Creatine and Heart Health: What the Science Really Shows

Creatine Beyond the Gym

Ask most people about creatine and they will talk about muscle, strength, and gym performance. That reputation is well earned, but it hides a much bigger story. The heart is also a muscle, and it happens to be the hardest working one in the body. It never rests, never takes a day off, and depends on a constant supply of energy that creatine helps to deliver.

Few researchers have examined this connection as closely as Maurizio Balestrino, a professor at the University of Genova in Italy who has spent much of his career studying creatine. In a lecture titled Role of Creatine in the Heart: Health and Disease, which mirrors a peer reviewed article he published under the same title in the journal Nutrients in 2021, Balestrino walks through what creatine does in a healthy heart, what happens to it in heart failure and heart attacks, and why it might one day help protect cancer patients from the cardiac side effects of chemotherapy.

This article unpacks his talk and checks its main claims against independent research, from animal experiments dating back decades to modern clinical trials and Cochrane analyses. The short version: the science on creatine and the heart is genuinely fascinating, some of it is surprisingly strong, and some of it is still early. We will be clear throughout about which is which.

The Body’s Fastest Energy System

To follow the heart story, you first need to understand what creatine actually does. Every cell runs on adenosine triphosphate, or ATP, the universal energy currency of biology. Balestrino explains that creatine’s job is to keep ATP available exactly where and when it is needed, through a simple chemical partnership. The enzyme creatine kinase attaches a phosphate group to creatine, turning it into phosphocreatine. When energy runs short, phosphocreatine hands that phosphate back to adenosine diphosphate, instantly rebuilding ATP. The reaction runs in both directions, needs no oxygen, and, among all the ways cells restore ATP, it is the quickest at buffering energy levels when demand suddenly spikes.

That buffering matters in two situations. The first is intense effort, when a muscle burns ATP faster than it can produce it. The second is disease, when blood or oxygen supply fails. In a heart attack, for example, Balestrino notes that phosphocreatine steps in to regenerate ATP at the very moment the heart cannot make it through normal means, and this emergency reserve may allow cells to survive a short critical period that would otherwise kill them.

The system also works as a transport network, something researchers call the creatine shuttle. According to Balestrino, ATP is a very large molecule that diffuses slowly through the crowded, organelle filled interior of a cell, so moving it from the mitochondria, where it is made, to the distant sites where it is spent is cumbersome. Phosphocreatine is much smaller and travels far more easily. So the cell loads phosphate onto creatine near the mitochondria, lets phosphocreatine drift down its concentration gradient to wherever energy is needed, and rebuilds ATP on the spot. The creatine then diffuses back to collect another load, and the cycle repeats.

Where does creatine come from in the first place? Balestrino’s review explains that the kidneys and liver build it from the amino acids arginine and glycine, with a methyl group added along the way, and that roughly half of the body’s supply normally arrives through food. Creatine exists only in animal products such as meat and fish, which is why people who eat little or none of them tend to run lower and, in his view, should consider supplementing. One further detail matters enormously for everything that follows: creatine cannot simply drift into cells. It requires a dedicated creatine transporter to cross the cell membrane, and heart cells are no exception.

The Relentless Energy Demands of the Heart

Balestrino emphasizes that the heart, like the brain, is excitable tissue. It fires electrical signals called action potentials and stays ready to fire by maintaining a resting electrical charge across each cell membrane, with sodium concentrated outside the cell and potassium inside. Holding that gradient in place requires molecular pumps that run continuously, and those pumps burn ATP around the clock. On top of this electrical housekeeping comes the mechanical work of contraction itself, which consumes enormous amounts of energy with every single beat.

The numbers are hard to believe. Researchers in cardiac energetics estimate that the heart turns over several kilograms of ATP in a single day, yet it stores only a few seconds’ worth at any given moment, so the entire supply must be rebuilt continuously. Cardiologist Stefan Neubauer surveyed this field in a New England Journal of Medicine review titled The Failing Heart: An Engine Out of Fuel, arguing that disturbed energy metabolism sits near the center of heart failure. This is precisely the situation the creatine system evolved to handle: phosphocreatine waits as an instant reserve that can be cashed in the moment supply falters.

