New‐Onset Acute Heart Failure With Reduced Ejection Fraction Associated With Severe Microcytic Anemia

Authors: Annabel Ricci, Cassandra Hunt, Chabelly Gomez, Gerson Santafe, Aimee Gonzalez, Martha Duarte

Abstract

Severe microcytic anemia may serve as a potentially reversible precipitating factor in heart failure with reduced ejection fraction (HFrEF). This case highlights the diagnostic complexity and hemodynamic consequences of severe, microcytic anemia with undetermined etiology in a patient presenting with newly diagnosed heart failure. A 60‐year‐old Hispanic woman presented with new‐onset acute dyspnea, chest pain, and bilateral edema. Investigations revealed severe microcytic anemia (hemoglobin 4.5 g/dL, MCV 60.8 fL) and an ejection fraction of 33%. Iron studies (iron 40 μg/dL, ferritin 14 ng/mL, total iron binding capacity 541 μg/dL, transferrin saturation 7%) were consistent with presumed iron deficiency anemia. Imaging and fecal occult blood testing did not identify a source of bleeding or malignancy, and endoscopic imaging was not completed due to financial constraints. The patient received packed red blood cells and intravenous iron to stabilize the acute condition. This case highlights the importance of considering severe anemia as a possible precipitating factor in new‐onset heart failure, as well as the need for comprehensive evaluation to identify potentially reversible triggers.

Introduction

Severe anemia is a clinically significant condition diagnosed at hemoglobin levels below 7 g/dL, with increasing mortality at levels below 5 g/dL [1, 2]. As hemoglobin declines, less oxygen is delivered to tissues, triggering compensatory cardiovascular responses to maintain perfusion. These include increases in heart rate, stroke volume, and overall cardiac output, accompanied by reductions in systemic vascular resistance [3]. When sustained, this hyperdynamic state can lead to increased ventricular wall stress, chamber dilation, and eventually systolic dysfunction.

Anemia can be further classified by red blood cell morphology, with microcytic anemia defined by a mean corpuscular volume (MCV) below 80 fL. Iron deficiency is the most common cause of microcytic anemia, but other causes include thalassemia, chronic inflammatory diseases, and lead poisoning [1]. While the relationship between anemia and chronic heart failure is well established, with numerous studies demonstrating associations with worse functional status and increased mortality, the role of severe anemia in newly diagnosed heart failure is less clearly defined [4, 5]. Severe anemia may act as a precipitating factor in de novo heart failure by impairing oxygen delivery and eliciting compensatory hemodynamic responses, which may be partially reversible following correction of the underlying anemia [6, 7]. This distinction highlights the importance of considering severe anemia not only as a comorbidity but also as a potential driver of acute cardiac decompensation in patients without previously diagnosed heart failure.

History of Presentation

A 60‐year‐old Hispanic female with a past medical history of hypertension and obesity presented to the emergency department with acute‐onset shortness of breath, chest pain, and bilateral leg edema. The episode lasted approximately 10 min. No prior similar episodes were reported, and there were no symptoms of nausea, vomiting, dizziness, headache, fever, or recent illness.

Upon arrival, vital signs revealed a blood pressure of 155/90 mmHg, a pulse of 111 beats per minute, a respiratory rate of 17 breaths per minute, and an oxygen saturation of 99% on room air. The physical examination revealed a well‐appearing woman with pale sclera and dry oral mucosa. Cardiovascular examination revealed a grade II holosystolic murmur heard in the accessory aortic focus, jugular venous distention, and 3+ bilateral pitting edema. The remainder of the physical examination was unremarkable. Initial evaluation for myocardial ischemia included serial cardiac troponin measurements, which were mildly elevated (32.5 ng/L, then 29.7 ng/L, then 24.9 ng/L), without a rising trend. Creatine kinase levels remained within normal limits (43 U/L followed by 42 U/L), as did CK‐MB (0.6 ng/mL followed by 0.9 ng/mL) and CK index (1% followed by 2%). This pattern is more consistent with myocardial injury or demand ischemia, although ischemic cardiomyopathy cannot be definitively excluded. The patient had limited English proficiency and lacked health insurance, both of which affected comprehensive evaluation and follow‐up care (Table 1).

