Professor Thomas Münzel and his team at the University Medical Center Mainz, together with an international group of cardiologists spanning the United States, Italy, the United Kingdom, and Switzerland, set out to test that logic directly. Their conclusion, published across two major papers in 2025 and 2026, is unambiguous: the fire is a real danger for the vessels and the heart, but so, surprisingly, is the nicotine. So, tobacco-free products are less harmful, but far from being harmless.

“We wanted to settle a question that has been argued for years,” Professor Münzel explains. “Is the cardiovascular harm caused by nicotine solely related to tobacco smoking, or is nicotine toxic by itself?” It’s a question with enormous stakes. If nicotine itself is also a significant problem, then no amount of clever engineering, no heating instead of burning, no water filtration, no tobacco-free pouch, can make a nicotine product genuinely safe for the heart.

To answer it, Münzel’s team, together with co-authors including Professor Filippo Crea, Professor Thomas Lüscher, Professor Sanjay Rajagopalan, Professor John Keaney, Dr. Marin Kuntic, Dr. Julia Lurz and Professor Andreas Daiber, pulled together three streams of evidence that are rarely examined side by side: detailed chemical data on what each product actually emits, mechanistic studies in cells and animals showing how nicotine acts on blood vessels, and large clinical studies tracking real-world cardiovascular outcomes in tens of thousands of people. The result, published in Nature Reviews Cardiology, is the most complete map yet of how nicotine attacks the cardiovascular system, and it traces a single molecular pathway running through every product on the market, from the cheapest cigarette to the sleekest vape.

Here’s what that pathway looks like. Nicotine binds to receptors, the same nicotinic acetylcholine receptors that make the drug so addictive in the brain, but these receptors also sit directly on the cells lining our blood vessels, on the adrenal glands, and on the nerves that control heart rate and blood pressure. The moment nicotine binds, two things happen almost simultaneously.

First, it triggers the release of stress hormones, adrenaline and noradrenaline, raising heart rate, blood pressure, and the heart’s oxygen demand within seconds. That’s the sympathetic nervous system going into overdrive, and it’s the mechanism behind the immediate head-rush of a first cigarette or a first vape.

Second, and more insidiously, nicotine goes to work directly on the blood vessel wall. It switches off an enzyme called endothelial nitric oxide synthase, eNOS for short, which normally produces nitric oxide, the molecule that keeps vessels relaxed, flexible and open. Nicotine starves this enzyme of a key co-factor, causing what researchers call “eNOS uncoupling”: instead of producing protective nitric oxide, the enzyme starts pumping out damaging reactive oxygen species instead.

At the same time, nicotine stimulates release of endothelin-1, one of the body’s most powerful vessel-constricting hormones, while suppressing prostacyclin, a natural vasodilator that also stops platelets from clumping together. It activates platelets directly and reduces the blood’s ability to break down clots.

Nicotine also short-circuits the vessel’s own relaxation machinery. Smooth muscle cells in the vessel wall rely on potassium channels, including ATP-sensitive potassium channels, to let potassium flow out and calcium levels fall, which is what lets the vessel relax. Nicotine blunts this signal, so the vessel stays tighter than it should. At the same time, nicotine raises levels of a molecule called ADMA, short for asymmetric dimethylarginine, which acts like sand in the gears of the enzyme that builds nitric oxide, competing with its usual raw material and choking off the vessel’s supply of its own natural relaxant.

Put it all together, and a single molecule is doing four things at once: constricting vessels, inflaming them, stiffening them, and making the blood more prone to clot. “Nicotine is not a passive component that merely sustains addiction,” Professor Münzel says. “It causes measurable, reproducible vascular damage. This has been demonstrated in animal models as well as in healthy volunteers and clinical cohorts.” Crucially, these effects show up after a single exposure, one cigarette, one vape, one pouch, regardless of which product delivered it.

None of this means every nicotine product is equally dangerous. Far from it. When the team layered their chemical, mechanistic, and clinical evidence together, a clear hierarchy of harm emerged. Combustion products, cigarettes and waterpipes, sit at the top, generating thousands of additional toxicants beyond nicotine itself: carbon monoxide, tar, and heavy metals. Heated tobacco products come next, followed by e-cigarettes, then oral nicotine products like pouches and chewing tobacco. Complete abstinence remains the only truly risk-free position on that scale.

“E-cigarettes and heat-not-burn devices were initially marketed as reduced-risk alternatives to combustible cigarettes,” Professor Münzel notes, “but evidence points to these products being on a continuum of cardiovascular risk.” That distinction matters for public health messaging. A smoker who switches completely to vaping does measurably reduce their cardiovascular risk, with partial recovery of blood vessel function within weeks. But partial recovery is not safety, and the moment someone becomes a dual user, that benefit disappears: dual users carry cardiovascular risk indistinguishable from smokers who never touched an e-cigarette at all.

