Why blood vessels deserve attention
Cardiovascular disease is not a niche concern. The World Health Organization identifies cardiovascular diseases as the leading cause of death globally, claiming an estimated 17.9 million lives every year, with more than four out of five of those deaths caused by heart attacks and strokes. In the United States, the picture is just as stark. Nearly half of American adults, about 48 percent or almost 120 million people, live with hypertension, and high blood pressure was a primary or contributing cause of more than 690,000 deaths in 2021 alone.
These numbers are the backdrop for a conference presentation by researcher Holly Clarke of Florida State University, who has spent years asking an unusual question: could creatine, the supplement most people associate with the weight room, play a role in keeping blood vessels healthy? Clarke, who conducted this work with Robert Hickner and Michael Ormsbee, laid out her case in a talk based on two review papers her team published in the journal Nutrients in 2020 and 2021, plus her own doctoral trial in older adults.
Clarke explains that cardiovascular disease is an umbrella covering conditions of the heart and the vessels, and that the vascular side includes atherosclerosis, peripheral artery disease, hypertension, stroke, and coronary heart disease. These conditions are complex, but she highlights a handful of recurring drivers: oxidative stress (a buildup of damaging free radicals), dyslipidemia (unhealthy levels of circulating fats such as cholesterol), high blood glucose, mitochondrial dysfunction, and chronic inflammation. Her review notes that damage to the endothelial cells lining every vessel, whether from free radicals, inflammation, high blood sugar, or simply aging, leads to endothelial dysfunction, a loss of the vessel’s ability to relax and regulate blood flow that underlies most cardiovascular diseases.
Medications and procedures clearly help. Clarke is emphatic that she is not arguing against beta blockers, diuretics, or stents. Her point is narrower: these treatments can be invasive, expensive, and hard to access, and her review cites survey data showing that around one in five older adults does not take medication as prescribed because of cost. That gap is where she believes accessible nutritional strategies, from vitamin rich foods to supplements, could serve as adjuvant support alongside standard care, never in place of it.
Creatine beyond the gym
Creatine has one of the deepest evidence bases of any supplement, but almost all of it concerns muscle. The compound is found naturally in meat and fish, is made by the body, and is stored mostly in skeletal muscle, where it partners with the enzyme creatine kinase to rapidly regenerate ATP, the cell’s energy currency. Decades of studies support benefits for strength, power, and recovery, and the International Society of Sports Nutrition’s position stand concludes that supplementation is safe and well tolerated across populations, even at doses up to 30 grams per day taken for as long as five years.
Clarke’s argument is that this energy story is only part of the picture. According to her, newer research suggests creatine may also behave as an antioxidant, may influence blood lipids, and may calm certain inflammatory processes. Set those emerging properties next to the list of vascular disease drivers above, and the overlap becomes hard to ignore. Her review argues that because creatine appears to reduce free radicals, support mitochondria, and reduce inflammation, all of which are tied closely to vascular disease, it could plausibly serve as an adjuvant therapy for vascular health in at risk populations, while stressing that clinical trials in this area are scarce.
Creatine inside blood vessel cells
Before any mechanism matters, one basic fact has to be established: creatine must actually be present and active inside vascular tissue. Clarke walks through a line of cell research, beginning in the early 1990s, showing exactly that.
The clearest demonstration comes from Decking and colleagues in 2001. Working with endothelial cells from both the aorta and the microvasculature, they showed these cells take up creatine from their surroundings, hold measurable phosphocreatine stores, and express creatine kinase in both its cytosolic BB form and its mitochondrial form; when creatine was removed from the medium, phosphocreatine accumulation dropped by more than 90 percent, confirming an active transporter and a working creatine system. In other words, the same energy machinery that powers muscle also operates in the cells lining our blood vessels. Clarke’s review notes that studies by Loike, Nomura, and Sestili reached complementary conclusions, and Nomura’s group directly confirmed that supplementing cultured human endothelial cells with as little as 0.5 millimolar creatine raised intracellular creatine and phosphocreatine through the transporter.
