Highlights
10.7% of outpatients with heart failure and reduced ejection fraction (HFrEF) exhibited hypermagnesemia (>0.95 mmol/L).
Hypermagnesemia was associated with the highest incidence rate of the primary composite outcome (34.9 per 100 person-years) compared to normal or low levels.
Contrary to traditional belief, magnesium abnormalities were not associated with an increased risk of sudden death or ventricular tachyarrhythmias.
The findings suggest that elevated magnesium is a stronger prognostic marker for worsening heart failure than hypomagnesemia in contemporary HFrEF management.
Introduction: The Forgotten Electrolyte in Heart Failure
Magnesium is the second most abundant intracellular cation and plays a critical role in hundreds of enzymatic reactions, including those involving adenosine triphosphate (ATP) metabolism, muscle contraction, and cardiac electrophysiology. In the context of heart failure with reduced ejection fraction (HFrEF), electrolyte monitoring has historically focused heavily on potassium and sodium. Magnesium, often termed the forgotten electrolyte, has generally been scrutinized for its potential to trigger arrhythmias when levels are low—a condition frequently exacerbated by the use of loop diuretics.
However, the prognostic significance of serum magnesium across its full range in contemporary HFrEF populations has remained poorly defined. While clinicians often proactively supplement magnesium to prevent sudden cardiac death, recent data from the GALACTIC-HF trial suggest that we may need to re-evaluate our priorities. This analysis explores whether our traditional focus on hypomagnesemia might be overlooking a more significant clinical signal: the risk associated with hypermagnesemia.
Study Design: The GALACTIC-HF Magnesium Sub-analysis
The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) trial was a landmark randomized, double-blind, multicenter study. It originally investigated the efficacy and safety of omecamtiv mecarbil, a selective cardiac myosin activator, in patients with HFrEF (LVEF ≤35%). This specific sub-analysis evaluated 6,147 outpatients from the trial who had available baseline serum magnesium data.
The primary outcome of the analysis was a composite of a first worsening heart failure event (hospitalization or urgent clinic visit) or cardiovascular death. Secondary outcomes included all-cause mortality, sudden death, and ventricular tachyarrhythmia. The researchers categorized patients into three groups based on their baseline magnesium levels: hypomagnesemia (0.95 mmol/L).
Prevalence and Distribution of Magnesium Abnormalities
Among the 6,147 patients analyzed, magnesium abnormalities were common. Hypomagnesemia was present in 17.6% (n=1,082) of the cohort, while 10.7% (n=655) exhibited hypermagnesemia. The majority (71.7%) fell within the normal range. It is noteworthy that hypermagnesemia was slightly less common than hypomagnesemia but carried a significantly heavier prognostic burden.
Patients with hypermagnesemia were more likely to have higher baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and more severe renal impairment, both of which are established indicators of advanced heart failure. This correlation suggests that elevated magnesium may serve as a surrogate marker for the cardiorenal syndrome often seen in end-stage HFrEF.
Primary Outcomes: The Surprising Risk of Hypermagnesemia
The incidence rates for the primary composite outcome provided a clear picture of the risk distribution. The rate was highest in patients with hypermagnesemia at 34.9 per 100 person-years (95% CI 31.2-39.0). In contrast, the rates for patients with hypomagnesemia (21.5) and normal magnesium (20.9) were remarkably similar and significantly lower than those in the hypermagnesemia group.
When adjusting for baseline characteristics, hypermagnesemia remained a potent predictor of adverse events. The risk of death specifically from worsening heart failure was also highest in the hypermagnesemia group. These results challenge the clinical intuition that low magnesium is the primary electrolyte driver of poor outcomes in heart failure. Instead, it appears that elevated levels signal a higher risk of pump failure and cardiovascular collapse.
The Sudden Death Question: Challenging Conventional Wisdom
One of the most significant findings of this study relates to sudden death and ventricular tachyarrhythmia. Magnesium has long been used in clinical practice as an anti-arrhythmic agent, particularly in the management of Torsades de Pointes. Consequently, it has been a long-held belief that hypomagnesemia predisposes HFrEF patients to sudden cardiac death.
