Iron deficiency anemia (IDA) constitutes the most prevalent nutritional deficiency disorder worldwide, affecting approximately 1.2 billion individuals globally and representing a significant public health concern [1]. Beyond its hematological manifestations, accumulating evidence suggests that IDA exerts profound effects on cardiovascular physiology through multiple pathogenic mechanisms including impaired oxygen delivery, compensatory hemodynamic alterations, and direct myocardial cellular effects [2].

The cardiovascular system responds to chronic anemia through various adaptive mechanisms, including increased cardiac output, reduced systemic vascular resistance, and neurohormonal activation [3]. These compensatory responses, while initially beneficial, may predispose to maladaptive cardiac remodeling over time. Jankowska and colleagues demonstrated that iron deficiency, independent of anemia, adversely affects prognosis in chronic heart failure patients, highlighting the importance of iron homeostasis in cardiac function [4].

Contemporary research has increasingly focused on subclinical cardiac abnormalities detectable through advanced imaging modalities before the onset of symptomatic heart disease. Speckle-tracking echocardiography (STE) enables precise quantification of myocardial deformation through global longitudinal strain (GLS) analysis, demonstrating superior sensitivity compared to conventional ejection fraction measurements for detecting early myocardial dysfunction [5]. Studies have established GLS as a robust predictor of cardiovascular outcomes across diverse pathological conditions [6].

The relationship between IDA and subclinical cardiac dysfunction has garnered increasing attention. Anker and colleagues established the therapeutic benefit of iron repletion in heart failure patients with iron deficiency, suggesting a causative role of iron metabolism in cardiac pathophysiology [7]. Furthermore, investigations have revealed that iron deficiency impairs mitochondrial function and oxidative metabolism in cardiomyocytes, potentially explaining the observed cardiac manifestations [8].

Diastolic dysfunction represents an early manifestation of cardiac impairment preceding systolic abnormalities. Tissue Doppler imaging provides sensitive assessment of myocardial relaxation velocities, and the E/e' ratio serves as a validated surrogate marker of left ventricular filling pressures [9]. Previous studies examining diastolic function in anemic populations have yielded variable results, necessitating further investigation [10].

Despite existing literature, significant knowledge gaps remain regarding the prevalence and determinants of subclinical cardiac dysfunction specifically in adults with mild-to-moderate IDA without pre-existing cardiovascular disease. Most prior investigations focused on severe anemia or populations with established cardiac pathology. Additionally, comprehensive assessment combining conventional echocardiography, tissue Doppler imaging, and speckle-tracking analysis in this population remains limited [11].

The aim of this study was to evaluate the association between iron deficiency anemia and subclinical cardiac dysfunction using comprehensive echocardiographic assessment including speckle-tracking strain analysis in adults without known cardiovascular disease.

Study Design and Population

This cross-sectional observational study was conducted at the University Teaching Hospital.

Sample Size Calculation

Sample size was calculated using G*Power software (version 3.1.9.7) based on detecting a medium effect size (d=0.5) for GLS differences between groups, with 80% power and 5% significance level. The minimum required sample size was 64 participants per group. To account for potential dropouts and incomplete data, 93 participants were enrolled in each group.

Participant Selection

The study enrolled 93 adults diagnosed with iron deficiency anemia (IDA group) and 93 age- and sex-matched healthy controls. IDA was defined according to World Health Organization criteria: hemoglobin concentration <12 g/dL in females and <13 g/dL in males, combined with serum ferritin <30 ng/mL and transferrin saturation <20%.

Inclusion criteria comprised: age 18-60 years, confirmed diagnosis of IDA, willingness to participate, and adequate echocardiographic image quality. Exclusion criteria included: known cardiovascular disease (coronary artery disease, heart failure, valvular heart disease, cardiomyopathy), hypertension (blood pressure >140/90 mmHg or antihypertensive medication use), diabetes mellitus, chronic kidney disease (estimated GFR <60 mL/min/1.73m²), chronic liver disease, thyroid disorders, malignancy, pregnancy, obesity (BMI >35 kg/m²), current smoking, and conditions causing secondary anemia (hemoglobinopathies, chronic inflammatory diseases, hemorrhagic disorders).

Clinical and Laboratory Assessment

All participants underwent comprehensive clinical evaluation including detailed medical history, physical examination, and anthropometric measurements. Blood pressure was measured using calibrated sphygmomanometers following standardized protocols after 10 minutes of rest. Body mass index was calculated as weight (kg) divided by height squared (m²).

Venous blood samples were collected following overnight fasting for laboratory analysis including complete blood count, serum iron, ferritin, total iron-binding capacity, transferrin saturation, fasting glucose, lipid profile, renal function tests, and liver function tests. All analyses were performed using standardized automated analyzers.

