The results of the first phase of the study—an epidemiological survey of approximately 10,000 persons in six geographically different regions characterized by differences in the primary source of dietary fat—were reported in the Journal of Lipid Research in 1995.

The most striking finding was the genetically low levels of high density lipoprotein cholesterol (HDL) in Turks, which are 20–25% lower than those in Americans and Europeans. About 53% of Turkish men and 26% of Turkish women have abnormally low HDL levels (<35 mg/dl), compared with only 15% of U.S. men and 5% of U.S. women.

The first team of investigators with the Turkish Heart Study (l to r): Sedat, Altuğ, Dr. Palaoğlu, Dr. Oryal, Ebru, Nurgül, Ibrahim, Doğan, and Dr. Mahley. “Ayvalik was the first area we traveled to,” said Mrs. Mahley, “and we didn’t have any idea the response we’d get. We were a very small team: Judy Dawson (the first member of the Gladstone lab), Erhan, Dr. Oryal, and Doğan from the American Hospital, five medical students, and me, to draw the blood. Hundreds of people showed up. Judy and I had to process all the samples ourselves.”

Several factors were associated with the low HDL levels in Turks, including elevated levels of hepatic lipase. That suggested a mechanism, but it didn’t identify the underlying cause. An intriguing clue came from a study of Turkish school children. During puberty, HDL levels in Turks plummet by more than 20 mg/dl, a 40% drop. The decrease may not have anything to do with sex hormones, though. It could involve leptin, adiponectin, or other hormones that affect HDL either directly or indirectly.

Currently, study investigators are performing genome scans of large families to identify the gene or genes associated with lipid problems. In collaboration with GlaxoSmithKline, a six-nation consortium is studying problems related to the metabolic syndrome: low HDL, high triglycerides, hypertension, obesity, and diabetes. About 3500 sibling pairs—one with and one without the metabolic syndrome—in the U.S., Canada, Finland, Switzerland, Australia, and Turkey have been enrolled.

The Story behind The Turkish Heart Study

Mankind is a single body and each nation is a part of that body. We must never say ‘What does it matter to me if some part of the world is ailing?’ If there is such an illness, we must concern ourselves with it as though we were having that illness.
—M. Kemal Atatürk, Father of the Turkish Republic

The scientific achievements of the Turkish Heart Study have been well documented. But the human side of the story—the people who made it possible and the challenges they faced, the joys and satisfactions they found, and the friendships they established—is less well known. Recently, the Gladstone Focus talked with Dr. Mahley about the study. Why Turkey, we asked, and how did he manage to launch and carry out a large-scale epidemiological study in a developing country halfway around the world? “I’d always wanted to do an international study of risk factors for cardiovascular disease,” he said, “and after 10 years of successful operation of the cardiovascular institute, I was looking for a new challenge, something totally different from anything I’d done before.”

Medical student Sezai, now a cardiovascular surgeon in Istanbul, conducting an interview in a school classroom turned into a clinic.

In 1987, with the support of the Gladstone Trustees, he began looking for a population in which no thorough study of risk factors for heart disease had been done. Turkey met all the criteria. “The country has excellent doctors and several high-quality medical schools, and I was also able to identify a place where I could set up a laboratory—the American Hospital in Istanbul.”

The contact with the American Hospital was through Dr. Antonio Gotto, a friend of Dr. Mahley’s from medical school and the NIH, who had helped establish a cardiology department at the hospital. He offered to make all the arrangements for Dr. Mahley to work there. With that, Dr. Mahley flew immediately to Houston to discuss the offer and then returned to San Francisco. He and his wife, Linda—a certified medical technologist who made key contributions to the study—left the next morning for Turkey.

Getting Started

Amazingly, when the Mahleys reached the American Hospital, an office and laboratory space were already in place, thanks to hospital director Dr. Warren Winkler. “He simply opened the door, which said ‘Gladstone Research Laboratories,’ and asked what could be done to help us get to work,” said Dr. Mahley. “That was the easy part. The hard part began with standardizing the clinical laboratory. That took a year.”

Key to the success of the laboratory was its director, and in that Dr. Mahley was fortunate. “Dr. Erhan Palaoğlu became my closest collaborator and best friend.

He is an outstanding biochemist, the equal of any in the world.”Input from the Turkish doctors was also critical, and they were tremendously interested in all aspects of the project— the overall study design, research protocols, equipping the laboratory, training the staff—everything that needed to be done before patients could be seen.

