European Journal of Cardiovascular Medicine

Pulmonary arterial hypertension (PAH) is a rare but serious disorder characterized by increased pulmonary vascular resistance, leading to right ventricular hypertrophy and eventual heart failure. The etiology of PAH is multifactorial, with genetic, environmental, and comorbid conditions contributing to its development.

Iron deficiency anaemia (IDA) and vitamin B12 deficiency anaemia are two common hematological disorders that can lead to systemic hypoxia and endothelial dysfunction. Recent studies indicate that iron metabolism plays a crucial role in pulmonary vasculature, and deficiencies in iron and vitamin B12 may contribute to the pathogenesis of PAH.

Chronic anaemia leads to reduced oxygen-carrying capacity, inducing compensatory mechanisms such as increased cardiac output and altered vascular tone. IDA is known to impair nitric oxide (NO) metabolism, increase oxidative stress, and promote vascular remodeling. Similarly, vitamin B12 deficiency is associated with elevated homocysteine levels, which can result in endothelial dysfunction and increased pulmonary arterial pressures.

Given the global burden of anaemia—affecting over 1.6 billion people worldwide—understanding its role in PAH is critical for early detection and management. This study assesses the prevalence of PAH in patients diagnosed with IDA and vitamin B12 deficiency anaemia, exploring potential pathophysiological mechanisms and implications for clinical management.

Genetic Susceptibility: Bridging Hereditary PAH and Anemia-Related PAH

BMPR2 Mutations and Iron Metabolism Crosstalk

The bone morphogenetic protein receptor type 2 (BMPR2) gene plays a crucial role in PAH pathogenesis, with loss-of-function mutations present in >50% of hereditary PAH cases [1]. These mutations disrupt TGF-β signaling pathways, leading to uncontrolled pulmonary vascular remodeling. Interestingly, iron deficiency has been shown to downregulate BMP/Smad signaling independently, creating a potential synergistic effect in patients with both genetic predisposition and acquired iron deficiency [2].

The HFE gene mutations associated with hereditary hemochromatosis (particularly C282Y and H63D variants) demonstrate complex interactions with PAH development in anemic patients [3]. While systemic iron overload occurs in hemochromatosis, pulmonary iron deposition patterns may paradoxically influence PAH progression. Animal models suggest hepatic iron accumulation may be protective against PAH by reducing pulmonary oxidative stress [4].

Hypoxia-Inducible Factor (HIF) Polymorphisms

Genetic variations in hypoxia response pathways significantly modify PAH risk in anemic populations:

• HIF1A Pro582Ser variant enhances hypoxic responses and is particularly prevalent in high-altitude populations.
• EGLN1 mutations alter prolyl hydroxylase domain 2 (PHD2) function, stabilizing HIF-2α and increasing erythropoietin production.
• VHL gene mutations (associated with Chuvash polycythemia) demonstrate how dysregulated hypoxia sensing contributes to PAH.

Study Objectives

This study aims to:

1. Determine the prevalence of PAH in patients with IDA and vitamin B12 deficiency anaemia.
2. Evaluate the clinical and demographic characteristics of affected patients.

Study Design

A retrospective cross-sectional study was conducted using data from clinical records of patients diagnosed with IDA and vitamin B12 deficiency anaemia. Pulmonary arterial pressures were assessed using echocardiography.

Patient Selection Criteria

• Inclusion criteria:
• Patients aged 18–70 years with confirmed laboratory diagnoses of IDA (serum ferritin <15 ng/mL) or vitamin B12 deficiency (serum B12 <200 pg/mL).
• Diagnosis of PAH based on echocardiography (Pulmonary Artery Systolic Pressure ≥35 mmHg).
• Exclusion criteria:
• Patients with known congenital heart disease/rheumatic heart disease
• Chronic obstructive pulmonary disease (COPD),
• Pre-existing pulmonary hypertension.
• Chronic kidney disease (CKD) or severe systemic infections
• Collagen vascular diseases

Data Collection

Demographic information, haemoglobin levels, ferritin levels, vitamin B12 levels, echocardiographic findings, and pulmonary arterial pressures were collected.

Statistical Analysis

Data were analyzed using SPSS 25.0. Prevalence rates of PAH in IDA and vitamin B12 deficiency anaemia groups were compared using chi-square tests. Correlations between haemoglobin levels and pulmonary pressures were assessed using Pearson correlation coefficients. Multivariate regression models were used to adjust for potential confounding factors such as age, gender, and comorbidities.

Patient Demographics

Demographic Characteristics of Study Population (n=344)

1. Sex Distribution

Key Findings:

• Significant female predominance (62.8% of total cohort)
• Females had significantly higher PAH prevalence (47.7% vs 30.5% in males, p=0.002)
• Male patients were more likely to be in the PAH- group (69.5%)

2. Age Distribution

Age Stratification:

Key Findings:

• No significant age difference between PAH+ and PAH- groups (p=0.24)
• Majority of patients were middle-aged (31-60 years: 73.9% of total)
• Similar age distribution patterns in both PAH+ and PAH- groups

3. Sex-Specific Age Characteristics

Clinical Implications:

1. The female predominance (62.8%) suggests possible hormonal influences on PAH development in anemia patients
2. The peak prevalence in reproductive-age females (31-45 years) may indicate menorrhagia as a contributing factor to iron deficiency
3. The lack of age difference between PAH+/- groups suggests age is not a primary risk factor in this population

Prevalence of PAH in Anaemia Patients

Overall PAH Prevalence

PAH Prevalence by Anemia Type

1. Iron Deficiency Anemia (IDA) vs. Non-IDA

Key Finding:

• PAH was 3× more prevalent in iron-deficient patients (59.9% vs. 19.1%, p<0.001).

2. Vitamin B12 Deficiency vs. Sufficiency

Key Finding:

• B12-deficient patients had significantly lower PAH prevalence (22.3% vs. 60.9%, p<0.001).

Key Findings

1. Higher prevalence of PAH in anaemic patients compared to the general population.
2. IDA and vitamin B12 deficiency appear to contribute to pulmonary vascular remodeling.
3. Female patients are at greater risk, potentially due to hormonal or genetic factors.
4. Correlations between low haemoglobin levels and increased pulmonary artery pressures suggest a causal relationship.

Clinical Implications

Given these findings, we recommend:

• Routine echocardiographic screening for patients with severe anaemia.
• Early intervention strategies include iron and vitamin B12 supplementation.
• Further research into the molecular mechanisms linking anaemia to PAH.

This study highlights a significant association between PAH and hematological deficiencies such as IDA and vitamin B12 deficiency. Given the potential impact on pulmonary circulation, routine screening for PAH in anaemic patients may be beneficial. Future research should focus on mechanistic pathways and potential interventions to reduce the burden of PAH in these populations.

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