Echocardiographic Examination

Comprehensive transthoracic echocardiography was performed using Philips EPIQ CVx ultrasound system (Philips Healthcare, Andover, MA, USA) equipped with X5-1 transducer. All examinations were conducted by experienced cardiologists blinded to participants' clinical status, following American Society of Echocardiography guidelines.

Conventional parameters assessed included left ventricular end-diastolic diameter (LVEDD), end-systolic diameter (LVESD), interventricular septal thickness (IVSd), posterior wall thickness (PWd), left atrial diameter (LAD), and left atrial volume index (LAVI). Left ventricular ejection fraction (LVEF) was calculated using Simpson's biplane method. Relative wall thickness (RWT) and left ventricular mass index (LVMI) were calculated using standard formulas.

Diastolic function assessment included pulsed-wave Doppler of mitral inflow for peak early (E) and late (A) velocities, E/A ratio, and E-wave deceleration time. Tissue Doppler imaging was performed at septal and lateral mitral annulus for early (e') and late (a') diastolic velocities. Average E/e' ratio was calculated.

Speckle-Tracking Echocardiography

Two-dimensional speckle-tracking analysis was performed using QLAB software (Version 13.0, Philips Healthcare). Apical four-chamber, two-chamber, and three-chamber views were acquired at frame rates of 60-80 frames/second. Global longitudinal strain (GLS) was calculated as the average of peak systolic strain values from all segments. Regional strain analysis was performed for basal, mid, and apical segments.

Statistical Analysis

Statistical analysis was performed using SPSS software (Version 26.0, IBM Corporation, Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation after confirming normal distribution using Shapiro-Wilk test. Categorical variables were presented as frequencies and percentages. Between-group comparisons utilized independent samples t-test for continuous variables and chi-square test for categorical variables. Pearson correlation coefficients assessed relationships between continuous variables. Multiple linear regression analysis identified independent predictors of cardiac dysfunction parameters. Statistical significance was defined as p<0.05.

Baseline Characteristics

Baseline demographic, clinical, and laboratory characteristics of study participants are presented in Table 1. The IDA and control groups were well-matched for age (38.4 ± 11.2 vs 37.9 ± 10.8 years, p=0.756), sex distribution (68.8% vs 66.7% female, p=0.753), and body mass index (24.3 ± 3.6 vs 24.8 ± 3.4 kg/m², p=0.326). Hemoglobin levels were significantly lower in IDA patients (9.8 ± 1.4 vs 14.2 ± 1.1 g/dL, p<0.001). Iron studies demonstrated markedly reduced serum iron (38.2 ± 14.6 vs 98.4 ± 22.3 μg/dL, p<0.001), ferritin (12.4 ± 6.8 vs 78.6 ± 32.4 ng/mL, p<0.001), and transferrin saturation (11.8 ± 4.2 vs 28.6 ± 8.4%, p<0.001) in the IDA group.

Table 1: Baseline Demographic, Clinical, and Laboratory Characteristics

BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; MCV: mean corpuscular volume; TIBC: total iron-binding capacity; eGFR: estimated glomerular filtration rate

Conventional Echocardiographic Parameters

Conventional echocardiographic findings are summarized in Table 2. Left ventricular dimensions and wall thicknesses were comparable between groups. LVEF was preserved in both groups but significantly lower in IDA patients (58.2 ± 4.6% vs 62.4 ± 3.8%, p<0.001). Left atrial volume index was significantly elevated in the IDA group (32.4 ± 6.8 vs 26.7 ± 5.2 mL/m², p<0.001). Cardiac output was higher in IDA patients (5.8 ± 1.2 vs 4.9 ± 0.9 L/min, p<0.001), reflecting compensatory mechanisms.

Diastolic function parameters demonstrated significant abnormalities in IDA patients. The E/e' ratio was markedly elevated (9.8 ± 2.7 vs 7.2 ± 1.8, p<0.001), while septal and lateral e' velocities were significantly reduced. Diastolic dysfunction (grade I or higher) was present in 38.7% of IDA patients compared to 8.6% of controls (p<0.001).

Table 2: Conventional Echocardiographic Parameters

LVEDD: left ventricular end-diastolic diameter; LVESD: left ventricular end-systolic diameter; IVSd: interventricular septal thickness in diastole; PWd: posterior wall thickness in diastole; RWT: relative wall thickness; LVMI: left ventricular mass index; LVEF: left ventricular ejection fraction; LAD: left atrial diameter; LAVI: left atrial volume index; DT: deceleration time

Speckle-Tracking Strain Analysis

Global longitudinal strain analysis revealed significant impairment in IDA patients (Table 3). GLS was markedly reduced in the IDA group (-17.8 ± 2.4% vs -20.6 ± 1.9%, p<0.001). Regional analysis demonstrated that strain impairment affected all segments, with basal segments showing the greatest difference (-16.2 ± 2.8% vs -19.4 ± 2.2%, p<0.001). Abnormal GLS (>-18%) was present in 52.7% of IDA patients compared to 11.8% of controls (p<0.001).

