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Long-term use of over-the-counter heartburn medications such as Nexium, Prevacid and Prilosec has been linked to a higher risk of heart attacks, dementia and kidney failure, and now researchers at Houston Methodist think they can explain why.

A study published online Tuesday by the journal Circulation Research concluded that the class of drugs known as proton pump inhibitors prematurely age the cells that line the inside of blood vessels, making them less resistant to blockages that can cause heart attacks and strokes.

"We now have the smoking gun," said Dr. John Cooke, chair of the department of cardiovascular sciences at the Houston Methodist Research Institute and senior author of the study. "It raises the question of should these drugs be (sold) over the counter."

Proton pump inhibitors are among the mostly widely sold drugs in the world, accounting for more than $9 billion in prescription sales in 2014. They can be purchased in the U.S. without a prescription but are intended for only short-term use, up to four weeks. According to the Food and Drug Administration, one in 14 Americans takes one of these drugs.

The researchers bathed endothelial cells, which provide the Teflon-like coating within blood vessels, in a solution containing a proton pump inhibitor. Within weeks, the cells began to change in appearance, taking on the typical fried-egg look of cells when they age. When the researchers looked closer, they could see the waste accumulating in the endothelial cells.

The researchers presumed that the proton pump inhibitors were interfering with the lysosomes, which produce acid to break down waste products within the cell.

"They're like little garbage disposals. They get rid of the junk that's accumulating in those cells," Cooke said. "We've found that the proton pump inhibitors are impairing the ability of those little garbage disposals to make acid."

As proteins build up in the cells, the endothelial cells age faster and the lining becomes sticky allowing blood components to adhere to the vessel wall and form clots. Those clots could then block blood vessels causing heart attacks or break free causing strokes. Damage to the lining cells in blood vessels in the kidneys or brain also could explain the higher risk for renal failure and dementia.

"These endothelial cells line every blood vessel in the body and it has been shown that the health of that lining is important for heart health, brain health and kidney health," Cooke said. "So it could be the unifying mechanism."

Dr. Mark Creager, a cardiovascular disease specialist at Harvard Medical School and president of the American Heart Association, called the study "outstanding science" but cautioned it was not definitive and should not yet change clinical practice.

"It's a question worthy of further exploration," Creager said. "I think it would be very premature and not appropriate for clinicians to be taking their patients off these drugs if they prescribed them for the right reasons."

Last year, Cooke collaborated with researchers from Stanford University to scour some 16 million records from nearly 3 million patients to find which of them had taken medications for gastroesophageal reflux disease, and how of many of them had heart attacks.

That study found that patients taking drugs known as proton pump inhibitors, such as Nexium, Prilosec and Prevacid, had a 16 percent to 20 percent higher risk of heart attack than those who took H2 blockers, a class that includes Zantac and Tagamet.

At least 30 studies have found a correlation between long-term use of proton pump inhibitors and increased risk of heart attacks. But none of those studies was performed in a way that allowed researchers to conclude a causal link. It was impossible to tell from those studies whether other factors, such as obesity or smoking, could be behind the increased risk for both heartburn and heart attacks.

Cooke said many patients with severe heartburn need proton pump inhibitors, but others could rely on other types of antacids that do not have the same negative effect. Cooke called for regulatory authorities to reconsider the sale of the drugs without a prescription, until long-term studies could be completed to quantify the risks with chronic use.

"They are safe and effective short term. But long term, I have concerns," he said. "I think it's time for physicians to stop prescribing these without a thought."

Creager said patients should check with their physicians any time they use an over-the-counter drug for a prolonged period of time.

"Independent of this study, any drug if not prescribed, it is reasonable and appropriate for the patients to have a conversation with their health provider to see if that's something they should be doing," he said.