Letter regarding the article “Hypocapnia is an independent predictor of in‐hospital mortality in acute heart failure”

The role of hypocapnia in acute heart failure (AHF) remains poorly understood. Tang and colleagues found that hypocapnia was associated with worse renal and cardiac function and a higher in‐hospital, all‐cause mortality in a cohort of patients with AHF. ¹ Respiratory rate was similar (approximately 20 breaths per minute; P = 0.857) for those with or without hypocapnia, suggesting that increased ventilation was not responsible for hypocapnia. Interestingly, the authors report that patients receiving SGLT2 inhibitors were less likely to have hypocapnia (P = 0.032); a difference that remained even after a propensity score matched analysis (P = 0.014).

Sodium/glucose cotransporter 2 inhibitors reduce glucose utilization in favour of a higher proportion of energy derived from beta‐oxidation of fatty acids. ² Glucose is a six‐carbon molecule rather than a longer carbon‐chain fatty‐acid. Glucose oxidation requires less oxygen, produces less CO₂ but also produce less ATP, with an even greater reduction of CO₂ and ATP production if the process occurs in anaerobiosis, which leads to increased lactate production. In contrast, fatty‐acid oxidation requires more oxygen, produces more CO₂, but generates at least three times more ATP molecules than glucose oxidation, depending on the length of the long‐chain fatty acid (LCFA). In fact, it is possible to predict how many ATP molecules can be obtained from a LCFA depending on the length and saturation of the fatty‐acid. For a saturated, even‐numbered fatty acid of 16 carbons (e.g. palmitic acid), the formula {ATP = [7 · (C‐2)] + 8} provides an estimate of 106 ATP molecules produced. ³ Ketones are a by‐product of and signal for LCFA metabolism, but ketones might also be an efficient substrate for energy production in failing cardiac myocytes².

The stoichiometry of the two chemical reactions to produce energy from glucose and palmitic acid are shown:

Glucose oxidation:

• during aerobiosis: C ₆ H₁₂O₂ + 6 O₂ $->$ 6 CO ₂  +  36 ATP + 6 H₂O

• during anaerobiosis: C ₆ H₁₂O₂ $->$ 2 ATP + 2 Lactate

Fatty acid oxidation (e.g. 16 C):

• C ₁₆ H₁₂O₂ + 23 O₂ ‐ >  16 CO ₂  +  106 ATP  + H₂O

With worsening haemodynamics, less oxygen is delivered to the tissues in combination with a metabolic reprogramming of the failing cardiomyocyte, whereby aerobic or anaerobic glucose utilization displaces fatty acid oxidation as the energy supply. ² If so, lower pCO₂ and higher lactate should reflect less ATP and lead to worse cardiac and renal function and worse outcomes. Moreover, lower pCO₂ may conspire with lower pO₂ levels ⁴ to feed a vicious cycle of increased glycolysis.

Gliflozins, by increasing fatty acids oxidation, ² should increase pCO₂, which might improve outcome, consistent with the authors' findings. Hypocapnia may be a useful marker of the metabolic substrate and explain, at least in part, the mechanism of action and benefits of gliflozins. Further research to understand the prevalence and significance of hypocapnia in other clinical settings and any interaction with the benefits of sodium/glucose cotransporter 2 inhibitor is warranted.

Guarnaccia, A. , Sinagra, G. , and Cleland, J. G. F. (2023) Letter regarding the article “Hypocapnia is an independent predictor of in‐hospital mortality in acute heart failure”. ESC Heart Failure, 10: 3232–3233. 10.1002/ehf2.14495.