However, the GALACTIC-HF data showed that the incidence rates of sudden death and ventricular tachyarrhythmia did not differ significantly among the three magnesium groups. This suggests that in the era of modern guideline-directed medical therapy (GDMT)—which includes beta-blockers, mineralocorticoid receptor antagonists (MRAs), and potentially SGLT2 inhibitors—the arrhythmogenic risk of mild hypomagnesemia may be mitigated. This finding calls into question the routine, aggressive correction of low magnesium levels solely for the purpose of preventing sudden death in stable outpatients.
Mechanistic Insights: Why High Magnesium Matters
Why is hypermagnesemia associated with such poor outcomes? There are several biological and clinical factors to consider:
Renal Dysfunction and the Cardiorenal Axis
Magnesium is primarily excreted by the kidneys. As heart failure progresses, cardiac output decreases, leading to reduced renal perfusion and a decline in the glomerular filtration rate (GFR). Hypermagnesemia in these patients is often an indicator of significant renal impairment. This study suggests that magnesium may be a more sensitive or specific marker of the underlying cardiorenal pathology that leads to worsening heart failure than some traditional measures.
Advanced Disease Severity
Patients with higher magnesium levels tended to have more advanced symptoms and higher biomarker levels. Elevated magnesium might reflect a state of metabolic breakdown or a failure of homeostatic mechanisms as the body reaches the limits of compensation. It could also be related to the use of specific medications or supplements in the most symptomatic patients, although the study adjusted for many of these variables.
Expert Commentary: Clinical Implications
The GALACTIC-HF sub-analysis provides a necessary pivot in how we view electrolyte monitoring. For decades, clinicians have been trained to fear the ‘lows’—hypokalemia and hypomagnesemia. While severe hypomagnesemia certainly requires attention, this study suggests that mild-to-moderate low magnesium may not be the primary threat we once thought.
More importantly, the study highlights hypermagnesemia as a clinical ‘red flag.’ When a clinician encounters an elevated magnesium level in an HFrEF patient, it should be interpreted not as a laboratory fluke, but as a sign of high risk for worsening heart failure and cardiovascular death. This should prompt a thorough review of the patient’s renal function, medication adherence, and overall clinical trajectory.
Furthermore, the lack of association between magnesium levels and sudden death suggests that we should focus our efforts on optimizing GDMT rather than chasing minor fluctuations in serum magnesium. The routine correction of hypomagnesemia in the absence of symptoms or severe depletion may not provide the mortality benefit many expect.
Limitations
As with any post-hoc analysis of a clinical trial, there are limitations. The magnesium levels were baseline measurements, and longitudinal changes were not accounted for in this specific analysis. Additionally, while the study adjusted for many confounders, the possibility of residual confounding—particularly regarding the exact cause of renal impairment—remains. Finally, the study population consisted of outpatients, so the findings may not be directly applicable to acute, decompensated heart failure patients in the intensive care unit.
Conclusion
In the GALACTIC-HF trial, hypermagnesemia emerged as a significant and independent predictor of poor outcomes in HFrEF, while hypomagnesemia did not show a similarly strong association with risk. Perhaps most surprisingly, magnesium levels were not linked to the risk of sudden death or arrhythmias in this contemporary cohort. These findings suggest a shift in clinical focus: elevated serum magnesium should be recognized as a marker of advanced disease and high risk, while the routine correction of mild hypomagnesemia may be less critical than previously believed. Monitoring magnesium remains important, but our interpretation of the data must evolve to match the realities of modern heart failure management.
Reference：
Chimura M, Docherty KF, Jhund PS, Yang M, Ono R, Henderson AD, Metra M, Liu G, Divanji PH, Heitner SB, Kupfer S, Malik FI, Felker GM, Solomon SD, Teerlink JR, McMurray JJV. Serum magnesium and outcomes in heart failure with reduced ejection fraction: the GALACTIC-HF trial. Eur Heart J. 2025 Aug 31:ehaf706. doi: 10.1093/eurheartj/ehaf706 IF: 35.6 Q1 . Epub ahead of print. PMID: 40886161 IF: 35.6 Q1 .