The idea that a failing heart is a heart starved of energy is older than most people realize. As Neubauer recounts, the physicians Herrmann and Decherd reported back in 1939 that failing human heart muscle contained significantly less creatine than normal, and proposed that energy depletion lies near the root of heart failure. As we will see, modern research has largely vindicated their intuition.

Creatine and the Healthy Heart

What happens when you give a normal heart extra creatine? The earliest answers came from the laboratory. Balestrino describes experiments from the 1970s in which strips of frog heart muscle contracted more forcefully when bathed in creatine at concentrations of roughly 9 to 20 millimolar. Intriguingly, the effect reversed at far higher concentrations: between 20 and 70 millimolar, the force of contraction declined. His review stresses that such extreme levels are almost certainly impossible to reach in a living body, so the harmful findings say little about real world supplementation. Later work on isolated rat hearts found that creatine perfusion slowed heart rate, raised the pressure generated by the left ventricle, improved coronary blood flow, increased ATP content and reduced a marker of cell death, although Balestrino’s review notes that the same paper made a claim about conduction abnormalities under low glucose without presenting any data to support it. Other laboratory work showed that supplemented heart cells raised their phosphocreatine stores even under low oxygen conditions, despite the fact that low oxygen itself reduces creatine uptake.

Living animals tell a more nuanced story. The healthy heart already holds far more creatine than organs like the liver or kidneys, and the human heart holds even more than rodent hearts do. Partly for that reason, some researchers doubted that supplementation could raise cardiac creatine at all, and two rodent studies from a single laboratory found no increase. Balestrino pushes back on those negative results. He points out that in both studies creatine failed to rise even in skeletal muscle, where adequate supplementation reliably works in humans and animals alike, which strongly suggests the animals simply received too little; the papers reported doses as a percentage of feed without measuring how much the animals actually ate. Other groups, using generous doses for longer periods, did see gains: cardiac creatine rose by 11 percent in one study, and by 15 to 28 percent across guinea pigs, mice and rats in another, though the increase took about four weeks of supplementation to become significant.

Genetic experiments add both a caution and a reassurance. Mice engineered to overexpress the creatine transporter can accumulate up to four times the normal cardiac creatine, and in some laboratories those extreme levels produced thickened, failing hearts, while another group found no harm at all from similar increases. The clearest reading, per Balestrino’s review, is that trouble appears only with very large increases: raising cardiac creatine by up to about 60 percent of baseline showed no adverse effects. Since creatine supplementation raises human muscle creatine by less than 50 percent, and a natural ceiling prevents further uptake, ordinary supplementation cannot come close to the danger zone.

The honest gap in all of this is human data. As Balestrino states plainly, no study has ever tested whether creatine supplementation increases the force of contraction of a healthy human heart. The laboratory findings are suggestive, and nothing more.

Cardiac Safety of Creatine Supplements

Safety is a different matter, and here the evidence is broad and consistent. Balestrino’s review highlights a study that compared bodybuilders who supplemented with creatine, bodybuilders who trained without it, and men who did neither. The only cardiac difference detected was that creatine users showed slightly less of the slow resting heart rate that intense training normally produces, while blood pressure and the QT interval on the electrocardiogram were identical across groups. Nothing in the results suggested harm, and resting heart rates in all groups sat comfortably within the normal range.

Larger bodies of evidence agree. The International Society of Sports Nutrition’s position stand, which draws on hundreds of published studies, concludes that creatine monohydrate is safe and well tolerated in healthy people and in many patient populations, from infants to the elderly, at intakes of up to 30 grams per day for as long as five years. A separate review of creatine in medical conditions, which Balestrino coauthored in Medicinal Research Reviews, reached the same conclusion and found no signal of cardiac adverse events.