Professor Filippo Crea, one of the paper’s co-authors, frames the significance of the work this way: “This review closes an important evidence gap by evaluating, for the first time, existing mechanistic, biomarker and clinical data across products. It is apparent that nicotine is an active driver of endothelial dysfunction, the earliest step on the path to atherosclerosis, hypertension and heart failure, and only abstinence is risk free.”

That phrase, “endothelial dysfunction,” is worth pausing on. The endothelium is the thin layer of cells lining every blood vessel, and its health is one of the earliest, most sensitive predictors doctors have for future heart attacks and strokes. Across every nicotine product the team examined – a single cigarette, a single vaping session, a single nicotine pouch – that same early warning sign showed up. It’s what makes endothelial function such a powerful biomarker for regulators: a fast, measurable signal of harm that doesn’t require waiting decades for outcome data to accumulate.

Mechanistic evidence, however detailed, only changes practice if it reaches the people who write the rules. That’s why, in a companion policy paper published in the European Heart Journal, Professor Münzel, together with Professor Crea, Professor Rajagopalan, and Professor Lüscher – who also serves as President of the European Society of Cardiology – distilled the cardiovascular case against nicotine into twelve evidence-based key messages for policymakers and practising cardiologists.

The numbers behind those messages are sobering. Tobacco use accounts for roughly 7.7 million deaths every year worldwide, with cardiovascular disease as the single largest cause. In Europe alone, tobacco is responsible for around 1.2 million deaths annually, and the associated healthcare and productivity costs exceed 300 billion euros a year. And the crisis is no longer confined to smoking: up to 40 percent of European adolescents report having tried e-cigarettes, and in some countries, more teenagers now vape than smoke.

The twelve key messages build outward from the science, layer by layer. The first several messages simply restate, for a policy audience, what the mechanistic paper demonstrated: nicotine is a direct cardiovascular toxin regardless of delivery method; no nicotine product, however it’s engineered, is safe for the heart or blood vessels; e-cigarettes are less harmful than cigarettes, but far from harmless; and passive exposure – secondhand smoke, secondhand vapour, and secondhand waterpipe smoke – poses a real and measurable cardiovascular risk to bystanders, not just users.

From there, the messages turn pointedly toward policy failure. One sharp observation concerns how the industry has adapted its playbook for a new generation. Flavoured products, such as mango, cotton candy, and mint, are marketed through social media influencers with millions of adolescent followers, while “tobacco-free” labelling encourages the false belief that pouches are somehow safer, when their addictive potential rivals traditional cigarettes. In some European countries, over 90 percent of sixteen-year-olds can buy nicotine pouches and e-cigarettes online with essentially no age verification.

The authors’ recommendations are equally direct: ban flavoured nicotine products outright; tax all nicotine products by nicotine content rather than product category, so no delivery method escapes regulation through a loophole; mandate plain packaging across e-cigarettes, heated tobacco, and oral pouches; close online sales and advertising loopholes; and extend smoke-free laws to outdoor spaces where children gather, such as playgrounds, café terraces, transport stops, and hospital grounds.

Professor Lüscher, speaking as President of the European Society of Cardiology, connects the science directly to policy already in motion. “This research underscores why the ESC and the EU are calling for updated tobacco and nicotine regulation as an integral part of the Safe Hearts Plan,” he says. “The evidence is clear that nicotine cannot be considered harmless. We must take this seriously in how these products are regulated, marketed, and communicated to the public, especially to young people.”

Perhaps the most striking feature of this body of work is how it reframes the regulatory conversation. For twenty years, tobacco control has evolved product by product: a law for cigarettes, a loophole for e-cigarettes, a gap for nicotine pouches regulators are still scrambling to close. Münzel and his colleagues argue this fragmented approach was always going to fail, because it treats each new product as a fresh question, when the underlying biology says the answer is always the same.

“Nicotine’s cardiovascular toxicity, combined with its well-documented, high dependence-forming potential,” Professor Münzel argues, “make the case for a coherent, nicotine-based regulatory framework rather than the current patchwork of product-specific rules.” His point is pharmacological, not just political: nicotine’s addictive potential is ranked alongside that of cocaine and heroin, yet it continues to be marketed, in pouch and vape form, as a barely-there stimulant comparable to caffeine. Until regulation catches up with the pharmacology, the industry will simply keep inventing new products one step ahead of the law.

For Professor Münzel and his co-authors, the message that emerges from combining the molecular biology with the policy analysis is deliberately simple: there is no version of nicotine that is safe for the human heart. Not smoked, not heated, not vaped, not tucked under the lip in a small white pouch. The delivery method changes the dose and the speed of harm. It does not change the destination.