCA crisis. The above study was not able to establish this relationship with the pre-crisis HR of the SCA patients, in which case the crisis may be the cause of the raised HR. Furthermore, the studies that reported the untoward influence of HR on cardiovascular outcomes didn’t establish this in the general population or SCA patients (31), rather they were carried out among subjects suffering from ardiovascular diseases (30, 32, 33). Moreover, the earlier studies (34, 35) worked on resting HR to determine the effects on all-cause mortality, but not in compensatory instances like, chronic mild anaemic adaptation. The increased HR may be compensatory in chronic mild haemolytic conditions (26). Moreover, a prospective community-based study comprising over twenty thousand subjects reported that cardiac deaths are more associated with lower HRs than moderately higher HRs (36). Consequently, the present study report that both HR and QTc (a better index of cardiovascular risk than QT) are significantly higher in the steady sub-group compared to the crisis sub-group, because of the better compensatory tendencies of the former sub-group, hence is able to stay without much crisis. This is corroborated by the RPP values of the sub-groups displayed in figure 3c.

Meanwhile, as seen in the present data, haemodynamic parameters does not bear any relationship with P-R interval in individuals without cardiovascular perturbations (22, 23).

PCV and SO₂

Higher PCV levels, enhanced HR and RPP demonstrated by the sub-group in steady may explain the better oxygen delivery and utilization to the tissues and less crisis among individuals who might be homozygous for the SCA genotype. Importantly, the present study showed that this is true, even when the PCV is significantly lower than the average value observed among the normal population. Indeed, SCA patients have lower PCV levels (24, 25).

Furthermore, hypoxia is a pathophysiological feature of vaso-occlusive crisis (VOC) in SCA patients (1). The rate and volume of blood delivered to the tissue may explain the VOC tendencies or otherwise in SCA patients. Moreover, increase sympathetic discharge is said to aggravate SCA crisis (8), but intravenous fluid infusion is recommended in individuals with crisis (37, 38). Indeed, plasma volume expansion in the patients will enhance venous return and likely to increase heart rate by the Bainbridge mechanism (28, 29). Furthermore, repeated blood transfusion is reported to be able to reduce the risk of stroke in SCA patients by 92% (6). Importantly, in the presence of optimum systolic functions, increased HR will result in improved cardiac output and oxygen delivery to tissues will be better. Consequently, the present study showed significant relationship between HR and SO₂in the steady sub-group.

Therefore, as much as fluid therapy is indicated in alleviating crisis in SCA patients, the PCV must be optimum alongside normal cardiac functions, to achieve steady state. Otherwise, safe whole blood transfusion will be a better option, if available. Indeed, blood transfusion will provide both plasma volume expansion and PCV enhancement.

Limitations of study

The study sample size is small and may not be representative of the larger population of SCA patients in this environment. The study is also limited by its cross-sectional nature, therefore couldn’t proclaim causal effect. Proper measurement of the myocardiac systolic function would have been worthwhile, but we had no access to echocardiographic machines when collecting the data and therefore couldn’t carry out the measurements of ejection fraction or cardiac output.

CONCLUSION

Africa and indeed Nigeria has the highest burden of sickle cell disease globally (2-4), on a background escalating economic hardship. Consequently, we recommend that in addition to enhancement of factors such as foetal hemoglobin induction, reductions of cell elements aggregations, or increased nitric oxide bioavailability, SCA patients with optimum PCV alongside enhanced or normal ventricular functions (see table 2 and figure 3c) have the advantage of overcoming some of the hypoxic tendencies, and are likely to experience less crisis.

Acknowledgement

We are thankful to our patients for consenting to participate in the study. We are also grateful to Drs Isah Oboirien and Muawiyya Usman, of the Department of Internal medicine for the technical assistance on ECG interpretations. Mr. & Mrs. Igbokwe are sincerely appreciated for the assistance in initial data organization and normal subjects sourcing, respectively.

Duality of interest

None declared

Source of funding

No funding was received for this research

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