Past Medical History

Past medical history was notable for stage 2 hypertension and class 1 obesity (BMI 33.8), with no prior hospitalizations or known history of heart failure. No prior cardiac imaging was reported. Current medications included aspirin 81 mg daily, furosemide 20 mg daily, and metoprolol 25 mg twice daily. The patient reported that furosemide had been prescribed approximately one year prior for hypertension and not for a prior diagnosis of heart failure. There were no known allergies. The patient is unemployed, lives independently, and denies the use of tobacco, alcohol, or illicit drugs. The patient's mother passed away from a cerebral aneurysm, and the rest of the family history is noncontributory.

Differential Diagnosis (Potential Etiologies of Severe Anemia)

Acute Gastrointestinal Bleeding

Acute gastrointestinal bleeding can cause rapid‐onset iron deficiency anemia, leading to fatigue, dyspnea, and hemodynamic instability. The profound microcytosis, low ferritin levels, high total iron binding capacity (TIBC), and low transferrin saturation are consistent with presumed iron deficiency anemia. Although the patient denied melena, hematemesis, or hematochezia, and fecal occult blood testing (FOBT) and computed tomography (CT) imaging were negative, a gastrointestinal source of blood loss cannot be fully ruled out without an endoscopy.

Hypergammaglobulinemia

The patient's serum albumin level was significantly reduced at 1.8 g/dL, while total protein was elevated at 9.1 g/dL. This pattern raises concern for possible hypergammaglobulinemia, as elevated total protein in the setting of hypoalbuminemia suggests increased globulin fractions; however, serum protein electrophoresis (SPEP) was not performed due to cost. The ferritin level was low (14 ng/mL), which supports a diagnosis of presumed iron‐deficiency anemia; however, ferritin is an acute‐phase reactant. This means that ferritin can be influenced by inflammatory states, potentially limiting its ability to accurately reflect total body iron [8]. As a result, the measured ferritin value may overestimate true iron stores and underestimate the severity of iron deficiency. Additionally, there was no evidence of hepatic impairment, and urinalysis did not show proteinuria. The hypoalbuminemia may have contributed to bilateral lower extremity edema by reducing plasma oncotic pressure, leading to fluid accumulation in the interstitial space.

Hematologic Malignancy

Hematologic malignancy was a differential diagnosis given the anemia severity and the patient's age. However, the absence of weight loss, constitutional symptoms, lymphadenopathy, or findings on peripheral blood smear made this less likely.

Autoimmune Hemolytic Anemia (AIHA)

AIHA was considered, given the elevated LDH of 387 U/L and anemia, but the absence of jaundice, normal bilirubin levels, and a negative direct Coombs test ruled out hemolysis.

Thalassemia

Thalassemia trait was considered; however, the severity of anemia and iron studies showing low ferritin and elevated TIBC are more consistent with iron deficiency anemia, making this less likely, though it cannot be excluded without hemoglobin electrophoresis.

Nutritional Deficiency

Nutritional deficiency was considered; however, deficiencies such as vitamin B12 or folate typically cause macrocytic anemia, making this less likely given the patient's microcytosis (Table 2).

Investigations

Iron studies (iron 40 μg/dL, ferritin 14 ng/mL, total iron binding capacity 541 μg/dL, transferrin saturation 7%) were consistent with presumed iron deficiency anemia, supported by low iron, low ferritin, elevated TIBC, and low transferrin saturation; however, the ferritin level was only borderline low relative to the severity of the anemia. The reticulocyte count was 1.96%, which was mildly elevated by laboratory reference standards but may be inappropriately low given the degree of anemia. Additional laboratory results included glucose 132 mg/dL, total bilirubin 0.4 mg/dL (direct 0.3 mg/dL, indirect 0.1 mg/dL), total protein 9.9 g/dL, albumin 1.8 g/dL, and NT‐proBNP 2678 pg/mL. LDH was mildly elevated at 387 U/L, and a peripheral blood smear revealed normal leukocyte and platelet morphology, without blasts or dysplastic changes. Urinalysis, coagulation studies, direct Coombs test, and fecal occult blood test were unremarkable. Vitamin B12, folate, haptoglobin, serum protein electrophoresis, erythrocyte sedimentation rate, fibrinogen levels, beta‐2 microglobulin, serum kappa light chains, cold agglutinin titers, and IgG warm agglutinin levels were ordered but not completed due to cost. Endoscopy was also not performed due to financial constraints.

