The Heart: The Ultimate Fuel Omnivore

Dr Edward Leatham
Mar 23
9 min read

Updated: Jul 22

Cardiac metabolism is not a fixed programme but a dynamic, substrate-switching system — and understanding it changes how we interpret disease, drugs, and dietary intervention.

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The human heart is the original hybrid engine, and a better one than anything we have made. It is a metabolic omnivore: rather than depending on a single source of energy, it switches continuously between free fatty acids, glucose and ketones, adjusting from one heartbeat to the next according to workload, oxygen supply, hormones and how recently you last ate. No machine on the road can do what the heart does without a moment's conscious thought, several billion times over a life.

A pump that never rests

Before we look at the fuel, it is worth pausing on the scale of the task. The heart beats around a hundred thousand times a day and more than three billion times across an average lifetime, and it must make its energy — adenosine triphosphate, or ATP — continuously, with no meaningful pause to recover. Skeletal muscle can borrow against its energy supply and repay the debt later, gasping through the effort and recovering afterwards. The heart has no such luxury. Energy failure, for the heart, is not an inconvenience; it is the end.

That unforgiving job description has shaped the way the organ is powered. Its metabolism is built around two principles — efficiency and flexibility — and it is the second of these that turns out to matter most.

The engine and the motor

Think again about that hybrid, with its two power sources. The combustion engine offers steady, long-range power; the electric motor delivers instant torque and smooth acceleration the moment demand climbs. The heart runs on much the same logic.

For most of the day, in a healthy adult, the heart cruises on fat. Around sixty to seventy per cent of its energy at rest comes from free fatty acids — a share that climbs towards ninety per cent after an overnight fast — and it is easy to see why: fatty acids are energy-dense, abundant, and superb for sustained, moderate-intensity work, exactly the endurance task the heart performs decade after decade. Fat is the heart's combustion engine: the muscular V8 that powers long-distance cruising.

Glucose is its electric motor. When the heart is asked to work harder — during exertion, stress, or a surge of sympathetic drive — glucose metabolism comes to the fore, and for a reason that matters enormously in disease: glucose yields more ATP per molecule of oxygen than fat does. When oxygen becomes the limiting factor, as it does when a coronary artery narrows, glucose is the more economical fuel — instant, efficient power, called on the moment it is needed.

The very finest hybrids blur even that distinction, and here the analogy earns its keep. In a car like the Porsche Cayenne Turbo E-Hybrid, the electric motor does not replace the petrol V8 when demand peaks; it layers its 174 horsepower on top of the engine's 591, so that both power units fire together — nearly 730 horsepower that neither could produce alone. The athlete's heart at full effort does something remarkably similar. It does not abandon fat for glucose so much as recruit glucose and lactate alongside it, all burning hard at once, to reach an output neither could sustain by itself. The steady combustion of fat and the instant electric surge of glucose run together, and the gentle either/or of everyday cruising becomes an emphatic both/and at the redline.

Beyond the hybrid

Here the analogy starts to strain, because a car has only its two modes and the heart has more. It also burns ketone bodies, lactate and — to a limited degree — amino acids, which makes it less a hybrid than an intelligent multi-fuel engine.

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Figure 1. The heart's fuel menu. Six substrates the myocardium can draw on — free fatty acids, glucose, glycogen, ketones, lactate and, in extremis, protein — each shown with its origin, the conditions under which the heart calls on it, its route to acetyl-CoA, and an everyday engine analogy. Every pathway converges on the same molecule, acetyl-CoA, and ketones reach it most directly of all, bypassing both glycolysis and the long spiral of β-oxidation. © VAT-TRAP 2026. — **Figure 1.** The heart's fuel menu. Six substrates the myocardium can draw on — free fatty acids, glucose, glycogen, ketones, lactate and, in extremis, protein — each shown with its origin, the conditions under which the heart calls on it, its route to acetyl-CoA, and an everyday engine analogy. Every pathway converges on the same molecule, acetyl-CoA, and ketones reach it most directly of all, bypassing both glycolysis and the long spiral of β-oxidation. © VAT-TRAP 2026.