Why does this matter? Endothelial cells are not passive pipe lining. They release nitric oxide and other signals that control vessel diameter, blood pressure, clotting, and inflammation. If creatine can be taken up and used by these cells, then supplementing it could, at least in principle, change how they function.
Early human trials on blood flow
When Clarke surveyed the literature for her review, she found something surprising: only four clinical studies had directly examined creatine’s effect on vascular outcomes using dedicated vascular methods.
The first, by Arciero and colleagues in 2001, tested creatine alone or combined with resistance training in 30 healthy young men, using 20 grams per day for five days followed by 10 grams per day, with limb blood flow measured by venous occlusion plethysmography. According to Clarke, forearm and calf blood flow increased significantly, but only in the group that combined creatine with training. Creatine alone did nothing measurable, which she reads as evidence of a synergistic rather than independent effect.
A 2011 trial in the European Journal of Applied Physiology looked instead at how vessels respond to exercise stress. Sixteen healthy young men took 10 grams of creatine daily (in two 5 gram doses) or placebo for three weeks; after intense isokinetic leg exercise, the creatine group showed a much smaller rise in systolic blood pressure at five minutes (about 5.6 versus 14 mmHg), blunted heart rate responses at five and fifteen minutes, suppressed increases in arterial stiffness measured by pulse wave velocity, and a faster return of blood pressure toward resting values. Clarke points out that exaggerated pressure responses and stiffening arteries are both markers of vascular trouble, so blunting them is a meaningful signal.
The remaining two studies examined the microvasculature, the network of tiny arterioles and capillaries. In a 2014 open label study, 40 healthy, moderately active young men took 20 grams of creatine daily for one week; skin functional capillary density and capillary recruitment after brief occlusion both increased significantly, microvascular vasodilation improved, and total cholesterol and LDL cholesterol fell. Clarke’s review flags the study’s limitations honestly: there was no placebo, and participants knew what they were taking. The follow up by Van Bavel and colleagues addressed some of these gaps and chose an interesting population: vegans, who consume no dietary creatine at all. Forty nine vegans aged 20 to 45 took 5 grams of creatine or a maltodextrin placebo daily for three weeks; capillary density at rest and capillary recruitment after occlusion increased significantly only in the creatine group, homocysteine fell only in participants who started with elevated levels, and the drop in cholesterol was a nonsignificant trend.
Clarke then raises the critique that shaped her own research. Every one of these trials studied healthy, mostly young people, exactly the group with the least room to improve. In her words, the real question is what happens when creatine is given to people whose vessels have already begun to decline. If small but significant gains show up even in the healthy young, effects could plausibly be larger in older or at risk adults. That hypothesis, she notes, is what her dissertation set out to test.
Creatine as an antioxidant
The first mechanism Clarke proposes runs through oxidative stress. Free radicals damage lipids, proteins, and DNA, and her review describes how the accumulation of reactive oxygen species underlies hypertension, atherosclerosis, and stroke, and how our natural antioxidant defenses weaken with age, smoking, poor nutrition, and inactivity.
Could creatine help here? The trail begins in an unexpected place: neuroscience. In 1998, Matthews and colleagues fed creatine to rodents given toxins (malonate and 3-nitropropionic acid) that model Huntington’s disease; creatine raised brain phosphocreatine, dramatically reduced the resulting brain lesions, and, notably, reduced biochemical markers of hydroxyl radical generation. That last finding hinted that creatine was doing something beyond energy supply.
Lawler and colleagues then tested creatine directly against isolated radical generating systems. They found a clear dose response: creatine removed superoxide anions and peroxynitrite and improved overall scavenging capacity, but showed no significant activity against hydrogen peroxide, making it a selective rather than universal antioxidant. Sestili’s group took the next step, into living cells. Creatine at concentrations similar to those reached in plasma after supplementation protected three different cell lines, including human umbilical vein endothelial cells, against several oxidative insults, and the protection depended on the creatine actually getting inside: when the transporter was blocked with an inhibitor, intracellular creatine no longer rose and the benefits disappeared.