The next step was to staff the laboratory. The first member, hired in 1989, was Judy Dawson, a biochemist from Canada. She was soon joined by Zerrin Atak, a research associate with a background in biology, biochemistry, and molecular biology. For many years, they were the only full-time staff. Work on the Turkish Heart Study continues today with new laboratory staff, including Guy Pépin and Sibel Tanir.

For the first few years of the study, Dr. Mahley would spend about three months in Turkey each summer, setting up new procedures and preparing the staff to carry out studies over the next nine months. During those summers, the small Istanbul staff was supplemented with one or two medical students or doctors from the U.S.

The final element of the research team was Turkish medical students. The major surveys were done between 1990 and 1995, but the really heavy work was done from 1990 to 1993. Twice a year, in the summer and winter, Dr. Mahley would take a dozen medical students to the study site. The trips were about two weeks each, and the locations were usually remote. To recruit the students, he would visit a medical school on his prior visit, give some lectures, and talk with the dean. Together, they created a competition to find 12 outstanding students who spoke English fluently.

With a Lot of Help from Friends

There were serious logical challenges to overcome. Nearly 25 people had to be moved around a country where moving around is not always easy. And a lab had to be set up in each location. “We had to carry everything in,” said Mrs. Mahley, “test tubes, Band-Aids, syringes, and even a refrigerated centrifuge!”

The local arrangements would come together over several days and gallons of tea. (Tea lubricates all social and business interactions in Turkey.) Drs. Mahley and Palaoğlu would go to the next site a couple of weeks ahead of the rest of the team. They would wander the city and surrounding villages, drink a lot of tea, and visit the local doctors. Then they would find a location to set up the lab, get to know the owner, and slowly but surely take over. They needed ice, a refrigerator, freezers, an air-conditioned area for the staff to work, and a place for Dr. Mahley’s daily lectures for the medical students. “I don’t think we ever made a request at a hotel or school or village where we turned down,” he said. “Everybody was proud to be a part of the study.”

To recruit urban participants, Dr. Mahley used the Rotary Club: there was one in almost every city. He and Dr. Palaoğlu would invite themselves to a meeting, speak about the project, and then set up a clinic for the club members.

Recruiting in villages called for a different strategy. Turkish men spend much of the day in the teahouse, while the women work in the fields. So Drs. Mahley and Palaoğlu would go to the teahouse, usually in the center of the town, and sit and drink tea. Eventually, they would ask to meet with the muhtar, or mayor. The muhtar would buy more tea, and they would tell him about the project.

The village would become part of the national survey defining the risk factors for heart disease in the Turkish people, they would say. In a week the researchers would return with Turkish doctors and medical students. They would take blood samples from 100 men and 100 women, weigh them, and ask them a series of medical questions. If the muhtar liked the plan—and invariably he did—someone would go to the mosque to fetch the imam.

After the imam arrived and more tea was ordered, they would explain the project to him. The imam always agreed that the study was important. Dr. Mahley made sure that there was a Friday between visits. Many Moslems go to the mosque on Friday, so the imam could explain the study and tell them when and where to show up. On the appointed day, he would announce the study from the minaret. If people were not showing up fast enough, Dr. Mahley would walk up and down the streets of the village in his tie and white coat. “Pretty soon I was leading a parade of people back to the clinic,” he said.

A Typical Day in the Turkish Heart Study

The days began early. The team rose about 5:30 a.m., ate breakfast, drove to the survey site, and set up the clinic. Many of the participants were farmers or factory workers, who had to be reached before they went to went to work, typically at 7:00 a.m. Even more challenging, the samples had to be taken before the participants had eaten.

The medical students conducted the interviews, using a standard questionnaire to obtain a social and medical history, including information on education, type of work, exercise, smoking, alcohol consumption, and family medical history. Mrs. Mahley did a lot of the blood draws and worked in the lab. Dr. Mahley and the Turkish physicians did the physical examinations.

The team would work until noon. Afternoons were consumed by the lab work. Every tube of blood was divided into at least 12 samples each of serum, plasma, and buffy coats—36 aliquots in all. The maximum number of participants who could be surveyed each day was about 200, half men and half women. That’s a lot of work for a dozen medical students.

The scene at the clinic was often chaotic. Family members didn’t want to be kept outside. A throng would gather at the front door. People would do anything to get in—even faint or pretend to faint. To help control the crowd, septuagenarian photographer Bernice Condit was stationed at the front door. The people were too respectful to trample an older lady.

In one village, Dr. Mahley was checking the height, weight, blood pressure, and pulse of each participant. The enthusiasm of the participants was so great that everyone was jostling for position, and the person in the front would grab his knee. That’s how they knew who was next. One after the other, the next woman in line gripped his knee. “When I got back to the hotel that night, my knee was black and blue!”

