European Journal of Cardiovascular Medicine

The common haematological condition known as iron deficiency anaemia (IDA) is characterised by low iron stores that prevent the generation of enough red blood cells, which lowers haemoglobin levels and impairs oxygen transport. It is a worldwide health issue that affects people of all ages, but it is most common in children, teenagers, women who are fertile, and the elderly. India is contributes to more than half of the world's malnourished people.[1] According to a WHO research conducted between 1993 and 2005, 25% of people globally are anaemic.[2] According to the National Family Health Survey-3 (NFHS-3), 56% of people may be anaemic. In contrast, the National Nutrition Monitoring Bureau Survey (NNMBS) from 2006 indicates that 69.7% of women and 68.6% of men suffer from anaemia.[3,4]

Although the haematological effects of IDA are the main cause of its clinical manifestations, new research indicates that IDA may also have an effect on left ventricular (LV) function.

The left ventricle is an essential component of the circulatory system, circulating blood that is oxygenated throughout the body. Variations in left ventricular function can have a big impact on cardiovascular health and general well-being. A number of investigations have looked into the possible correlation between IDA and changes in left ventricular function in an effort to clarify the pathophysiological processes behind the cardiovascular effects of iron deficiency.[5,6]

Iron is necessary for many physiological functions, such as contractile function, oxygen consumption, and myocardial energy metabolism. Reduced iron availability in the setting of IDA may affect cardiac function, resulting in changes to the function of the left ventricle, myocardial hypertrophy, and poor contractility. Furthermore, anaemia caused by iron deficiency may worsen the mismatch between the supply and demand of oxygen in the heart, further impairing left ventricular function.[7]

In addition, IDA has been linked to endothelial dysfunction, oxidative stress, and systemic inflammation—all of which can exacerbate cardiovascular disease, including left ventricular failure. Chronic iron deficiency may potentially influence the remodelling and function of the heart.

There is a growing interest of research on the correlation between IDA and left ventricular (LV) function, but the results are inconsistent. While some studies reveal reduced LV systolic and diastolic function in IDA patients, others find no discernible correlation. The variety of results may be attributed to variations in study demographics, sample sizes, methodology, and LV function testing procedures.[8]

More research on LV function in IDA patients is necessary because of the possible effects on cardiovascular health and patient outcomes. Advanced imaging techniques such cardiac magnetic resonance imaging (MRI), myocardial strain analysis, and echocardiography can be used to comprehensively examine left ventricular function and gain important insights about how IDA affects the structure and function of the heart.[9,10]

In order to guide therapeutic interventions for affected persons, identify cardiac issues early, and stratify risk, it is important to understand the link between IDA and LV function.

Examining left ventricular function in this patient population has substantial therapeutic importance and may lead to better patient care and outcomes, especially given the rising prevalence of iron deficiency anaemia and its possible cardiovascular consequences

The aim of this study is to address the gap in existing research by investigating the clinical, ECG, and echocardiographic parameters in patients with iron deficiency anemia. Specifically, we aim to comprehensively evaluate left ventricular mass cavity dilation, EF, wall thickness, and volume in these patients. By focusing on these parameters, we seek to improve early detection of heart failure associated with iron deficiency anemia.

The study was done in 100 patients  diagnosed with severe iron deficiency anemia in a tertiary care hospital and teaching centre in the Department of General Medicine, Rajendra Institute of Medical Sciences, Ranchi, participated in an observational cross-sectional study. The study was conducted over 18 months. From April 2020 to September 2021.

Inclusion Criteria

• Age > 18 years in medical wards.
• Hemoglobin < 6gm% (according to WHO criteria). [1]
• Microcytic, Hypochromic blood picture in peripheral smear
• Red cell indices suggestive of iron deficiency anemia.

Exclusion Criteria

• Chronic renal failure
• Chronic liver disease
• Dimorphic anemia
• Other cardiac diseases (Ischemic heart disease, Rheumatic heart disease and Infections related)

Method of collection of data:-

Patients with iron deficiency anemia with hemoglobin less than 6 gm% was included after applying the exclusion criteria. informed consent and ethical clearance was obtained from institutional ethical committee. Demographic and clinical profile of the cases were recorded.

