Peter Kwiterovich, M.D.
What attracted you to blood cholesterol and lipoproteins?
I was always interested in the mechanisms, etiology and genetics of human disease. Then, during my summers and electives in medical school at Johns Hopkins, I was able to work with Victor McKusick, the “Father of Genetics.” I was most fortunate to have him as a mentor.
What was that experience like?
It was an adventure. He sent me out to Holmes County, Ohio, to study Down syndrome in Old Order Amish families, to see if they had a predilection for Down syndrome, on a genetic inbred basis. I’d go to Amish farmhouses and draw blood by candlelight, do lipid profiles, check for heart murmurs, dermatoglyphics, and karyotypes. It was a great experience working in the trenches to learn a number of skills. We did not find Down syndrome more common in the Amish. Decades later genes were found that affected this relationship. I found it a very interesting experience because it involved both laboratory and clinical laboratory research related to human disease. This early work influenced the path I’ve followed since then.
Other early influences?
After my internship at Boston Children’s, I ended up in the lab of Donald Frederickson, chief of the molecular disease branch of the National Heart, Lung, and Blood Institute (NIHLB). He was also co-editor of “The Metabolic Basis of Inherited Disease,” considered the classic text on metabolism when we were in training in the 1960s. Each chapter was written by someone who had discovered something new about molecular disease. Training in his lab I focused on glyco- sphingolipids and familial hypercholesterolemia (FH), at a time when there were not many lipid investigators. It was an invaluable experience.
I was able to publish my first two genetic and lipid papers in the field. One, published in 1973, showed that FH could be diagnosed in cord blood at birth in families at risk for high cholesterol and heart disease. The other, published in 1974, showed that FH was completely expressed in children between two and 18 years of age. The prevalence of FH was as high as 1/300 to 1/500.
What came next?
Experts had been assembled by the National Institutes of Health (NIH) to develop a national plan to address the major question: “Did elevated cholesterol cause diseases of the blood vessels of the heart, brain, kidneys, etc., and did treatment of hypercholesterolemia decrease coronary artery disease (CAD)?” Three major research areas were developed: cholesterol and lipoprotein measurement; determination of normal and abnormal lipid levels in different populations including children; and, examination of the effect of lowering cholesterol on the development of cardiovascular disease (CVD) in healthy hypercholesterolemic men. Twelve Centers, the Lipid Research Clinics (LRC), were established in 1971 and 1972, one of which was at Johns Hopkins, where the focus on research was on dyslipidemic children and their parents. I returned to Hopkins to play a major role in setting up the LRC program there. Paul Bachorik, M.D., Ph.D; Simeon Margolis, M.D., Ph.D; Catherine Neill, M.D.; Gary Chase, Ph.D; and G. William Benedict, M.D., Ph.D, were importantly involved.
And the results?
A score of epidemiological studies provided evidence that as cholesterol went up, so did the prevalence of CVD. However, there was no evidence that reduction of cholesterol and its major carrier in the blood—low density lipoprotein (LDL)—decreased the risk of CVD in healthy subjects. In a 7-year study of some 3,600 hypercholesterolemic men ages 35-59 without CVD, those treated with a cholesterol lowering drug, cholestyramine, experienced a 20-percent drop, on average, in total cholesterol, as well as 10 percent fewer heart attacks—an observation confirmed in multiple studies with statin drugs.
What was most important about the findings?
The findings illuminated the severity of the expression and familial nature of lipid disorders. Even if you didn’t have any clinical problems, if your brother had FH, then you’d better get checked out. The research shaped the development of our own lipid clinic, likely the oldest such clinic for children in this country. We attracted patients from Ohio, Pennsylvania, West Virginia, New York and New Jersey, among other states, which gave us and other investigators a unique opportunity to collect and compare biochemical and genetic data across multiple generations. This led to the elucidation of the molecular basis of certain lipid disorders such as LCAT deficiency, ABCG5 and ABCG8 mutations leading to phytosterolemia, and molecular variants such as apoB-100 Hopkins and apoA-I Baltimore.
Other areas of research?
Interested in finding new ways to prevent and reverse cardiovascular disease through diet and nutrition, we were one of the lead centers in a multi-year study on the effects and safety of a low-fat diet among teens with moderately high cholesterol. At the time, many pediatricians were concerned that a diet low in fats could pose a threat to the rapidly growing bodies of teenagers, but we demonstrated the safety of the diet.
How did your research influence clinical practice?
Detecting cholesterol in children and adolescents was a new thing for people to think about, and the pediatricians and internists were excited about it. Like night and day, the way clinical medicine was practiced began to change, with more emphasis on screening patients and their families for lipid disorders, new therapies, exercise and diet. Today, our lipid clinic is a national leader in offering patients the most sophisticated technologies to evaluate protein and fat levels in their blood so that medication and diet plans can be tailored to meet individual needs. Today, the cut-points developed from the LRC program are used to first define dyslipidemia in children and adults, secondly, to set cut-points for the use of statins and other drugs in such patients, and finally to decide whether treatment has been successful in preventing coronary artery disease.
Recently we began to offer patients with an extreme form of homozygous FH an alternative cholesterol-lowering therapy known as LDL apheresis. Similar to kidney dialysis, blood is continually removed from a patient’s vein in the arm and run through a machine that separates the plasma from the red blood cells. The LDL and other “bad” lipoproteins are filtered out of the plasma while high-density lipoprotein (HDL), or “good” cholesterol, albumin and other beneficial plasma proteins are allowed to pass. The LDL depleted plasma is then recombined with the blood cells and returned to the patient via a different vein. So it removes all of the atherogenic molecules but not your good HDL.
With your retirement, will the Lipid Clinic continue at Johns Hopkins?
I believe that it is critical. We must continue our leadership by example in pediatric dyslipidemia, to continue the early diagnosis and treatment of affected children and their parents in the Lipid Clinic, and to form a partnership with Joel Brenner, head of pediatric cardiology and his staff. Yes, it’s critical; you don’t want to lose 40 years of clinical research evidence showing that all of this is important. At the moment, we’re not sure how it’s all it’s going to evolve. But, it’s been a great ride. I’ve been extremely fortunate. I am indebted to my patients, my research staff, and to the faculty members to continue the Johns Hopkins Lipid Clinic.
Any take-home messages for pediatricians?
Sure, know your own cholesterol, triglycerides, lipoproteins, and other risk factors such as obesity, high blood pressure and fasting blood sugar you might have. And measure these lipid and non-lipid risk factors in every one of your patients, starting with children ages 9 to 11.