The one consistent caution involves the kidneys. Creatine naturally breaks down into creatinine, the very molecule doctors measure to gauge kidney function, and Balestrino’s review names preexisting kidney damage, signaled by elevated blood creatinine, as the possible exception to creatine’s excellent safety record. People with kidney disease should not take creatine without medical guidance, and anyone having kidney tests should mention their supplement use, since supplementation can nudge creatinine readings upward even when the kidneys are perfectly healthy.

Creatine Loss in the Failing Heart

Heart failure, as Balestrino describes it, is a mismatch between the blood the body needs and the amount the heart manages to deliver. The European Society of Cardiology, whose definition his review cites, frames it as a clinical syndrome of breathlessness, fatigue and fluid retention arising from a structural or functional abnormality that reduces the heart’s output. It can follow coronary artery disease, high blood pressure, rhythm disorders, valve disease, inflammation of the heart muscle and more. It is common, serious, and usually has no cure.

One of the most consistent biochemical findings in this disease, documented across more than sixty years, is that creatine and phosphocreatine fall. Balestrino traces the evidence from guinea pig experiments in 1962 through dog studies in 1965, in which phosphocreatine and total creatine dropped by roughly a third or more while ATP fell only about 12 percent. A particularly revealing study came in 1999, when researchers induced heart failure in dogs through continuous cardiac pacing and watched left ventricular creatine decline steadily as the disease progressed, falling earlier than ATP did. The authors concluded that the heart was spending its phosphocreatine to prop up ATP, sacrificing the reserve to protect the currency.

Balestrino identifies two mechanisms behind the loss. First, the creatine transporter itself is downregulated in failing hearts. Researchers demonstrated this directly in failing human heart tissue as well as in animal models, which means a sick heart physically cannot pull in creatine as well as a healthy one, no matter how much is circulating. Second, phosphocreatine is continuously consumed to delay ATP exhaustion, exactly as the paced dog experiments suggested. Human measurements match the animal data at every step: failing human hearts show reduced creatine kinase activity and reduced creatine content, and magnetic resonance spectroscopy, a technique that measures these molecules noninvasively in living patients, confirms the depletion in people with heart failure of many different causes.

Does the depletion actually matter, or is it just a bystander? Experiments say it matters. Balestrino’s review describes rodent hearts depleted of creatine that looked deceptively normal at rest but could not ramp up output when stimulated, losing what cardiologists call contractile reserve, and that proved more vulnerable to ischemic damage. One researcher argued in the 1990s that creatine never falls far enough in heart failure to cripple the creatine kinase enzyme, but the clinical numbers that followed make that position hard to sustain.

The most striking human evidence came in 1997, when Stefan Neubauer’s team followed 39 patients with dilated cardiomyopathy for roughly two and a half years after measuring the phosphocreatine to ATP ratio in their hearts with magnetic resonance spectroscopy. Among patients whose ratio was below 1.60, total mortality reached 40 percent, and every one of those deaths was cardiovascular. Among patients with normal ratios, mortality was 11 percent. The ratio predicted death independently, adding prognostic information beyond standard clinical measures. Later work by a Japanese group found that myocardial creatine concentration correlates with left ventricular ejection fraction, the standard index of pumping strength, across a range of heart diseases. In short, the less creatine a failing heart retains, the worse its outlook.

Supplement Trials in Heart Failure Patients

If failing hearts lose creatine and that loss predicts death, restoring it is an obvious idea, and Balestrino argues that the rationale is strong. The clinical trials conducted so far are small, but they follow a clear pattern.

In 1995, a double blind, placebo controlled Swedish study gave creatine to chronic heart failure patients and found increased skeletal muscle phosphocreatine along with better muscle performance. In 1998, a placebo controlled British trial using 20 grams per day for five days reported that patients could sustain significantly more contractions before exhaustion at 75 percent of their maximum voluntary strength, with lower lactate and ammonia production, both signs of healthier muscle metabolism. Balestrino recalls that an accompanying editorial muddied the waters by claiming the benefit applied only to patients with low muscle creatine, something the trial never measured; in his reading, the data support benefit for heart failure patients as a population, since earlier work had already shown that this population runs low on muscle creatine and responds to supplementation. The same editorial worried about the safety of prolonged use, a concern later research would dispel.