Ketones deserve particular attention. During fasting, prolonged exercise or carbohydrate restriction, ketone levels in the blood rise, and the heart takes them up readily; under some conditions it may even prefer them, because they are rapidly oxidised and, like glucose, comparatively economical with oxygen. There is a growing and genuinely interesting body of work suggesting that the failing heart turns towards ketones and glucose, as though an engine sensing its own inefficiency were reaching for the most economical fuel it can find. We should be careful here — much of this is still being worked out — but it is one of the more intriguing frontiers in modern cardiology, and it is part of why some of the newer diabetes therapies appear to help the heart in ways their effect on blood sugar alone cannot fully explain.

The conductor: mitochondria

None of this flexibility would be possible without the mitochondria, the tiny power plants packed inside each cardiac muscle cell. The heart is one of the most mitochondria-rich tissues in the body — by volume, these organelles make up something close to a third of the muscle. They act as the engine's onboard computer, reading hormonal signals, the fuels on offer, the oxygen available and the workload demanded, and adjusting the mixture continuously. The result is a fuel blend re-optimised every second, without a flicker of conscious effort.

When the flexibility is lost

The brilliance of the system, then, is not any one fuel. No fuel is villain or hero; the heart needs all of them. The brilliance is the switching — and it is precisely the switching that metabolic disease takes away.

In insulin resistance and high visceral adiposity, the heart is flooded with free fatty acids while its ability to draw on glucose falters. It becomes locked into fat-burning, losing the nimbleness that kept it efficient. And burning fat when you cannot readily switch to glucose is a subtly worse deal: fat is less oxygen-efficient, and over-reliance on it raises oxidative stress and strains the mitochondria. The engine still runs, but it has lost a gear.

The trouble, though, runs well beyond the fuel itself — and this is where visceral fat shows how far its reach extends. It degrades all three things an engine needs at once: the quality of the fuel, the lines that deliver it, and the load the engine must work against.

Consider the fuel lines first. Visceral adiposity and insulin resistance accelerate coronary atherosclerosis, injure the lining of the vessels and impair the smallest branches of the circulation. The supply lines narrow at the very moment the engine is losing efficiency.

Then the fuel quality. Visceral fat is not the inert padding it was once assumed to be; it is a metabolically active, restless tissue that pours inflammatory messengers — interleukin-6, tumour necrosis factor-alpha and others — into the bloodstream, sustaining a low, smouldering inflammation throughout the body. In engine terms, it is running on contaminated fuel: the inflammation and oxidative stress that follow impair ATP production and injure the vessel wall from within.

And finally the load. Where visceral fat and insulin resistance push blood pressure up, the heart must eject against greater resistance with every beat — the equivalent of driving permanently uphill. Wall stress rises, the muscle thickens, efficiency falls, and over years the risk of mechanical failure — in the heart's case, heart failure — climbs.

Put those three together and you have the essence of cardiometabolic disease: a heart forced to run on poorer fuel, through narrowing supply lines, while working against a rising load. It is a near-perfect recipe for inefficiency and, in time, exhaustion.

The paradox of the failing heart

There is a final twist worth telling, because it captures the organ's ingenuity even in decline. The failing heart often shifts its fuel preference once more — leaning away from fat and towards glucose and ketones — in what looks like a last attempt to wring more energy from each molecule of oxygen. The engine, sensing that ATP is running short, quietly changes gear again. And as it turns out, we may already have stumbled on a way to help it.

Cardiac energy metabolism: multi-fuel ATP production

Figure 2. Cardiac energy metabolism: the convergence of several fuels on a single pathway. Glucose, lactate, free fatty acids and ketone bodies each cross into the heart muscle cell through their own transporters and are converted — by routes of very different length — into acetyl-CoA, the one molecule that feeds the Krebs cycle. Ketones reach it especially directly, bypassing both glycolysis and the long spiral of β-oxidation. Acetyl-CoA then drives the Krebs cycle, generating the NADH and FADH₂ that power the electron transport chain and, with oxygen as the final electron acceptor, yield ATP — the final common currency of energy. The creatine–phosphocreatine shuttle buffers that ATP for the instant it is needed for contraction. © VAT-TRAP 2026.

