Why is there cachexia in heart failure with reduced ejection fraction

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heart failure cachexia mechanisms review

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In HFrEF, cachexia is a systemic catabolic state, not simply “poor appetite.” It usually occurs in advanced, longstanding heart failure when several processes reinforce each other:

Low cardiac output and poor tissue perfusion reduce skeletal-muscle blood flow and exercise capacity. Inactivity then accelerates muscle loss.
Chronic sympathetic and RAAS activation increases energy expenditure and promotes catabolism. Angiotensin II also has anorexigenic effects, contributing to reduced food intake and weight loss.
Inflammation drives protein and fat breakdown. TNF-alpha, IL-1, and IL-6 promote skeletal-muscle proteolysis, impair anabolic signaling, and contribute to anorexia. Harrison’s describes gut congestion, intestinal permeability, endotoxin exposure, and cytokine activation as contributors to cardiac cachexia. [Harrison’s Principles of Internal Medicine, p. 2025]
Venous and intestinal congestion cause bowel-wall edema, early satiety, nausea, impaired nutrient absorption, and sometimes intestinal ischemia. This both reduces intake and amplifies systemic inflammation.
Neurohormonal and metabolic abnormalities including insulin resistance, reduced anabolic hormones, mitochondrial dysfunction, and an imbalance favoring muscle proteolysis over synthesis cause loss of lean mass.
Renal dysfunction and repeated decompensations add uremia, inflammation, dietary restriction, hospitalization, and further loss of appetite and muscle.

So the central sequence is:

HFrEF severity -> low output plus venous gut congestion -> neurohormonal activation and inflammation -> anorexia, malabsorption, hypercatabolism, and muscle proteolysis -> cardiac cachexia.

Clinically, cardiac cachexia is often described as unintentional, edema-free weight loss exceeding 5% over 12 months, with visible temporal or upper-body muscle wasting. It is a poor prognostic marker, as supported by recent systematic-review evidence and a 2025 meta-analysis.

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