Interview of William Kannel, MD

Interview of William Kannel, MD

Progress in Cardiovascular Diseases 53 (2010) 4 – 9 www.onlinepcd.com Editorial Interview of William Kannel, MD Dr Wilson: Welcome. This is an inter...

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Progress in Cardiovascular Diseases 53 (2010) 4 – 9 www.onlinepcd.com

Editorial

Interview of William Kannel, MD Dr Wilson: Welcome. This is an interview with Bill Kannel from the Framingham Heart Study, and the interview is being conducted by Peter Wilson from Emory University and Henry Greenberg from Columbia University and the Editor-in-Chief of Progress in Cardiovascular Diseases, I'm going to start with a fundamental question for Dr Kannel, what was the purpose of the Framingham Heart Study? Dr Kannel: Originally, it was a response to the recognition by the Public Health Service in 1948 that we were experiencing an epidemic of coronary disease. Joseph Mountin, who was the Director of Bureau of State Services, wanted to have a cardiovascular disease control demonstration program. The newly formed National Heart Institute reported that by 1948, about 44% of deaths in the US could be attributed to cardiovascular disease. That was an increase of about 20% since 1940. At that time, the causes of cardiovascular disease unfortunately were poorly understood. Dr Wilson: So, why Framingham? Were there other places? Why was that site chosen? Dr Kannel: Well, actually, there were 2 others, but Framingham was chosen because it was an ethnically diverse, stable population that had been shown to be cooperative in a long-term tuberculosis study, without much loss of subjects on follow-up. Framingham was also close to major medical centers in Boston and initially had only 2, and later 1, hospital in town where subjects' admissions could be closely monitored. Dr Wilson: Tell us a little bit about recruitment and involvement of town leadership and how did that work out? Dr Kannel: Sure. Well, the Framingham investigators recruited community leaders, and they were to form the core of a town executive committee, suggesting that the heart disease study belonged to the community of Framingham as part of the local health department program and that it will provide a service for the advancement of medicine. The town leaders were encouraged to invite their neighbors to participate by face-to-face persuasion, a policy that every study participant should come into the

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study on the basis of an invitation from somebody he knew and in whom he had confidence. Dr Greenberg: That's an innovative approach. We don't recruit for clinical trials now by having patients come in because someone they know and trust recommends it, other than their physician or the staff. So that kind of approach back then was really quite imaginative. Who was the person responsible for that kind of insight into the culture of the community? Dr Kannel: I think it probably was the original director, Gilcin Meadors, who Thomas “Roy” Dawber replaced, who had that approach. Also, you've got to remember the context in which this all occurred. This was a time when President Truman was advocating a social medicine program. And everybody, particularly the doctors, was very fearful that this was the entering wedge of government medicine. So, we had to get the investment from the local doctors and from the community to endorse it and allay those fears. Dr Wilson: Dr Kannel, you have been recognized as the person to first use the term risk factor for heart disease. Maybe, in my review, it first started to occur in the literature in the 1950s. What is your personal recollection of how that started out? Dr Kannel: Well, let's see now. Well, I guess the concept sort of was floating around out there. I can't say with assurance that we necessarily invented the concept, but the term was probably coined in Framingham. NIH had developed 28 factor-specific hypotheses that might be related to CVD. And these hypotheses followed a common logical form, linking coronary disease with degree of exposure. For example, a tobacco hypothesis, which stated that degenerative disease—well, in that time we were calling it degenerative cardiovascular disease—appears earlier and progresses more rapidly in persons who habitually use tobacco. These hypotheses were to be the basis of future data analyses. And one of them was that an attribute of the core exposure increases the probability of disease occurrence. Now, although the concept of risk factor may predate Framingham, the term itself only appears in a Framingham

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P. Wilson, H. Greenberg / Progress in Cardiovascular Diseases 53 (2010) 4–9