Human evidence is thinner but exists. In a randomized, double blind trial, Rahimi gave young men 5 grams of creatine four times daily for seven days; after a bout of resistance exercise, the creatine group showed significantly less urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and a blunted rise in plasma malondialdehyde, a marker of lipid peroxidation.
One honest complication belongs here, and it comes from Clarke’s own data. As covered below, her trial in older adults found vascular improvements without any significant change in oxidative stress biomarkers, and her dissertation states plainly that the improvements were not mediated by any creatine dependent antioxidant effect. The antioxidant story is real in cells and after intense exercise, but it may not be the mechanism behind creatine’s vascular effects in humans.
The nitric oxide connection
Why would reducing free radicals help vessels at all? Clarke’s answer centers on nitric oxide (NO), the molecule endothelial cells release to relax vessel walls. Her review documents that reduced NO bioavailability is linked to atherosclerosis, hypertension, type 2 diabetes, arterial stiffness, stroke, heart disease, and overall mortality, and that NO is extremely vulnerable: superoxide reacts with it almost on contact, converting it into peroxynitrite and stripping it of its benefits. Free radicals also attack tetrahydrobiopterin (BH4), a cofactor the NO producing enzyme requires; when BH4 is oxidized, the enzyme uncouples and starts generating radicals instead of NO, compounding the damage.
The proposed chain is therefore straightforward. If creatine lowers the radical load, more NO survives and more BH4 stays intact, so vessels dilate better. Clarke is careful to present this as hypothesis rather than fact, though supporting cell data exist: her review describes work by Ahsan showing that phosphocreatine protected endothelial cells injured by oxidized LDL, reducing cell death and radical generation, improving NO content, and sustaining signaling through the PI3K/Akt/eNOS pathway that drives NO production. Whether any of this happens in human arteries after oral supplementation remains untested.
Mitochondria and the vessel wall
Mitochondria are a major internal source of reactive oxygen species, and Clarke notes that mitochondrial dysfunction is a recognized feature of vascular disease. A key detail is the mitochondrial membrane potential: when it is poorly regulated, radical production climbs. The creatine system sits right in this machinery; mitochondrial creatine kinase, together with creatine and phosphocreatine, shuttles high energy phosphates from where ATP is made to where it is used and recycles ADP within the mitochondria, both of which help keep the membrane potential stable.
Two studies give this idea experimental teeth. Meyer and colleagues showed that supplemental creatine stimulated efficient mitochondrial creatine kinase function in rats, stabilizing ADP to ATP ratios and reducing hydrogen peroxide production through creatine kinase dependent ADP recycling; Barbieri’s group then showed that creatine preserved mitochondrial membrane potential and integrity in muscle cells deliberately injured with hydrogen peroxide. Clarke’s argument follows naturally: if creatine helps mitochondria run cleanly, it could reduce the mitochondrial radical burden seen in diseased vessels. As with the NO chain, the vascular half of this argument is inference, not demonstration; no one has yet shown creatine improving mitochondrial function inside human blood vessels.
Calming inflammation in the endothelium
Chronic inflammation and endothelial dysfunction feed each other, and inflamed vessels become leaky, letting immune cells and molecules cross where they should not. Clarke highlights one study that speaks directly to this. Nomura and colleagues, working with cultured human pulmonary endothelial cells, found that 5 millimolar creatine significantly suppressed the endothelial permeability triggered by serotonin and hydrogen peroxide and reduced the adhesion of neutrophils to the endothelium, while concentrations as low as 0.5 millimolar inhibited the expression of ICAM-1 and E-selectin. Those last two are adhesion molecules, the docking sites inflamed vessels display to recruit immune cells, so dialing them down is meaningful. (In the talk they are described as cytokines; adhesion molecules is the accurate term, and the functional point stands.)
The wider inflammation picture deserves balance, though. In a mouse model of airway inflammation, four weeks of creatine did not reduce inflammation and appeared to upregulate some inflammatory mediators, and a 2026 pooled analysis of eight randomized trials found no significant effect of creatine on circulating inflammatory markers such as C reactive protein or interleukin 6 in humans. The endothelial cell findings are promising, but calling creatine an anti inflammatory agent in people would overstate the evidence.
