Anaemia ↔ Heart Disease: The Vicious Cycle

PART 1: How Anaemia Causes Heart Disease

1. Haemodynamic Compensation → High-Output State

• Decreased blood viscosity → reduced peripheral vascular resistance → vasodilation
• Increased heart rate (tachycardia) and stroke volume → elevated cardiac output
• Neurohormonal activation — increased sympathetic tone and activation of the renin–angiotensin–aldosterone system (RAAS), causing sodium and water retention, further increasing preload

2. Left Ventricular Hypertrophy (LVH) and Dilation

• Sustained volume overload from high-output state leads to eccentric LVH — increased LV internal dimensions with a normal wall-thickness-to-cavity ratio (similar to other volume overload states)
• LV dilation follows, which may be only partially reversible even after anaemia correction
• Anaemia is an independent risk factor for LVH in CKD patients — Comprehensive Clinical Nephrology, 7th Ed.

3. Myocardial Ischaemia

• Anaemia reduces oxygen supply to the myocardium while simultaneously increasing demand (due to tachycardia and increased cardiac work)
• This mismatch can precipitate or worsen angina, trigger arrhythmias (including atrial fibrillation), and increase the risk of myocardial infarction — especially in patients with underlying coronary artery disease
• Tachycardia also shortens diastolic filling time, reducing coronary perfusion

4. Iron Deficiency and Cardiomyocyte Dysfunction

• Impaired activity of respiratory chain complexes I, II, and III
• Reduced contractile function
• Structural cardiac changes: LV hypertrophy, irregular sarcomere organisation, mitochondrial swelling, cardiac fibrosis

PART 2: How Heart Disease Causes Anaemia

1. Renal Dysfunction → Reduced Erythropoietin (EPO) Production

• Heart failure reduces renal perfusion (cardiorenal syndrome)
• Impaired kidneys produce less EPO → anaemia of CKD/cardiorenal anaemia
• EPO deficiency is relative (not absolute), making serum EPO levels unhelpful diagnostically — the level is inappropriately low for the degree of anaemia — Comprehensive Clinical Nephrology, 7th Ed.

2. Neurohormonal Activation → Blunted Erythropoiesis

• Angiotensin II directly inhibits erythroid progenitor cell proliferation
• ACE inhibitors accumulate N-acetyl-seryl-lysyl-proline (Ac-SDKP), an endogenous inhibitor of haematopoiesis, worsening anaemia as a drug side effect
• Reduced endogenous EPO production through haemodynamic effects — Comprehensive Clinical Nephrology, 7th Ed.

3. Chronic Inflammation → Anaemia of Chronic Disease

• Cytokines stimulate hepcidin release from the liver
• Hepcidin internalises and degrades ferroportin → iron sequestration in macrophages and liver → functional iron deficiency despite adequate stores
• Direct suppression of bone marrow erythropoiesis by inflammatory cytokines

4. Nutritional Deficiencies

• Gut oedema in heart failure impairs absorption of iron, B12, and folate
• Reduced appetite, cardiac cachexia, and malnutrition → absolute iron/B12/folate deficiency
• Congestion of the GI mucosa can also cause occult blood loss

5. Haemodilution

• Sodium and water retention in heart failure expands plasma volume → dilutional anaemia (pseudoanaemia)
• Haemoglobin concentration falls even if total red cell mass is normal or near-normal

6. Drug Effects

• ACE inhibitors / ARBs — reduce EPO production and accumulate Ac-SDKP
• Immunosuppressants — myelosuppressive
• SGLT2 inhibitors (notably) reverse this — they increase haematocrit and haemoglobin by reducing plasma volume and stimulating erythropoiesis, often correcting anaemia in HF patients

PART 3: The Vicious Cycle

        ANAEMIA
           ↓
   ↑ Cardiac output
   LV hypertrophy / dilation
   Myocardial ischaemia
           ↓
    HEART FAILURE
           ↓
   ↓ Renal perfusion → ↓ EPO
   ↑ Neurohormonal activation → ↑ hepcidin
   Chronic inflammation
   Malnutrition / malabsorption
   Drug effects (RAAS blockade)
           ↓
       WORSE ANAEMIA
           ↓ (cycle repeats)

PART 4: Specific Clinical Conditions Illustrating This Relationship

Management Implications

• Iron deficiency (with or without anaemia) should be corrected in HF: IV ferric carboxymaltose or ferric derisomaltose improves symptoms, quality of life, and reduces HF hospitalisation (serum ferritin <100 ng/mL, or 100–299 ng/mL with transferrin saturation <20%)
• Erythropoiesis-stimulating agents (e.g., darbepoetin): NOT beneficial in HF with anaemia (trials showed no benefit; possible harm)
• SGLT2 inhibitors: Independently improve haemoglobin/haematocrit in HF and are now standard of care
• Haemoglobin target in CKD: ~10–11 g/dL; aiming higher (>13 g/dL) increases cardiovascular risk (thrombosis, stroke, hypertension)