article in 1961, called the factors of risk in the development of coronary disease.1 Dr Wilson: One of the early concepts that came up was determining if risk factors generally multiply risk or are they additive or—and how was this done? This is not just back of the envelope calculation. This required computer help to put this concept together. Dr Kannel: Oh, sure. Obviously, it's more than simply additive. And the trick here was to establish an independent contribution of particular risk factors so that we could see that they were, in fact, making a contribution and not riding on the back of something else. And, therefore, we had to develop or stimulate the development of multivariable analysis. That was a new concept; it didn't exist before. Originally, we used punch cards to sort and count data, which were analyzed without the aid of computers, using simple cross classification to assess the net and joint effects. Now, this was, as you can imagine, a formidable task considering that there were 80 variables collected biennially to be accounted for. Fortunately, we were rescued from our dilemma by development of huge electronic computers stationed at NIH at that time. They were available, I must say at high cost depending on time required for the analysis, to our Bethesda-based statisticians. This ultimately was replaced by desktop computers used locally to analyze data on-site with our own programmers and statisticians. So, the Framingham initiators really had to learn or invent novel approaches to epidemiologic research, which formerly was almost exclusively focused on, let's say, infectious and nutritional disease, and use of cross-sectional analysis to assess the independent and joint effects. Dr Wilson: One other issue I think that's important for readers to understand is a point that you made at the outset, that the focus was on clinicians, and the idea of a visit every 2 years for the original cohort would be like a regular doctor's visit. And we'll ask you to describe that briefly and then segue into how did you decided whether a person had had a cardiovascular event. Dr Kannel: Okay. Well, basically, we developed a regular physical exam for the presence of CVD, as is still done today. And that was as recommended by our Boston consulting cardiologists. Histories were obtained, or rather, I must say, confined to cardiovascular complaints and to behaviors we thought might be operative for coronary disease development. These university cardiologist consultants also suggested additional variables to be included based on their clinical impression of what their patients were like, and as examples, they included obesity, smoking, lipids, and diabetics. And, as you know, we did surveillance by the biennial clinical exams in the study, weekly, checks of admissions

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to the local hospitals, and data requests from out-of-town hospitals where subjects indicated an interim admission or referral for a cardiovascular illness at their biennial clinic examinations. The events were adjudicated by review of medical hospital records. Framingham Study exam forms were used by a panel of at least 3 study investigators, using formulated criteria for a case. Early on, there was also a consultant opinion on the validity of the investigative panel's decisions. We quickly realized that they were always agreeing with us and stopped doing it. Dr Wilson: Dr Kannel, if we could move into the next part of this interview and some of your reflections, about your major clinical and epidemiological insights from the study, what you thought Framingham contributed to or how it had moved the field forward? Can you share your reflection on that? Dr Kannel: I think the following are the major clinical and epidemiologic insights. Framingham proposed the multivariable risk factor concept of the etiology of atherosclerotic cardiovascular disease and its application for risk assessment. We no longer were thinking there was a single essential cause sufficient to produce the disease, which had been the current thinking. It also corrected clinical misconceptions, many of them, about the role of blood pressure, lipids, diabetes, obesity, moderate amounts of proteinuria, left ventricular hypertrophy, atrial fibrillation, and exercise in the promotion of cardiovascular disease. I think also that it provided important clues to the pathogenesis of atherosclerotic cardiovascular disease that stimulated further basic research. The study also aroused interest, I think, in preventive cardiology, which was really almost nonexistent and established epidemiology as its basic science. It also redefined acceptable values, I think, for predisposing factors. FHS replaced “usual” in the population as being “normal” with “optimal” in the population for avoiding cardiovascular disease. Dr Greenberg: Can I ask a question;? Something you said just triggered a thought. Epidemiology has a long history, but it was always focused on infectious disease. Dr Kannel: Right. Dr Greenberg: Did the field of epidemiology get transformed, in a sense, by the initial Framingham analyses causing people to think that we can look longitudinally at chronic disease, using the same techniques and analyses? Dr Kannel: Well, it wasn't precisely that but I think it did just that. It broadened the outlook for epidemiologic approaches to ferreting out the causes of disease. It did stimulate a broader outlook for this particular scientific approach to these kinds of problems and chronic disease in general, not only cardiovascular disease.

