Impact of iron deficiency on health-related quality of life and functional status in adults with chronic heart failure in Nigeria

Abstract

Introduction

Iron deficiency (ID) has been associated with poor quality of life in chronic heart failure (HF) patients, especially among Whites. Reports are, however, scarce among Africans on the impact of ID in chronic HF among Black Africans. This study aimed to describe the impact of ID on the quality of life among Africans with chronic HF, using the KCCQ-12 instrument.

Methods

One hundred and forty (140) subjects with HF were recruited from the cardiology Units of LAUTECH and Bowen University Teaching Hospital, Ogbomoso, Nigeria. ID was defined by standardized criteria. KCCQ-12 was used to assess the quality of life among the participants. Statistical analysis was done using SPSS-25.0. P < 0.05 was taken as statistically significant.

Results

ID was present in 60% of the study participants. Patients with ID performed worse than patients with normal iron status in the Six-minutes walk test distance (6MWTD) in the study. They also scored significantly lower in symptom frequency score, physical limitation score (67.1 ± 27.6 vs. 78.6 ± 17.3 respectively, p < 0.05), clinical summary score (67.1 ± 26.7 vs. 78.3 ± 16.3, respectively p < 0.05), and social limitation score (70.1 ± 39.2 vs. 82.4 ± 25.9 respectively, p < 0.05), compared to those with normal iron status denoting worse quality of life. The mean 6MWTD was 180.3 ± 89.3 m among ID vs. 256.0 ± 100.3 m, p < 0.001 in normal iron status participants.

Conclusion

This study shows that ID is associated with worse functional capacity and the quality of life among HF subjects in Nigeria, irrespective of anaemia status. Treatment of ID in HF is a potential way to improve morbidity and mortality among Africans with HF.

Introduction

The hyper-mortality of HF among Africans has been linked with the increased number of comorbidities among which are iron deficiency (ID), anaemia, and sleep apnoea [1, 2]. Chronic HF is associated with significant morbidity and mortality, and consequent impact on functional status and the quality of life [3, 4]. ID has been demonstrated to be very common in HF [4–7]. The additional impact of ID on the quality of life especially among Black Africans is yet to be well explored. This impact on health-related quality of life has been shown in some studies among Whites to be irrespective of anaemia status. The place of iron in metabolism is important as iron is essential for key biological pathways including oxygen transport, DNA metabolism, and mitochondrial function [8].

Poor quality of life and exercise intolerance are indicators of poor prognosis in HF and are considered markers of disease severity [9]. Important treatment goals in HF include treatment aimed at achieving improved quality of life, improved exercise tolerance and improving clinical and functional status. Many recent advances in the treatment of HF have been shown to impact on the quality of life and evaluated based upon significant improvement in the quality of life, reduction of hospitalization and mortality [1, 2, 10]. Akintunde et al. demonstrated a prevalence of 60% of ID among chronic HF subjects in Ogbomosho, Nigeria [5]. It also showed that HF subjects with ID tend to have poorer clinical profile compared to those without ID irrespective of their anaemia status [5, 6].

An important comorbidity in HF is ID. Prevalence has been shown to range from 50% in HFrEF to 64% in HFpEF [10, 11]. ID is associated with prolonged hospitalization and higher health costs [10, 12]. There is evidence among Whites showing a strong association between ID and poor exercise intolerance and worse quality of life. Among these patients, parenteral iron therapy has been shown to have demonstrated significant clinical benefits [13–18].

An essential functional part of mitochondrial metabolism is iron use and exchange. Thus, ID leads to abnormalities in energy metabolism not only in the cardiac myocytes, but on the skeletal muscles [8]. The altered energy metabolism in the heart leads to left ventricular hypertrophy, diastolic dysfunction and increasing fibrosis. The interaction of skeletal muscle abnormalities, pulmonary, cardiac and haematological abnormalities due to deranged iron metabolism contributes to impaired exercise tolerance and poor quality of life in HF subjects [19]. Evaluation of patients’ reported outcomes is increasingly being used to assess care and prognosis. The use of patient self-filled outcome measures tends to improve prognosis and overall outcomes in HF.

This study aimed to examine the impact of iron deficiency (ID) on the quality of life using the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score among chronic HF patients in Ogbomosho, Nigeria.

Materials and methods

This was a prospective observational study of HF subjects done at LAUTECH Teaching Hospital, Ogbomosho, Nigeria and Bowen University Teaching Hospital, Ogbomoso, Nigeria. One hundred and forty (140) HF patients who had been managed for at least six months were included in the study. Details of this study were previously highlighted in a recent article by the same group [5]. Patients were recruited if they met the diagnostic criteria according to the European Society of Cardiology guidelines. Other criteria include age > 18 years and having an expected life expectancy of at least 2 years. Exclusion criteria include presence of chronic medical conditions such as malignancies, chronic kidney disease, strokes, and a previous history of medical admission in the past six weeks. Patients with a history of ongoing infections were also excluded from the study.