The pattern continued. A 2006 German crossover trial in severe heart failure, giving 4 grams five times daily for six weeks, found improved muscle strength and body weight, yet ejection fraction sat unchanged at around 30 percent, and peak oxygen uptake, walking distance and quality of life scores did not move. A six month Brazilian trial at 5 grams per day likewise found no change in its main functional endpoints, though only the creatine group showed a significant correlation between peak oxygen consumption and distance covered in a six minute walk, which the authors interpreted as a hint of more efficient oxygen use. Balestrino’s review also cites a randomized trial that combined a small daily dose of creatine with coenzyme Q10 and recorded higher peak oxygen consumption with no adverse effects, but the combination makes it impossible to credit creatine alone, and commentators suspected the benefit arose in skeletal muscle rather than in the heart.

Independent assessors agree the question remains open. A 2011 Cochrane review identified 11 randomized trials of creatine and related compounds, covering 1474 patients with heart failure, hypertension or heart attack, and concluded that larger clinical studies are needed before firm recommendations can be made.

Balestrino’s own synthesis is candid. Creatine supplementation may have some positive effects on cardiac function in heart failure, but its most robust and repeatable benefit is stronger, longer lasting skeletal muscle. He considers that valuable in itself, since weakness and fatigue erode daily life in a condition that usually cannot be cured, and he argues that heart failure patients with prominent weakness, and with normal kidney function, are reasonable candidates to trial supplementation. He also calls for future studies that measure cardiac creatine directly, for instance with magnetic resonance spectroscopy, to learn which patients stand to benefit most. That is his clinical judgment rather than a treatment guideline, and heart failure patients should never add supplements without their cardiologist’s input.

Phosphocreatine and the Ischemic Heart

On paper, ischemia, the blood starvation behind angina and heart attacks, is where creatine should shine, because phosphocreatine can regenerate ATP without oxygen. Animal research supports the logic in both directions. Studies reviewed by Balestrino found that depleting cardiac creatine left rodent hearts more vulnerable to ischemic injury and raised mortality after experimental infarction, while a moderate elevation of cardiac creatine, achieved genetically through the transporter, protected mice against experimental heart attack. Another rodent study he cites found that creatine given before ischemia improved heart contraction during the event, though curiously only in sedentary animals and not in exercised ones.

Then comes the surprise Balestrino calls out directly: creatine supplementation has never been tested in human heart attack patients. Not once. The Cochrane reviewers made the same observation, noting that the heart attack trials in the literature evaluated only intravenous creatine phosphate.

That distinction matters more than it might seem. Phosphocreatine, given as a drug, has produced encouraging results in cardiac ischemia, but Balestrino explains that it is a fundamentally different intervention. Phosphocreatine does not cross cell membranes, it has no known transporter, and his own laboratory showed that adding it to brain tissue raised neither creatine nor phosphocreatine inside the cells. Its cardiac benefits are instead attributed to actions outside the cell, such as inserting into and stabilizing heart cell membranes and inhibiting platelet aggregation. The Cochrane assessment, for its part, found the phosphocreatine evidence still insufficient to recommend routine clinical use. So the one form of this chemistry that has been tested in human heart attacks works, if it works, through mechanisms unrelated to the creatine energy system, and the form you can actually buy as a supplement remains untested in this setting. Balestrino sees this as a gap that future research should fill.

Creatine and Chemotherapy Heart Damage

The newest chapter in this story involves cancer treatment. Anthracyclines, a drug family that includes doxorubicin, daunorubicin, epirubicin and idarubicin, are among the most effective and widely used chemotherapy agents, deployed against breast cancer, lymphomas, leukemias and other malignancies. Their power comes at a price. Balestrino explains that they generate reactive oxygen species that damage mitochondria, and that they block DNA replication by binding topoisomerase, with additional harm arising from interactions with cellular iron. This oxidative assault hits the heart especially hard. Cardiac toxicity ranges from silent rises in damage markers to severe heart failure, it limits the doses oncologists can safely give, and despite research into protective candidates such as dexrazoxane, ACE inhibitors, angiotensin receptor blockers and beta blockers, no preventive treatment is in routine use.