In another village, the women were all lined up and refused to allow the men in. “The men just sit around the teahouse drinking tea,” the women said. “We do all the work. The men aren’t important; you don’t need them.” The study required samples from the men, too. But the women would not be persuaded. So, Dr. Mahley told the medical students to take their time interviewing the women. Then he and Mrs. Mahley took half the students, climbed out a back window so the women at the front door couldn’t see them, and ran over to the teahouse, where they hurriedly set up another clinic for the men.

Around 5:00 p.m., Dr. Mahley would begin lecturing the medical students on heart disease, lipids, and lipoprotein metabolism. “By the end of the summer, they knew everything I knew about heart disease,” he said. Around 7:00 p.m., the lab staff had finished their work, and everyone would go to dinner.

And the next day, the cycle started over again.

Looking Back with Satisfaction

The Turkish Heart Study has brought enormous satisfaction to the Mahleys.

“We had no idea what we were going to find,” Dr. Mahley said. “A lot of my colleagues asked why I expected to find anything in Turkey that hadn’t been found elsewhere in the world. ‘Well, until you look,’ I said, ‘you don’t know what you’re going to find.’”

What they found was the major risk factor for heart disease in Turks, and it’s different than in the U.S. and western Europe. The Turks have very low levels of HDL (good cholesterol), some of the lowest in the world.

Another source of satisfaction is the large number of Turkish doctors who have been trained. Some 3500 physicians, mostly specialists, have taken Dr. Mahley’s intensive two-day course in managing heart disease. The courses grew out of the lectures for the medical students. Dr. Palaoğlu and Dr. Oryal Gökdemir, a close friend and distinguished cardiologist, translated them for publication in Turkey. More recently, Dr. Thomas Bersot joined the project to assist in the teaching.

“At the outset, we had to start with ‘A lipoprotein is….’ Now, we’ve trained a cadre of Turkish physicians. Last year, for the first time, we didn’t do any courses,” Dr. Mahley said. “I felt we had saturated the field. The Turkish Society for Cardiology has established the Turkish Lipid Working Group. These people know the literature, and they can do their own teaching now, in Turkish.”

The Turkish doctors have developed their own guidelines for the treatment of dyslipidemia, and those guidelines are different from those used in the U.S. Earlier this year, Dr. Mahley was talking about the metabolic syndrome to a group of Turkish physicians. He challenged them to question the definition of the metabolic syndrome based on U.S. diagnostic criteria. “They were quite taken aback, but incredibly interested,” he said.

In fact, Dr. Mahley has written two textbooks on lipids, lipoproteins, and atherosclerosis that have been translated into Turkish. These educational materials are used extensively by students and faculty in medical schools throughout Turkey. In recognition of his contributions to health care in Turkey, Dr. Mahley was elected to membership in the Turkish Society of Cardiology, a rare honor for a non-Turk.

Recently, Dr. Mahley was introduced to a young Turkish doctor as someone who had studied Turks. When asked if he was aware of that Turks have very low HDL levels and that this is an important finding, Dr. Mahley replied modestly, “By golly, you’re right.” Upon learning that Dr. Mahley had discovered the low HDL levels, the young doctor was embarrassed. But Dr. Mahley reassured him that it was all right. “He’d learned the critical lesson!”

“So that’s satisfaction, too—getting the message out,” he said. “And satisfaction is seeing Turkish physicians who know as much about lipids, lipoproteins, and heart disease as anyone else in the world.”

Watching the students become independent thinkers was also gratifying. “Read it, memorize it, and regurgitate it—that was the Turkish education system” said Mrs. Mahley. “Bob refused to let the students get by with that. He sprinkled his lectures with questions. The students had to be listening and thinking because they never knew when he’d call on them.”

Hope for the Future

In its 17 years, the Turkish Heart Study has had many successes, but perhaps its greatest accomplishment has been its contribution to public health in Turkey. “We haven’t found the cause of the low HDL levels yet,” said Dr. Mahley, “but we are making progress.” In the mean time, Turkey is in a much better position to put in place the measures needed to cope with the adverse health effects of the Western-style diet that is increasingly popular throughout the country, particularly in the large cities.

In a sense, the admonition of Atatürk—a personal hero of Dr. Mahley’s—has come full circle in the Turkish Heart Study. Dr. Mahley has concerned himself with heart disease in Turkey as though he himself were having that illness. And Mrs. Mahley has been there at every step, with compassion, humor, and consummate professionalism.

“The Turkish people are absolutely wonderful, the most generous, hospitable people in the world,” said Dr. Mahley. “Linda and I love Turkey, and we love the Turkish people.”