Bilateral lower extremity ultrasound showed no evidence of deep venous thrombosis (DVT). Chest radiography demonstrated an enlarged cardiac silhouette but was otherwise unremarkable. Transthoracic echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 33% (normal > 55%). The electrocardiogram showed absent T waves and a left bundle branch block. CT of the abdomen and pelvis revealed fatty liver without acute pathology (Figures 1, 2, 3).

Management

Based on pre‐hospital functional capacity, the patient likely met New York Heart Association (NYHA) Class III criteria, indicating significant limitation in activity with symptoms occurring when walking a short distance [9].

The patient was managed with guideline‐directed medical therapy for heart failure, including intravenous furosemide 20 mg every 12 h, metoprolol 25 mg orally twice daily, lisinopril 5 mg orally once daily, and spironolactone 25 mg orally once daily. Hydralazine 20 mg was administered intravenously as needed for blood pressure control.

The transfusion guidelines recommend administering blood at a hemoglobin level of 7 g/dL; therefore, two units of packed red blood cells were administered. The transfusion was administered at a controlled rate with close monitoring of volume status, including serial vital signs, respiratory assessment, and strict intake and output tracking to reduce the risk of transfusion‐associated circulatory overload. The hemoglobin and hematocrit post‐first blood transfusion were 6.6 g/dL and 22.4%, respectively, and then 8.3 g/dL and 28.6% following the second transfusion.

Iron was administered in two doses of 100 mg of iron sucrose diluted in normal saline, infused intravenously. In patients with HFrEF and iron deficiency, intravenous iron therapy has been shown to improve functional capacity and reduce heart failure hospitalizations [10].

Outcome and Follow‐Up

Throughout the patient's hospital stay, clinical improvement was noted, but a follow‐up echocardiogram was not performed. The patient reported resolution of shortness of breath and chest pain. The physical examination on discharge revealed improvement in the lower leg edema with 1+ in the right and 2+ in the left lower extremity. Causality between anemia correction and improvement in systolic function could not be objectively confirmed due to the absence of repeat imaging.

Due to the patient's improved status and financial constraints, the patient was discharged. At discharge, guideline‐directed medical therapy, including metoprolol 25 mg, furosemide 20 mg, lisinopril 5 mg, spironolactone 12.5 mg, and aspirin 81 mg, was prescribed, and continuation of iron supplementation was recommended. The patient was instructed to obtain outpatient follow‐up with primary care and cardiology; however, the patient was lost to follow‐up, and data are unavailable.

Discussion

Structural and functional cardiovascular disorders highlight the inherently unpredictable and potentially fatal trajectory of cardiovascular disease, reinforcing the need for early recognition and comprehensive investigation of potentially reversible triggers, as illustrated in this case of severe microcytic anemia associated with new‐onset HFrEF [11]. The literature on microcytic anemia in the setting of acute heart failure focuses on hemoglobin levels of 10‐12 g/dL [12]. In this case, the severity of anemia is clinically significant. When hemoglobin levels decline, the body compensates by increasing cardiac output and heart rate, along with increasing peripheral vasodilation, to maintain tissue perfusion. Although initially adaptive, this sustained hyperdynamic state may increase ventricular wall stress and, over time, contribute to a mismatch between circulatory demand and cardiac capacity [3]. These changes promote chamber dilation and eccentric left ventricular remodeling [4]. As the compensatory mechanisms become fatigued, this process may lead to systolic dysfunction.