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Now, here are some of the major findings that I think didn't get enough attention The concept of age as a reflection of the length of exposure to risk factors is certainly one. The chances of living to 85 years, we found, decreases sequentially with the number of CVD risk factors acquired. And if you have absolutely none and don't acquire them throughout the study, you are almost immune for the development of the disease. The lifetime risk was exceedingly small in that case. You know, people say that we only have a small proportion of the explanation of the disease occurrence, but we really can explain about 70% to 90% within the population based on this known set of risk factors. Now, the variable CVD risk of a positive family history of CVD, depending on its associated risk factors, is another that I don't think has had enough attention. We've shown that if you take people with a positive family history, not by history, but by our actual examination, and look at the risk they have, it varies over a wide range in relation to the cluster of risk factors that it is associated with, much as it does in people without such a family history. So it suggests that this is not an irrevocable death sentence that you can do something about it. I think the data showed that the influence of the total to HDL ratio on CVD risk operates independently of its 2 lipid value components. This has not gotten the attention it deserves. Whether the cholesterol is high or low, it appears that it's the ratio that determines the risk. And also, I think the predisposition of hypertension, as well as diabetes, to silent myocardial infarction that we've shown also have not received as much attention as it should. Furthermore, there is the pulse pressure phenomenon and the J curve phenomenon, which we have linked. We found that the pulse pressure is an explanation of the J curve phenomenon, and I don't think this has received as much attention as it should. Because of this, physicians have been reluctant to lower the systolic pressure too much because they fear lowering the diastolic too low is going to cause a problem. It's the pulse pressure that counts. And also, I think the utility of the total vital capacity as a CVD risk factor has also not received enough attention. It's also an excellent way to follow the progress of somebody in heart failure. The Framingham Study insight on the mechanism for menopause as a risk for CVD has also, I think, been too much neglected. Framingham shows that it's related not only to premature CVD occurrence in women, but it's related to the severity of disease, which shifts from predominant angina to MI and sudden death. And it also seems to influence the disease occurrence, at least in Framingham, whether the ovaries are removed or not. This is an important feature that needs further investigation or confirmation elsewhere. And finally, I think the reversible triggering mechanism for the adverse influence of

cigarette smoking on CVD has needed more attention than it got. Dr Wilson: You mentioned things beyond heart disease. What are some of the other outcomes that the study even branched into which were perhaps not anticipated at the outset? Dr Kannel: Well, besides coronary disease, as you point out, we looked into stroke. We looked into peripheral artery disease and heart failure. But then, we went off into things like Alzheimer's disease, other dementias, arthritis, osteoporosis, various cancers, and a whole host of other noncardiovascular events because it turns out that many of the same risk factors apply to some of these other conditions. It provided a population base that had already been characterized by their risk factor status, and we had information on other kinds of outcomes from hospital surveillance to apply to other diseases. This has been exploited by many investigators, both here and abroad and particularly other investigators from Boston University. Dr Wilson: Could you make some comments about the Framingham role as a vanguard in terms of the development of observational studies, both in North America and around the world? Dr Kannel: Well, I think Framingham has served as a model for many other longitudinal cohort studies and was the first that included women. I think the study created a worldwide transformation of preventative medicine and changed the way in which the medical profession and the general population perceived the genesis of disease. Dr Wilson: What are the studies that come to your mind? For instance, the Chicago studies2 were slightly different, but the Tecumseh Study3 was fairly similar in design. The Kuopio Study in Finland4 was similar in design. Dr Kannel: Well, as you know the Heart Institute itself initiated studies that were strongly modeled after Framingham in Puerto Rico.5 There was a study in Hawaii6 and one in Yugoslavia7 that Roy Dawber was a consultant to. And I was a consultant to the Gothenburg Study in Sweden.8 So, there are many studies in which we provided consultation and which we helped get started. Dr Greenberg: I would like to explore that a little more because that's really not widely known. I think that the investigators abroad, to whom I have spoken, certainly credit Framingham as a trigger for their activities. But I have always had the sense it is through their knowledge of what was done here, as opposed to having a direct relationship. One of the questions I had is whether or not there ever thought of getting fellows or trainees from abroad where the problems were perceived as significant and bringing in people to work with Framingham, understand the methodologies, the techniques, and the analyses, and

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then take them back. I don't sense that occurred in the history that I've read and I think that there were budget constraints that may have limited that, at least early on. Dr Kannel: Let me set you straight. Many foreign observers visited Framingham over the years on their own initiative. We didn't even have to invite them. Anybody who came to the US who was an epidemiologist or an investigator of cardiovascular disease made it a point to stop in at Framingham. We were constantly showing visitors from abroad around. And currently, Framingham has many epidemiologic research fellows from all over the world. We have a different crop every couple of years that come through. Dr Greenberg: I understand now that Framingham has become recognized for what it is, and that people from all over the world would come. But I'm asking about the '50s or 60s when certainly the people who were there realized that this was a valuable gold mine for research in an important area. When did the attraction to foreign investigators get started, and was it active or passive? In other words, if people heard about it and came, you were good hosts and generous in sharing what you were doing. That's one thing. But on the other hand, did NIH ever support a program in which you would actively go out and recruit people who you knew might be interested because of what they had done in their own countries? Dr Kannel: Well, not except for the ones I mentioned, where they were specifically involved in doing it. The others were simply on the basis of people asking us to come visit and provide some help. And Roy Dawber spent about—I think a year at the WHO, helping them get studies and, you know, this perspective on things. And that probably had an influence on the studies that were done in Europe. Dr Wilson: So when we move into the modern era, Dr Kannel, risk factors have evolved through computers and score sheets and calculators to become a multivariable assessment or global risk assessment. Where do you think we are on that and where do you think we should be going? Dr Kannel: Well, I think we have stimulated a lot of statistical research from some very talented statisticians who were based at the NIH. And they developed, very robust analytical techniques based on Framingham's need to handle all these data and sort out the net and joint effect of the risk factors. There are many people who contributed a lot to our understanding of multivariable analysis of these kinds of data. We had a huge impact by stimulating research in that area because we had actual data they could analyze and test out these theories of multivariable analysis and see if the results made sense. I hope that answers your question. Dr Wilson: Well, part of it. There are also the Framingham risk equations which have been tested across