Investigation such as Hemogram, peripheral smear, red cell indices, Serum ferritin, Electrocardiogram and Echocardiography was done.

Patients with iron deficiency anemia underwent 2D ECHO evaluation, determining parameters like LV mass, relative wall thickness, concentration and eccentric hypertrophy, HFrEF and HFpEF.

During our study, a total of 100 patients with iron deficiency anemia visiting to our OPD or admitted in the Department of Medicine, Rajendra Institute of Medical Sciences, Ranchi. Iron deficiency anaemia (IDA) was predominantly seen in female population in our study. All patients of severe iron deficiency anaemia have low serum iron and serum ferritin level. Fatigue and breathlessness were most common clinical feature of IDA.

In our study, 65% of patients with iron deficiency anemia exhibited an increase in left ventricular (LV) mass relative to body surface area, while the remaining 35% had normal LV mass. Of the 65 patients with increased LV mass, 49 were female and 16 were male, indicating a significant association between iron deficiency anemia and elevated LV mass, particularly in females.

Concentric hypertrophy was more prevalent in males (33.3%) compared to females (11.5%). Similarly, Eccentric hypertrophy was notably predominant in females (67.2%) compared to males (10.3%). Overall, eccentric hypertrophy was more common than concentric hypertrophy, with 45 patients exhibiting eccentric hypertrophy and 20 displaying concentric hypertrophy. Additionally, 35 patients did not demonstrate either hypertrophy pattern. Among these, 33 patients had normal LV mass and geometry, while 2 patients had normal LV geometry despite an increase in LV mass.

TABLE 1: RELATIONSHIP BETWEEN P WAVE PROLONGATION ON ECG WITH THAT OF HFpEF ALONE

Figure 1: HFrEF with P wave prolongation in ECG

TABLE 2: RELATIONSHIP OF HFpEF ALONE WITH LVH PRESSURE OVERLOAD ON ECG

TABLE 3: STATISTICAL RELATIONSHIP OF HFrEF WITH LVH  PRESSURE OVERLOAD ON ECG

Figure 2: HFrEF with LVH volume overload on ECG

TABLE 4: STATISTICAL RELATIONSHIP HFpEF ALONE WITH LVH VOLUME OVERLOAD IN ECG

In our study, heart failure with reduced ejection fraction (HFrEF) was defined as EF < 45%, while heart failure with preserved ejection fraction (HFpEF) was defined as EF > 45%. LV dysfunction was observed in 59 out of 100 patients, with 48 of them exhibiting LV HFrEF and 11 showing HFpEF alone. Additionally, 41 patients had no LV dysfunction. Among the 20 patients with concentric hypertrophy, only 8 had HFrEF, while 11 had HFpEF alone, and 1 had neither HFrEF nor HFpEF. Statistical analysis revealed that 36 patients (75%) with eccentric hypertrophy had HFrEF, while 9 patients (17.3%) did not.

In terms of HFpEF, 11 patients (11%) had HFpEF alone. Among those with concentric hypertrophy, 10 patients (90.9%) had HFpEF, while only 1 patient (9.1%) did not. HFpEF was predominantly associated with concentric hypertrophy.Comparing HFpEF without HFrEF to eccentric hypertrophy, only 1 patient (9.1%) with eccentric hypertrophy had HFpEF, while 44 patients (49.4%) did not.(table1, figure1)

The study identified 11 patients with heart failure with preserved ejection fraction (HFpEF) without heart failure with reduced ejection fraction (HFrEF), comprising 5 females (8.2%) and 6 males (15.4%). Among the 48 patients with HFrEF, 35 were females (57.4%) and 13 were males (33.3%).