The story begins with an unexpected clinical observation. The SGLT2 inhibitors — empagliflozin, dapagliflozin and their relatives — were designed as glucose-lowering drugs for type 2 diabetes, working by flushing surplus sugar out through the kidneys. What no one foresaw was how powerfully they would go on to help patients with heart failure, cutting hospital admissions and deaths across the whole span of the condition, in people with and without diabetes alike. The effect was so large, and so clearly independent of blood-sugar control, that it sent cardiologists looking for a different explanation.

One of the most compelling — though it remains a hypothesis under active test, not a settled fact — brings us back to fuel. By prompting a modest, sustained rise in ketone bodies, these drugs may hand the struggling heart a cleaner, more efficient fuel to burn. As Figure 2 shows, a ketone reaches acetyl-CoA by an unusually short road: where fatty acids must be dismantled through the long spiral of β-oxidation and glucose worked through the many steps of glycolysis, a ketone is converted in just a handful of reactions. It slips almost directly into the final common pathway, and it yields a little more energy for every molecule of oxygen consumed. For a heart whose defining problem is that it is energy-starved, a fuel that is both quick to reach the furnace and thrifty with oxygen may be close to ideal. This "thrifty substrate" idea, first advanced to explain the trial results, is not the only account on the table — these drugs also ease the heart's fluid load, quieten inflammation, and alter the handling of sodium inside the muscle, and the truth is likely woven from several of these threads at once. But the notion that some of the benefit may come from nothing more than feeding the failing heart a better fuel is among the more elegant ideas in modern cardiology, and a pointed reminder that the heart is, before all else, a metabolic organ.

Why this belongs in the VAT Trap

It would be easy to read all this as a curiosity of cellular biology, but it changes how we ought to think about cardiovascular risk. We are used to reducing that risk to three numbers — LDL cholesterol, blood pressure, weight — and each of them matters. Yet beneath them lies a plainer truth: the heart is a metabolic organ, and its wellbeing depends not only on the blood it receives but on the fuel it is offered and the flexibility it retains to choose between fuels.

Visceral fat sits at the centre of that story. It drives the free-fatty-acid flux, the liver's overproduction of VLDL and the insulin resistance that between them reshape not just the cholesterol panel but the very fuel the heart is bathed in. This is why improving metabolic health — through fat loss, movement and treatments that restore insulin sensitivity — so often does more for the heart than any change in cholesterol figures alone would predict. It is also why the four pillars of the VAT Trap framework — blood pressure, ApoB-containing lipoproteins, glucose-insulin regulation, and visceral fat — are best understood not as four separate targets but as four levers on the same engine.

The best fuel trainer we have

If there is one intervention that restores the heart's lost flexibility, it is exercise. Training builds mitochondrial density, sharpens the muscle's ability to burn fat and take up glucose, and rebuilds the very switching capacity that metabolic disease erodes. In the language of the analogy, exercise upgrades the engine's operating software — and unlike most upgrades, it is free.

There is an evolutionary logic to all of this. Our ancestors lived through feast and famine, long exertions and longer walks, and a heart that could change fuel at will was a heart that survived. What has changed is not the engine but the environment we now ask it to run in: constant food, little movement, and a steady accumulation of the visceral fat that jams the gearbox. The organ is as remarkable as it ever was. We have simply stopped giving it the conditions it was built for.

The engine that never stops

Perhaps that is the truest way to see the heart — not as a pump moving fluid, which is how we so often draw it, but as a self-optimising, multi-fuel engine designed for a lifetime of uninterrupted work. It cruises on fat, shifts to glucose when the effort or the oxygen demands it, reaches for ketones when the larder runs low, and does all of this seamlessly, silently, and without ever once shutting down for maintenance. Give it the metabolic environment it evolved for, and it will run, quite literally, for a lifetime.

Summary

The healthy heart is a metabolic omnivore, shifting between fatty acids, glucose, and ketones depending on workload and oxygen supply. This flexibility is central to cardiac function. When it breaks down in heart failure or ischaemia, the consequences drive real contractile dysfunction — not just biochemistry.