Information was collected using a data form that included demographic and clinical characteristics such as age, gender, occupation, tribe, address, history of hypertension and diabetes, medications, and presence of HF symptoms. All participants underwent clinical and general examinations, with parameters obtained including weight, height, body mass index, waist circumference, blood pressure, heart rate, and respiratory rate, among others. Investigations done include full blood count and full total iron study. The details of definition of iron status are detailed elsewhere using serum ferritin and transferrin saturation [5, 6]. ID was defined as serum ferritin < 100 pg/ml or transferrin saturation < 20%. Other investigations included a 12-lead electrocardiography and transthoracic echocardiography. Functional classification was assessed using the New York Heart Association Classification I-IV, and a 6MWTD was conducted for all participants. Anaemia was defined as serum haemoglobin < 13 g/dl for men and < 12 g/dl for women according to standardized criteria.

The quality of life was assessed using the Kansas City Cardiomyopathy Score-12 (KCCQ-12 Score). The KCCQ-12 score effectively captures symptom frequency, physical and social limitations, and quality of life impairment in both separate and overall domains. It has a very high correlation with the longer KCCQ-23 scores, high test-retest reliability, and high responsiveness, for example, after a hospital discharge. It also offers comparable prognostic significance and interpretation in many situations.

All KCCQ scores are scaled from 0 to 100 and are often summarized in 25-point ranges where the scores represent health status as follows: 0–24: very poor to poor, 25–49: poor to fair, 50–74: fair to good, and 75–100: good to excellent.

Statistical analysis was done using the Statistical Package for Social Sciences SPSS Chicago Ill., USA, Version 25.0. Qualitative data were summarized as frequencies and percentages while quantitative data were summarized as mean ± standard deviation. Student t-tests, analysis of variance, and Chi-square tests were used to determine differences between groups for continuous and categorical variables, as appropriate. Correlation statistics were used to assess univariate correlations between domains of quality-of-life scores and other clinical and demographic parameters, including iron parameters. Linear regression using forward selection model was performed to assess the determinants of poor quality of life and functional status among HF patients with and without ID, while multiple linear regression was done to assess for the determinants of the 6MWT distance. A p-value of < 0.05 was considered statistically significant. Written informed consent was obtained from all participants. The study was performed according to the International Declaration of Helsinki. Ethical approval was obtained from the Research Ethics Committee of Ladoke Akintola University of Technology, Ogbomoso, Nigeria. Written informed consent was obtained from all participants.

Results

The mean age of the study participants was 62.9 ± 16.3 years. There were more women in the study than males (57.1% vs. 42.9%). The mean (S.D) heart rate, ejection fraction, packed cell volume and haemoglobin of the study participants were 90.2 ± 18.8 beats per minute, 40.7 ± 9.4%, 32.3 ± 6.4%, 10.6 ± 2.7 g/dl, respectively. The mean (S.D) serum ferritin, atrial natriuretic peptides, and transferrin saturation were 227.2 ± 163.0, 161.1 ± 56.9 and 19.9 ± 10.7% respectively, as shown in Table 1. Iron deficiency was found in 84 (60.0%) of the study participants, while anaemia was documented in 106 (75.7%) of all study participants. The mean estimated glomerular filtration rate was 53.6 ± 39.9. Additionally, 42.9% of the study participants were in NYHA stage III, while 30.7% were in NYHA stage IV, as shown in Table 1. Clinical and demographic characteristics between participants with iron deficiency were also compared with those with normal iron status. Participants with ID had significantly lower haemoglobin concentration, mean serum ferritin, total iron, transferrin saturation, and a higher frequency of low serum total iron compared with those without iron deficiency. This sis also shown in Table 1.

Table 1.