Creatine, cholesterol, and liver fat
High triglycerides and LDL cholesterol are firmly linked to vascular risk, so any lipid effect of creatine would matter. The foundational study here dates to 1996. Earnest and colleagues ran a randomized, double blind, placebo controlled trial in 34 men and women aged 32 to 70 who all had total cholesterol above 200 mg/dl; participants took creatine four times daily for 5 days, then twice daily for 51 days, and the creatine group showed significant reductions in total cholesterol, triacylglycerols, and VLDL. Clarke summarizes the size of those effects as roughly 5 to 6 percent for total cholesterol and just over 20 percent for triacylglycerols and VLDL at weeks four and eight, and the triacylglycerol and VLDL reductions persisted four weeks after supplementation stopped, though LDL and HDL themselves did not change significantly. The Moraes microvascular study added its own signal, with significant drops in total and LDL cholesterol after just one week of loading.
Clarke deserves credit for flagging, unprompted, that contradictory evidence exists, and the newest synthesis bears her out. A 2026 systematic review pooling randomized placebo controlled trials found no statistically significant overall effect of creatine on total cholesterol, LDL, HDL, or triglycerides, rated the certainty of evidence low to very low, and concluded that creatine did not demonstrate clinically relevant effects on lipid profiles. Interestingly, the same authors note that the absence of lipid changes does not rule out cardiovascular benefits through other routes such as endothelial function and oxidative balance. The fair reading: creatine might nudge lipids in some people with elevated levels, but it is not a lipid lowering therapy.
The liver adds a separate, more consistent thread, at least in animals. Deminice and colleagues fed rats a high fat liquid diet for three weeks; adding 1 percent creatine monohydrate prevented the expected buildup of liver fat and liver triglycerides, normalized lipid peroxidation, preserved hepatic S-adenosylmethionine (SAM), and restored the expression of key genes governing fatty acid beta oxidation. Clarke explains the SAM logic: making creatine from scratch consumes a large share of the liver’s SAM, so supplying creatine spares this important methyl donor. She adds that follow up cell work by da Silva in 2014 supported the fatty acid oxidation mechanism. The relevance to vessels is indirect but plausible, since people with nonalcoholic fatty liver disease carry elevated vascular risk. Still, these are rodent and cell findings on an extreme diet; whether creatine affects liver fat in humans eating normal diets is unknown.
Potassium channels and blood vessel tone
The final mechanism Clarke describes is the most technical, and the most clearly speculative. Beyond nitric oxide and prostacyclin, vessels relax through endothelium derived hyperpolarization factors (EDHFs). Her review explains that even when NO and prostacyclin pathways are blocked, vessels still dilate thanks to this compensatory EDHF system, and that reduced EDHF capacity is associated with higher cardiovascular risk. The system runs on ion movement: potassium channels and the sodium potassium pump hyperpolarize vascular smooth muscle, closing calcium channels and relaxing the vessel. Crucially, the ATP sensitive potassium channels involved are governed by local ATP and ADP levels, opening at ADP concentrations of roughly 0.1 to 3 millimoles per liter, and work by Dzeja and Terzic and by Selivanov shows creatine kinase enzymes are physically coupled to these channels, controlling the nucleotide ratios that gate them.
Creatine’s role, then, would be as fuel logistics for the vessel’s electrical controls. One striking experiment supports the plumbing: Guerrero and colleagues showed in kidney cell epithelia that even with both glycolysis and oxidative phosphorylation shut down, the creatine kinase system supplied with 3 millimolar phosphocreatine could sustain the ATP needed to keep the sodium potassium pump running. Clarke connects the dots explicitly as hypothesis: supplementing creatine tops up the substrates of this local energy network, which could support the channels and pumps behind EDHF signaling and, ultimately, vessel tone. No study has yet tested this in vascular tissue with oral creatine, and she says as much.