Cardiac remodeling may be further driven by neurohormonal activation. The sympathetic nervous system and the renin–angiotensin–aldosterone system can exacerbate ventricular dysfunction by inducing sodium and water retention, increasing afterload, and promoting progressive myocardial fibrosis [4, 5]. These processes highlight how severe anemia, even in the absence of primary structural heart disease, can initiate a cascade leading to clinically significant heart failure.

Case‐based and observational data suggest that correcting severe anemia may improve ventricular function, particularly if the intervention occurs before irreversible remodeling develops [6]. Similar mechanisms were described in a case report of a 44‐year‐old man with a hemoglobin of 1.8 g/dL who developed HFrEF that resolved completely following blood transfusion and iron repletion [13].

Iron deficiency, on its own, may further impair heart function. It is prevalent in heart failure as it is seen in approximately 40%–60% of patients with HFrEF [14]. Beyond its hematologic role, iron is essential for mitochondrial function and cellular energetics. Therefore, iron deficiency may impair myocardial performance by reducing the efficacy of cardiac muscle contractions even in the absence of significant anemia [15]. Randomized controlled trials, including FAIR‐HF and AFFIRM‐AHF, have demonstrated that intravenous iron supplementation can improve symptoms, exercise tolerance, and quality of life in individuals with heart failure, with the AFFIRM‐AHF trial showing a reduction in heart failure hospitalizations [10, 16]. However, the largest trial to date, HEART‐FID, did not show a statistically significant improvement on the composite endpoint of death, heart failure hospitalizations, and six‐minute walk distance, highlighting ongoing uncertainty regarding the overall clinical impact of iron repletion in this population [17]. Although intravenous iron was administered in this case, the absence of follow‐up limits assessment of its therapeutic impact.

This case also highlights the impact of socioeconomic determinants on both diagnostic evaluation and disease severity. The patient's lack of insurance contributed to an incomplete diagnostic evaluation. As a result, the etiology of the patient's severe microcytic anemia remained undetermined. Additionally, the severity of presentation may have been influenced by social determinants of health. Black and Hispanic populations experience a greater burden of heart failure and poorer outcomes, in part due to disparities in access to care [18]. These factors highlight the importance of addressing systemic barriers to ensure timely diagnosis and appropriate management of potentially reversible conditions.

In contrast to chronic heart failure, where anemia is typically a comorbidity associated with worse prognosis, this case raises the possibility of anemia functioning as a precipitating factor in de novo heart failure. Anemia has been consistently associated with reduced functional capacity, increased hospitalizations, and higher mortality in heart failure populations; however, its role in initiating cardiac dysfunction is less well established [4, 5]. This distinction highlights the need to consider severe anemia not only as a marker of disease severity but also as a reversible contributor to acute cardiac dysfunction.

The principal limitations of this case include its single‐patient design, incomplete evaluation of anemia etiology, absence of post‐treatment cardiac imaging, and confounding comorbid conditions, which restrict long‐term prognostic conclusions.

Conclusion

This case highlights severe microcytic anemia as a potential precipitating factor in acute heart failure with reduced ejection fraction, emphasizing the importance of identifying anemia not only as a comorbid condition but also as a possible driver of decompensation. The physiologic consequences of profound anemia may contribute to cardiac dysfunction; however, definitive causality cannot be established without comprehensive diagnostic evaluation and follow‐up imaging. In this case, incomplete workup and loss to follow‐up, influenced by social determinants of health, limited the ability to determine the underlying etiology of anemia and assess reversibility of systolic dysfunction. These findings underscore the importance of thorough evaluation, timely investigation of anemia prior to discharge, and appropriate longitudinal follow‐up to guide management and improve outcomes in similar patients.

Author Contributions

Annabel Ricci: writing – original draft, writing – review and editing. Cassandra Hunt: data curation, writing – original draft. Chabelly Gomez: formal analysis, supervision, writing – review and editing. Gerson Santafe: formal analysis, supervision, writing – review and editing. Aimee Gonzalez: formal analysis, supervision. Martha Duarte: formal analysis, supervision.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying clinical details.

Conflicts of Interest

The authors declare no conflicts of interest.