Clinical characteristics of study participants

Variables	Mean (S.D)/n(%)	ID (84)	Normal iron status (56)	P value
Age (years)	62.9 ± 16.3	64.4 ± 13.9	60.8 ± 13.9	0.163
Heart rate (/min)	90.2 ± 18.8	91.8 ± 21.0	87.8 ± 14.6	0.241
EF (%)	40.7 ± 9.4	41.3 ± 10.6	39.7 ± 7.1	0.363
PCV (%)	32.3 ± 6.4	31.6 ± 7.2	33.3 ± 4.8	0.132
Haemoglobin (g/dl)	10.6 ± 2.7	10.3 ± 2.9	11.1 ± 1.6	0.042*
Ferritin (ug/L)	227.2 ± 163.0	205.0 ± 145.6	260.6 ± 182.4	0.047*
ANP (pg/ml)	161.1 ± 56.9	184.3 ± 56.1	126.4 ± 37.0	0.000*
TRANSFERRIN (mcg/dl)	200.0 ± 29.6	205.2 ± 31.4	192.3 ± 24.9	0.011*
TOTAL IRON (umol/L)	39.3 ± 20.7	30.0 ± 6. 0.3	53.3 ± 26.4	0.000*
TRANSFERRIN SAT (%)	19.9 ± 10.7	14.7 ± 3.0	27.7 ± 13.1	0.000*
WHR	0.93 ± 0.08	0.92 ± 0.09	0.95 ± 0.07	0.062
EGFR (	53.6 ± 39.9	48.4 ± 28.8	62.3 ± 53.0	0.162
Gender (M/F) (%)	42.9/57.1	32/52	28/28	0.163
NYHA III/IV (%)	35.7/30.7	58	35	0.471
Low Total iron, n (%)	106(75.6%)	80	26	0.000*
Anaemia, n (%)	106 (75.7%)	65	41	0.573
Low transferrin, n (%)	76 (54.3%)	42	34	0.277
High Ferritin/Normal Ferritin, n (%)	50(35.7%)/90(64.3%)	26/58	24/32	0.150
HFpEF/HFmrEF/HFrEF	15.3%/33.1%/51.7%	14/26/44	7/20/29	0.290

Key to table: EF Ejection fraction, PCV Packed cell volume, ANP Atrial natriuretic peptide, WHR Waist hip ratio, eGFR Estimated glomerular filtration rate, KCCQ Kansas City Cardiomyopathy Score, M Male, F Female, NYHA New York Heart Association, HFpEF HF with preserved ejection fraction, HFmrEF HF with mildly reduced ejection fraction, HFrEF HF with reduced ejection fraction

The mean KCCQ-12 scores used to evaluate the patient-reported quality of life are shown in Table 2. The overall summary score and clinical summary score were both significantly lower among HF patients with iron deficiency (ID) compared to HF without ID. Similarly, symptom frequency score, physical limitation score, and social limitation scores were all significantly lower in HF with ID compared to those with HF without ID except for the isolated quality of life score.

Table 2.

KCCQ-12 score profile of study participants

KCCQ Score Profile	Iron Deficiency (84)	Normal Iron Status (56)	P value
Symptoms Frequency Score	64.13 ± 25.0	74.3 ± 22.1	0.016*
Physical Limitation score	67.1 ± 27.6	78.6 ± 17.3	0.006*
Overall Summary Score	59.3 ± 22.7	70.2 ± 17.7	0.003*
Clinical Summary score	67.1 ± 26.7	78.3 ± 16.3	0.006*
Quality of Life Score	36.0 ± 30.5	45.5 ± 31.3	0.076
Social Limitation Score	70.1 ± 39.2	82.4 ± 25.9	0.041*

* Statistically significant

Key to table: KCCQ Kansas City cardiomyopathy-12 Score.

The mean difference in the overall clinical summary scores between the two groups is illustrated in Fig. 1. Figure 2 displays the mean difference in the 6MWTD distance among Africans with HF and ID compared to those without ID, and it was found to be statistically significant.

Fig. 1.

showing the mean overall summary score of KCCQ-12 Scores between HF with ID and HF without ID

Fig. 2.

showing the mean 6MWTD between HF with ID and HF without ID. Key to table: Normal i- Normal iron parameters, iron def- iron deficiency subjects

Table 3 shows the determinants of the patient self-reported health related quality of life core measured using the Kansas City Cardiomyopathy-12 score. The determinants include age, New York Heart Association Class, left atrial dimension, packed cell volume, serum ferritin, transferrin and the presence of ID. The model did not show any significant contribution of anaemia status to the KCCQ-12 score. In a similar fashion, only the presence of ID was a significant determinant of functional status as evaluated using the 6MWTD in this study. This was also irrespective of the anaemia status, as shown in Table 4. Table 5 shows that the model summary of the determinants of the 6MWTD in Table 4 was statistically significant.

Table 3.