ECG analysis revealed prolonged P wave duration in 39 patients, with 3 of them having both prolonged P wave duration and HFpEF. Correlation with HFrEF showed that 34 patients (87.2%) with prolonged P wave duration also had HFrEF. Among the 11 patients with HFpEF, 7 had left ventricular hypertrophy (LVH) with pressure overload, while 4 did not. Furthermore, LVH with pressure overload was significantly associated with HFpEF (p < 0.05). (table2) When correlating ECG changes with iron deficiency anemia, 3 patients with HFpEF had prolonged P wave duration, while 36 patients with prolonged P wave duration did not have HFpEF. No significant association was found between prolonged P wave duration and HFpEF in this study.(table 3)

In our study, correlation of left ventricular hypertrophy (LVH) with pressure overload in patients with heart failure with reduced ejection fraction (HFrEF) showed that 3 patients (6.3%) had LVH with pressure overload, while 45 patients (93.8%) did not, with a nonsignificant p-value of 0.145. Among the HFrEF patients, 27 patients (56.3%) exhibited LVH with volume overload on ECG, while 21 patients (43.8%) did not, with a significant p-value of <0.01, indicating a strong association. In patients with heart failure with preserved ejection fraction (HFpEF) alone, 11 patients had no LVH with volume overload on ECG, with a significant p-value of <0.05.(table 4, figure2)

The study conducted on 100 patients of iron deficiency anemia (IDA) yielded significant insights into its cardiovascular implications: Firstly, the prevalence of IDA was notably higher in females compared to males. Brady et al, also found the similar finding in his study.[11] Fatigue and breathlessness were most common clinical feature of IDA. Nikitha Hegde et al also showed the same result in her study.[12] Moreover, the impact of iron deficiency on the cardiovascular system, particularly the left ventricular (LV) mass, was more pronounced in females.

The investigation assessed the relationship between severe IDA and various clinical manifestations, electrocardiographic (ECG) findings, and echocardiographic observations. Notably, severe IDA was associated with an increase in LV mass, primarily manifesting as eccentric hypertrophy, although some cases exhibited concentric hypertrophy.

The findings of our study shed light on the differential impact of iron deficiency anemia (IDA) on the cardiovascular system, particularly in terms of left ventricular (LV) mass, hypertrophy patterns, and the prevalence of heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF).

We observed that an increase in LV mass was more prevalent in female IDA patients, with eccentric hypertrophy being more common than concentric hypertrophy among females. Additionally, HFrEF was found to be more prevalent than HFpEF in patients with IDA. This was particularly notable in cases of severe IDA, where HFrEF was predominant, possibly due to high output failure characterized by persistent tachycardia and increased stroke volume.

Furthermore, our study revealed gender differences in the distribution of heart failure subtypes, with HFrEF being more common in females and HFpEF more common in males among IDA patients. Electrocardiographic (ECG) findings showed that prolonged P wave duration was predominantly associated with LV HFrEF, suggesting impaired diastolic left ventricular filling. However, contrasting results were shown by Simsek et al in his study that Iron deficiency anemia may be associated with prolonged P wave duration and dispersion and impaired diastolic left ventricular filling. His study found contradicting result when compared to our study because the mean Hb was 7.5±1.6 which is high when compared to mean Hb 5.5gm/dl in our study.[13]

Regarding LV hypertrophy, pressure overload was predominantly associated with HFpEF, whereas volume overload was more common in HFrEF patients. Notably, no patients with HFpEF exhibited left ventricular hypertrophy with volume overload in our study. Furthermore, we observed that despite severe anemia, 41% of patients exhibited no LV dysfunction, particularly among a younger population without additional cardiovascular risk factors. This highlights the complex interplay between IDA severity, age, and cardiovascular outcomes. Nikitha Hegde et al showed that the resting human heart can withstand acute severe isovolemic anemia with hemoglobin levels as low as 5 g/dL, without evidence of inadequate tissue oxygenation. Acute isovolemic reduction to 5 g/dL in 33 healthy resting subjects induced neither hypoxia nor lactic acidosis.[14] The transition from a high-output (compensated) cardiac state to a state of LV dysfunction (decompensated) appears to begin at a hemoglobin level of approximately 7 g/dL in the iron-deficient patient. As the hemoglobin level drops further, so does the LV function. In a study of iron-deficient subjects, 24% of those with hemoglobin levels of less than 5 g/dL manifested congestive heart failure (CHF), compared with 6% of whose hemoglobin levels were between 5 and 7 g/dl.[12]