Table 3: Speckle-Tracking Strain Parameters

GLS: global longitudinal strain

Correlation and Regression Analysis

Hemoglobin levels demonstrated significant positive correlation with GLS (r=0.52, p<0.001) and negative correlation with E/e' ratio (r=-0.48, p<0.001). Ferritin levels correlated positively with GLS (r=0.46, p<0.001) and e' velocity (r=0.42, p<0.001). Multiple linear regression analysis identified ferritin (β=-0.34, p=0.002), hemoglobin (β=-0.29, p=0.008), and heart rate (β=0.18, p=0.042) as independent predictors of GLS after adjusting for age, sex, and BMI.

The present study demonstrates that iron deficiency anemia is significantly associated with subclinical left ventricular systolic and diastolic dysfunction in adults without known cardiovascular disease. Patients with IDA exhibited impaired global longitudinal strain, elevated filling pressures, and increased prevalence of diastolic dysfunction compared to matched healthy controls, despite preserved ejection fraction.

Our finding of reduced GLS in IDA patients (-17.8 ± 2.4% vs -20.6 ± 1.9%) aligns with emerging evidence supporting the sensitivity of strain imaging in detecting early myocardial dysfunction. Previous investigations by Potaczek and colleagues demonstrated similar GLS impairment in patients with chronic anemia of various etiologies [12]. The magnitude of strain reduction observed in our cohort, while indicating subclinical dysfunction, represents clinically meaningful differences associated with adverse cardiovascular outcomes in population-based studies [13].

The pathophysiological mechanisms underlying cardiac dysfunction in IDA are multifactorial. Chronic tissue hypoxia resulting from reduced oxygen-carrying capacity triggers compensatory cardiac responses including increased heart rate and stroke volume [14]. Our observation of elevated resting heart rate and cardiac output in IDA patients reflects these hemodynamic adaptations. However, sustained compensation may ultimately prove detrimental, precipitating myocardial remodeling and dysfunction [15].

Beyond hemodynamic effects, iron deficiency exerts direct cellular impacts on cardiomyocyte function. Iron serves as an essential cofactor for mitochondrial respiratory chain enzymes, and its depletion impairs oxidative phosphorylation and energy production [16]. Haddad and colleagues demonstrated that iron-deficient cardiomyocytes exhibit contractile dysfunction and increased susceptibility to oxidative stress, providing mechanistic explanation for our observations [17].

The significant diastolic dysfunction observed in our IDA cohort merits particular attention. Elevated E/e' ratio and reduced tissue Doppler velocities indicate impaired myocardial relaxation and elevated filling pressures. These findings corroborate earlier reports by Nair and colleagues who documented diastolic abnormalities in anemic patients [18]. Diastolic dysfunction represents an early manifestation of cardiac impairment that may precede systolic abnormalities and predispose to heart failure with preserved ejection fraction [19].

Left atrial volume index elevation in IDA patients reflects chronic diastolic burden and provides structural evidence of sustained filling pressure elevation. LA enlargement constitutes an established predictor of adverse cardiovascular events and validates the clinical relevance of our functional findings [20].

The strong correlation between iron status parameters and cardiac function measures supports a dose-response relationship. Both hemoglobin and ferritin levels independently predicted GLS impairment in multivariate analysis, suggesting that both anemia severity and iron stores contribute to cardiac dysfunction. This observation aligns with the FAIR-HF trial demonstrating that iron repletion improves symptoms and functional capacity in heart failure patients regardless of hemoglobin correction [21].

Our findings have important clinical implications. The high prevalence of subclinical cardiac dysfunction (52.7% with abnormal GLS) in asymptomatic IDA patients suggests that cardiovascular assessment may be warranted in this population. Early identification enables timely intervention through iron supplementation, potentially preventing progression to overt cardiac disease [22].

Several limitations should be acknowledged. The cross-sectional design precludes establishing causality between IDA and cardiac dysfunction. Selection of hospital-based participants may limit generalizability. Duration of anemia, which likely influences cardiac adaptation, could not be accurately determined. Additionally, right ventricular function assessment was not comprehensively performed. Future prospective studies examining cardiac changes following iron repletion therapy are warranted [23].

This study demonstrates a significant association between iron deficiency anemia and subclinical left ventricular systolic and diastolic dysfunction in adults without established cardiovascular disease. Patients with IDA exhibited impaired global longitudinal strain, elevated filling pressures, and increased left atrial volume despite preserved ejection fraction. Iron status parameters, including hemoglobin and ferritin levels, independently predicted the degree of cardiac dysfunction. These findings underscore the importance of cardiovascular evaluation in IDA patients and suggest potential benefits of early iron repletion in preventing cardiac complications. Integration of speckle-tracking echocardiography in the assessment of IDA patients may enable early detection of subclinical cardiac abnormalities, facilitating timely therapeutic intervention and potentially improving long-term cardiovascular outcomes.

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