Linear regression analysis of the determinants of HRQoL by KCCQ-12

Variables	Unstd. B	Stdized B	Sig	Lower Bound	Upper Bound
Constant	20.124	-	0.540	−44.83	85.07
Age (years)	0.348	0.276	0.001*	0.144	0.552
NYHA Class	−5.412	−0.209	0.040*	−10.582	−0.242
EF (%)	0.012	0.006	0.964	−0.515	0.540
LAD	−0.699	−0.395	0.001*	−1.099	−0.299
Pulm HTN	−6.242	−0.145	0.181	−15.449	2.965
PCV (%)	0.847	0.278	0.032*	0.074	1.621
Ferritin	−0.041	−0.331	0.000*	−0.064	−0.019
Transferrin	0.139	0.209	0.013*	0.030	0.248
Gender	3.219	0.076	0.453	−5.274	11.712
Iron deficiency	5.858	0.277	0.023*	0.814	10.90
Anaemia	−2.254	−0.045	0.739	−15.64	11.13

*Statistically significant

Key to Table: NYHA New York Heart Association, EF Ejection fraction, LVIDd Left ventricular internal diastolic dimension, LAD Left atrial dimensions, Pulm HTN Pulmonary hypertension, PCV Packed cell volume, Gender (F=0, M=1)

Table 4.

Multiple linear regression analysis of the determinants of the 6MWTD in study cohorts

Variables	Unstd. B	Stdized B	Sig
(Constant)	−159.520		0.439
AGE	0.058	0.011	0.934
NYHA CLASS	−26.270	−0.219	0.232
left atrial dimension (mm)	−0.204	−0.027	0.867
ejection fraction (%)	3.088	0.316	0.133
PRESENCE OF PULMONARY HYPERTENSION	13.176	0.066	0.639
PACKED CELL VOLUME (%)	4.492	0.280	0.185
FERRITIN (ng/ml)	−0.065	−0.112	0.408
iron deficiency group	8.901	0.321	0.043*
anaemia status	−24.138	−0.106	0.593

Key to table: NYHA New York Heart Association

Table 5.

Showing the model summary of the determinants of the 6MWTD in the study population

Model Summary
Model	R	R Square	Adjusted R Square	Std. Error of the Estimate	Change Statistics
					R Square Change	F Change	df1	df2	Sig. F Change
1	.691a	0.477	0.354	76.823	0.477	3.894	11	47	0.000

a. Predictors: (Constant), anaemia status, iron deficiency group, AGE, left ventricular internal diastolic dimension (mm), PRESENCE OF PULMONARY HYPERTENSION, FERRITIN(ng/ml), NYHA CLASS, left atrial dimension (mm), TRANSFERRIN SATURATION, ejection fraction (%), PACKED CELL VOLUME (%)

b. Dependent Variable: FIRST 6 min WALK TEST

Discussion

This study revealed that ID significantly impacts on the quality of life and functional status of Africans with HF irrespective of whether anaemia is present or not. Health-related quality of life (HRQoL) using the KCCQ-12 scores were shown to be associated with left atrial dimension, New York Heart Association classification, age, packed cell volume, serum ferritin, and serum transferrin. As evidenced in this study, these parameters determine impaired quality of life associated with ID in chronic HF subjects in a cohort of HF in southwest Nigeria. In a twist of fate, only iron deficiency was shown to predict the 6MWTD using the linear regression analysis in this study cohort. Almost all aspects of the KCCQ-12 HRQoL score, including symptoms frequency score, physical limitation score, clinical summary score, social limitation score, and overall summary score, were significantly lower among subjects with iron deficiency (ID) compared to those with normal iron homeostasis. This suggests a poorer quality of life related to higher symptom frequency, more physical limitations, and increased social limitations, all of which can significantly impair overall quality of life. This finding aligns with what has been reported in other populations, although there may be subtle differences in the degree and depth of impact in different populations [20, 21].

Iron is indeed a crucial component of the body necessary for the proper function of mitochondria, which are the powerhouses of cells. When there’s iron deficiency (ID), it can lead to alterations in energy metabolism within the heart muscles. This can manifest as cardiac enlargement, ventricular hypertrophy, diastolic dysfunction, and progressive cardiac fibrosis. Additionally, ID can have a significant impact on the striated muscle cells of the musculoskeletal system [22]. Thus, the exercise intolerance and the physical limitation observed in patients with HF is probably multifactorial, derived from the interaction of pulmonary, cardiac, haematological, and skeletal muscle impairments [23–27]. The aetiology of anaemia may be related to nutritional deficiencies, chronic inflammation, gastrointestinal blood loss and recurrent blood investigation and possibly menstrual cycle in females.