Several threads tie this toxicity directly to creatine. In 2012, researchers showed that exposing heart cells to doxorubicin at concentrations below those measured in patients’ blood during chemotherapy rapidly and irreversibly cut the cells’ creatine transport, stripping transporter protein from the cell surface. Other work reviewed by Balestrino found that anthracyclines inhibit creatine kinase, damage the mitochondrial form of the enzyme, and blunt creatine’s ability to stimulate respiration in isolated mitochondria. In other words, the drugs dismantle the heart’s creatine energy system from several angles at once. Creatine also happens to be an antioxidant in its own right: a 2002 study demonstrated that it directly scavenges free radicals, including superoxide, though less powerfully than glutathione, the cell’s principal antioxidant.

The protection experiments are striking. In a 2007 rat study, animals supplemented for 30 days with creatine at a dose equivalent to roughly 14 grams per day for an average adult, then given a single large dose of doxorubicin, survived twice as long as unsupplemented animals: six days versus three. Rats given vitamins C and E survived about seven days and did somewhat better on biochemical damage markers, which leads Balestrino to suggest that creatine’s antioxidant property may matter more here than its energy role. In 2015, researchers showed that a physiological concentration of creatine protected cultured heart cells from doxorubicin, reducing cell death, apoptosis and reactive oxygen production, with the protection depending on creatine actually entering the cells. The benefit extends beyond the heart, too. In muscle experiments, doxorubicin weakened isolated muscles and made them tire faster, and creatine pretreatment prevented that damage, findings later confirmed in living rats whose grip strength and resistance to fatigue were preserved.

Honesty requires some caveats. Genetically modified animal studies conflict: boosting creatine kinase improved cardiac energetics and survival after doxorubicin in one study, yet another group found no protection from raising creatine levels in isolated hearts. Every positive supplementation study gave creatine before the anthracycline rather than after, a timing detail Balestrino underlines. And all of this evidence is preclinical; no human trial has yet tested creatine against chemotherapy cardiotoxicity. Balestrino’s own position goes further than the data. Given creatine’s safety record, the unmet clinical need, and its twin actions on heart and skeletal muscle, he believes oncology patients might even now be given a period of creatine supplementation, possibly alongside vitamins C and E, before anthracycline treatment, while proper clinical trials are organized. Readers should understand this as a researcher’s informed proposal rather than medical guidance. Nobody undergoing cancer treatment should add any supplement without the explicit approval of their oncology team, because supplements can interact with treatment in ways patients cannot predict.

The Bottom Line for Supplement Users

Laid out honestly, the evidence forms tiers. The strongest tier is safety: decades of trials, position stands and reviews agree that creatine monohydrate at ordinary doses is safe for healthy people, with existing kidney disease as the main exception. The next tier is muscle: creatine reliably strengthens skeletal muscle, and small trials show this holds even for heart failure patients, in whom it improved strength and endurance. Below that sits the heart itself: failing hearts demonstrably lose creatine, that loss predicts mortality, and the biological rationale for replacing it is strong, yet no trial has shown that supplementation improves human cardiac function, in health or in disease. And at the earliest tier lies chemotherapy protection, where the animal and cell data are genuinely promising but human evidence does not yet exist.

That ranking is why this article carries an early evidence rating for direct heart benefits rather than something more enthusiastic. If you already take 3 to 5 grams of creatine monohydrate daily for training or general health, nothing in the cardiac literature suggests you are harming your heart, and the energy biology suggests you may be quietly supporting the most hardworking muscle you own. If you have heart disease or kidney disease, or you are undergoing cancer treatment, the research is interesting enough to bring up with your doctor and not yet solid enough to act on alone. The heart runs on creatine every second of your life. Whether topping up the tank can change the course of heart disease is a question science has finally begun, but not yet finished, answering.