A four week trial in older adults
All of these threads converge in Clarke’s own dissertation study, which has since been published as a peer reviewed pilot in Nutrients (December 2024). Aging is the biggest unmodifiable risk factor for vascular disease, so she recruited the population her critique demanded. Twelve sedentary but otherwise healthy older adults completed a double blind, randomized crossover trial, taking creatine monohydrate or placebo for four weeks each (20 grams per day in four doses for 5 days, then 5 grams per day for 23 days) separated by a four week washout, while the team measured brachial artery flow mediated dilation, normalized FMD, pulse wave velocity, microvascular reperfusion by near infrared spectroscopy, and blood biomarkers including BH4, malondialdehyde, oxidized LDL, glucose, and lipids. In her talk, Clarke describes the participants as aged 50 to 64.
The headline result concerns flow mediated dilation, the gold standard noninvasive test of endothelial function. Creatine supplementation improved flow mediated dilation, microvascular reperfusion, fasting glucose, and triglycerides compared with placebo, while pulse wave velocity and the oxidative stress biomarkers did not change. In the talk, Clarke quantifies the FMD gain at about 1.22 percentage points, a roughly 16 percent relative improvement she describes as physiologically significant, with normalized FMD improving by about a third even after accounting for the shear stress stimulus. The microvascular data were just as striking: the ten second reperfusion rate rose from 2.29 to 3.71 percent per second, fasting glucose fell from about 103.6 to 99 mg/dL, and triglycerides dropped from about 99.8 to 83.8 mg/dL, that reperfusion change being the roughly 62 percent improvement she cites. Her dissertation reports two further findings: creatine also improved short term memory and isokinetic muscle endurance versus placebo, though not muscle strength or visuospatial performance.
The oxidative stress result deserves emphasis, because it cuts against her own leading hypothesis and she reports it anyway. Despite the clear vascular gains, none of the oxidative biomarkers changed significantly (she notes only a trend toward lower malondialdehyde), and the dissertation concludes the improvements were not mediated by creatine dependent antioxidant effects, leaving the mechanism an open question. It is also essential to keep the scale in view: this was a pilot with twelve healthy participants over four weeks. It shows a signal worth chasing, not a settled answer. Clarke’s stated next steps include perfusing creatine directly into muscle via microdialysis to study blood flow and radical production, inhibiting specific radical sources such as the mitochondria and NADPH oxidase to locate creatine’s action, continuing cognition research in older adults, and, funding permitting, studying brain phosphagen content in older adults with mild cognitive impairment. She also says she would like to repeat the vascular trial in a genuinely at risk group, such as people who already have hypertension.
How strong is the evidence
Pulling everything together, the honest picture looks like this. The cell and animal work is genuinely consistent: creatine machinery exists in endothelial cells, creatine acts as a selective antioxidant in vitro, it protects mitochondria and endothelial barriers under experimental stress, and it prevents fatty liver in rodents. The human evidence is where caution is required. There are a handful of small trials showing better blood flow, capillary density, and exercise blood pressure responses, mostly in healthy young men, plus one twelve person pilot showing improved endothelial function in older adults. Set against that, pooled analyses find no significant human effects on blood lipids or inflammatory markers, the pilot found no oxidative biomarker changes, and no study has ever tested whether creatine changes hard outcomes such as heart attacks or strokes. That is why this article’s evidence rating is early rather than promising or strong: the signals are real and worth taking seriously, but they rest on very few, very small human studies.
None of this makes creatine uninteresting. It is inexpensive, widely available, and unusually well characterized for safety; the ISSN’s review of the literature reports that supplementation up to 30 grams per day for as long as five years has been safe and well tolerated in healthy people and many patient populations. Typical daily intakes for general use are far lower, around 3 to 5 grams. Anyone with kidney disease, anyone on medication for blood pressure or cholesterol, and anyone managing a cardiovascular condition should talk to their doctor before adding creatine, and no one should swap prescribed treatment for a supplement. As Clarke herself concludes, the field now needs translational trials in realistic, at risk populations. Until those exist, the fairest summary of creatine and vascular health is the one her own data suggest: an early, encouraging signal from a supplement that keeps turning out to be more interesting than its gym reputation implies.