Major principles of HF management often include minimizing disease progression and reducing death rates, hospitalization rate and optimizing patient’s health status including their symptoms, function and quality of life [2, 7, 18]. The additional impact of iron deficiency (ID) on the quality of life across various domains measured in this study using the KCCQ-12 score suggests the potential for reversibility when ID is treated, often with parenteral iron replacement [25, 28]. The relative ease of iron replacement, including oral preparations, suggests a potentially significant pharmacologic benefit for chronic HF in Africa. This is particularly important given the systemic issues, drug availability challenges, poverty, and lack of trained personnel that often undermine holistic cardiovascular care in the region [27].

Patient self-reported outcomes such as that evaluated with the KCCQ-12 questionnaire have significant benefits as it has been associated with prognosis as HF rehospitalizations and death [29]. ID negatively impacts symptoms burden, exercise capacity, thereby having a negative impact on the overall quality of life in HF subjects [30, 31].

Parenteral iron replacement therapy has been one of the only few interventions that have demonstrated clinical benefits in terms of health status in patients with chronic HFrEF including dapagliflozin, empagliflozin, sacubitril/valsartan, exercise training and IV ferric carboxymaltose [32]. Iron replacement therapy stands out as one of the most easily accessible interventions for African patients with HF (HF). Given the challenges in accessing comprehensive care and the potential benefits of addressing iron deficiency, such as reversing increased mortality rates in HF, this approach holds significant promise for improving outcomes and quality of life for HF patients in Africa [5, 32]. In the IRONMAN study, including a broad range of patients with HF, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for HF and cardiovascular death, further supporting the benefit of iron repletion in this population. [33]

It is noteworthy that other factors shown to be predictive of HRQoL as evaluated using the KCCQ-12 questionnaire include age, left atrial dimension, New York Heart Association, packed cell volume, serum ferritin and transferrin. These factors are indirectly predictive of ID status and have been shown in many studies that they are directly or indirectly associated.

This study also found that iron deficiency (ID) was strongly associated with functional status, as evaluated by the 6MWT. Interestingly, the association observed in the 6MWT was shown to have a similar predictive value in prognosis as the cardiopulmonary gas exchange exercise test, which is an important marker in HF management and risk stratification [34].

There’s a growing emphasis on patients’ preference for better overall health status, which includes a reduction in the use of traditional disease-specific endpoints like morbidity and mortality [35]. Targets in patients with HF have expanded to encompass improvements in functional capacity and health-related quality of life [4]. The 6MWT is an indicator of exercise capacity and prognosis in various cardiopulmonary conditions [36–39].

The relationship between ID and functional status and quality of life can, therefore, be a marker of identifying stable HF patients, who are already at risk of advanced disease and increased mortality for which parenteral iron replacement can be a potentially reversible pathway, to mitigate the increased CV risk [4, 17]. The association with conventional echocardiographic markers of increased cardiovascular risk including left atrial dilatation; left ventricular diastolic dimension also revealed that ID may also be partly responsible for the structural markers of poor prognosis because of widespread mitochondrial dysfunction and structural remodeling in the heart and other organs [17, 32]. The potential usefulness of iron replacement and the potential reversibility of major cellular dysfunction in cardiomyocytes and skeletal cells may likely herald the reversibility of major adaptations in HF and ensure reduced risk. Periodic iron replacement therapy can indeed be explored as a potential intervention in Africa, especially given the high mortality rates of HF in the region. The search for cost-effective yet life-changing therapies in the management of HF is of utmost importance and should be considered a priority.

Conclusion

This study revealed that ID is associated with poor functional status and poor quality of life in Africans with HF compared to those without ID [7, 11, 17]. The presence of ID may also correlate with the severity of some other conventional CV risk markers such as left atrial dimension, left ventricular internal dimension, and other haematological parameters of iron status including serum ferritin, transferrin, packed cell volume and increasing age [11, 17, 24, 30]. Early identification and frequent iron replacement preferably by parenteral method may potentially reverse the poor quality of life and functional status in Africans with HF [5, 17]. We recommend a yearly parenteral infusion of parenteral iron therapy in Africans with HF to potentially target the significant burden of ID in Africans with HF. Long-term prospective studies should indeed be encouraged among Africans with HF to document the benefits of frequent parenteral iron replacement therapy.

Authors’ contributions

AAA- was involved in study concept design, data collection, analysis, manuscript writing and final approval of manuscript STO- was involved in data collection, review of manuscript and final approval of manuscript.

Clinical Trial Reg No

Not registered initially but has been done and it is under processing.

Funding

This study was funded by the Tertiary Education Fund (TETFUND Nigeria) through the 2017/2018 Institutional Based Research Grant to Ladoke Akintola University of Technology, Ogbomoso.

Data availability

The dataset(s) supporting the conclusions of this article is(are) included within the article (and its additional file(s)).

Declarations

Competing interests

The authors declare no competing interests.