In summary, our study underscores the multifaceted relationship between IDA and cardiovascular health, emphasizing gender differences, hypertrophy patterns, and heart failure subtypes. These findings contribute to a better understanding of the cardiovascular implications of severe IDA and underscore the need for tailored management strategies in affected populations.

Iron deficiency anemia (IDA) is more prevalent in females and has a greater influence on left ventricular mass. Severe IDA leads to increased left ventricular mass, with eccentric hypertrophy more common. Echocardiography shows hemodynamic changes associated with IDA, which improves oxygen delivery. Severe IDA causes high heart rate and stroke volume, leading to increased cardiac output. Anemia and systolic blood pressure are the most modifiable risk factors for LV hypertrophy. Early diagnosis and management can prevent LV dysfunction and reduce major cardiovascular morbidity and mortality.

Limitation:

In our study, Cardiac evaluation by Echocardiography did not include newer modalities of left ventricular function assessment like longitudinal strain imaging etc. It was limited to functional and structural assessments, and further research is needed to understand the diversified consequences of decreased hemoglobin or serum iron.

1. World Health Organization. Anaemia prevention and control Geneva: WHO; 2011 [cited 2016 Aug 20].
2. Johansen D, Ytrehus K, Baxter GF. Exogenous hydrogen sulfide (H2S) protects against regional myocardial ischemia–reperfusion injury. Basic research in cardiology. 2006;101:53-60.
3. Worldwide prevalence of anaemia 1993-2005 WHO global database on anaemia.
4. National Nutrition Monitoring Bureau, Diet and Nutritional Status of Rural Population and Prevalence of Hypertension among adults in Rural areas, NNMB Technical Report No. 24. Hyderabad: NNMB, NIN; 2006.
5. Cappellini MD, Motta I. Anemia in Clinical Practice-Definition and Classification: Does Hemoglobin Change With Aging? Seminars in Hematology. 2015;52(4):261–9.
6. Camaschella C. Iron-deficiency anemia. New England Journal of Medicine. 2015;372(19):1832–43.
7. McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993–2005. Public Health Nutrition. 2009;12(4):444–54.
8. Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, Regan M, Weatherall D, Chou DP, Eisele TP, Flaxman SR, Pullan RL, Brooker SJ, Murray CJ. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123(5):615–24.
9. Pasricha SR, Drakesmith H, Black J, Hipgrave D, Biggs BA. Control of iron deficiency anemia in low- and middle-income countries. Blood. 2013;121(14):2607–17.
10. Hegde N, Rich MW, Gayomali C. The cardiomyopathy of iron deficiency. Texas Heart Institute Journal. 2006;33(3):340–4.
11. Brady PG. Iron deficiency anemia: a call for aggressive diagnostic evaluation. South Med J. 2007;Oct100(10):966-7.Top of Form
12. Nikita Hegde, Michael W. Rich, Charina Gayomali. The cardiomyopathy of iron deficiency. Tex Heart Inst J. 2006;33(3):340–344.
13. Simsek H, Gunes Y, Demir C, Sahin M, Gumrukcuoglu HA, Tuncer M. The effects of iron deficiency anemia on p wave duration and dispersion. Clinics. 2010 Aug;65(11):1067- 1071.
14. Wang T, Wang M, Fung JW, Yip GW, Zhang Y, Ho PP, et al. Atrial strain rate Echocardiography can predict success or failure of cardioversion for atrial fibrillation: a comparative transthoracic tissue Doppler and transoesphageal imaging study. Int J Cardiol. 2007;Jan 8;114(2):202-9.