But researching cancer, he stumbled on a fact that changed his career: Certain cultures around the world do not suffer from heart disease, the No. 1 killer in the Western world.
Esselstyn's practice took a dramatic turn -- from performing surgery to promoting nutrition. For more than 20 years, the Cleveland Clinic doctor has tried to get Americans to eat like the Papua New Guinea highlanders, rural Chinese, central Africans and the Tarahumara Indians of Mexico.
Follow his dietary prescription, the 77-year-old Esselstyn says, and you will be "heart attack proof" -- regardless of your family history.
"It's a foodborne illness, and we're never going to end the epidemic with stents, with bypasses, with the drugs, because none of it is treating causation of the illness," Esselstyn says.
The Esselstyn diet is tough for most Americans to swallow: no meat, no eggs, no dairy, no added oils.
sselstyn has written a book to spread the word, "Prevent and Reverse Heart Disease -- The Revolutionary, Scientifically Proven, Nutrition-Based Cure," and he has given talks around the world.
He is also a focus of the new documentary "Forks Over Knives." Esselstyn has won some high-profile allies -- such as Dr. T. Colin Campbell, co-author of "The China Study," and Dr. Terry Mason, chief medical officer at Cook County Hospitals in Chicago and the city's former health commissioner.
"We've eaten ourselves into a problem, and we can eat ourselves out of it," Mason says. But Esselstyn's prescription goes against conventional wisdom, which considers diet only one factor in preventing heart disease.
"Diet alone is not going to be the reason that heart attacks are eliminated," says Nancy Brown, CEO of the American Heart Association.
Other key factors include physical activity, cholesterol, blood pressure and weight, she says. The meat, dairy and egg industries defend the benefits of their protein-rich foods, all of which remain on the U.S. Department of Agriculture's MyPlate dietary guidelines for healthy eating.
Esselstyn's plant-based prescription also runs up against a culture where meat is served at most meals.
"Most doctors eat meat because most Americans eat meat, and if they don't really see for themselves or for their family why it might be a good idea to cut down or even cut meat out of their diet altogether, they might not be so inclined to recommend it to their patients," says Michele Simon, author of "Appetite for Profit."
Even doctors who see the benefits of Esselstyn's diet may not prescribe it for their patients.
"Anyone who is able to do that diet can have dramatic success. The problem is that many people are unable or unwilling to make these changes so in my practice, I try to take baby steps -- one step at a time," says Dr. Erin Michos, a cardiologist at the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins University.
To help heart patients and others make the leap to his diet, Esselstyn holds a monthly, five-hour seminar at the Cleveland Clinic Wellness Institute to explain the science behind "plant-based" nutrition.
Esselstyn's wife, Ann, offers practical advice on how to prepare kale, bok choy, collard greens and other foods that may not be on the typical family's shopping list.
Esselstyn began recruiting patients in 1985 and says his diet has worked even on people deemed too sick for surgery. Esselstyn has published results from a small group of patients showing how his diet either halted the progression of heart disease or reduced the blockages in the blood vessels leading to the heart.
"We know if people are eating this way they are not going to have a heart attack," says Esselstyn, whose father had a heart attack at 43.
Anthony Yen, an entrepreneur who emigrated from China and came to love the fried foods, meat and desserts of the American diet, adopted the Esselstyn program in 1987 after undergoing bypass surgery.
"I'm still alive because of this diet," Yen says, now 78.