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the United States with Dr D'Agostino other Framingham collaborators.9 This approach is now the foundation for some guidelines that are used to help gauge not only an individual's risk but a population's risk. Dr Kannel: The risk factor equations are used as a surrogate for waiting for events to occur in order to assess whether treatment is likely to be beneficial. They look to the equations as instruments to assess reduction of multivariable risk which suggests that it would be beneficial to take some behavioral or a medication approach to CVD prevention. Dr Wilson: What do you think of some of the newer areas such as our capacity to identify genes that can identify subclinical disease? We've gotten more and more sophisticated. But even as we can do this, you have mentioned that the basic exam has still not changed very much. Dr Kannel: No, it hasn't. But we have added new technical procedures which include echocardiograms, Holter monitoring, and MRIs. We did treadmill testing. We have added some new lab markers for inflammation, hemostatic factors, LP(a), and peptides. All of this allowed us to investigate the pathogenesis of atherosclerosis, hypertension, and factors predisposing to preclinical atherogenic states. And we are now, I think, targeting the subclinical disease, people on their way to an event and looking at predisposing factors for a progression of atherosclerotic indicators of disease. Dr Wilson: We keep coming back to the concepts of gradients; you mentioned how average is not good, but that the goal should be optimization. What do you think some of the optimal levels are for, for instance, smoking? One, I would imagine, is never smoked or minimal exposure over a lifetime. But what about some of the others? Blood pressure, lipids? What is your feeling and perspective at this point? Dr Kannel: Well, right now we are looking at a continuous graded influence of risk factors. I can't think of many or any risk factors that have a categorical gradient in which you say up to this point, nothing happens, and then when you go beyond that, things happen. In fact, it looks like it's a continuous graded influence going down well into what we have formerly regarded as normal or acceptable values. Now, I think, if you are asking—questions of the future, then Framingham needs to stress to young people that the lifetime risk of cardiovascular disease is very high and strongly related to the burden of established risk factors they allow themselves to acquire and that avoidance of atherosclerotic cardiovascular disease lies within their own personal control. That is by modifying their eating, exercise, smoking habits, and keeping track of their blood pressure, blood lipids, and blood sugar, by periodic medical checkups, they can greatly reduce their lifetime risk. We physicians, I think, must come to recognize that a heart attack, stroke, or heart failure in our patient represents a medical failure rather than the first indication

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for treatment. We need to stress the importance of changing the CVD risk behaviors in young people. I personally believe that behavior accounts for more disease in the community and behavior change is more effective in improving the health of the community than medical care. Dr Greenberg: I want to come in here. I think you're absolutely correct. I think in many environments, including in this country, the deck is often stacked pretty much against the individual. The agriculture subsidies favor the availability of cheap high-calorie food. As we all know, smoking advertising is incredibly powerful. There are a lot of cultural forces at work or political forces at work that make it difficult for the individual to cope. But the Framingham dataset is a powerful tool, a pretty powerful, arrow in the quiver to go out and stalk these antagonists. And what I see looking globally is, a powerful influence over the last 50 years of the Framingham Heart Study. Dr Kannel: Yes. Dr Greenberg: It is a profoundly important contribution of American medicine to global health. Dr Kannel: Well, you know, as you point out, the North Karelia Study, where intervening in a community proved to be very effective in changing the lipid status and lowering the very high cardiovascular disease rate they had. And I think the implication is that the behavioral modification they undertook in the community was responsible for this. But I can't help but reflect on the fact that in Framingham, we've seen a major reduction in the amount of disease since the study began without any direct intervention. A recent study by Caroline Fox in 200410 found that there was a temporal trend in coronary mortality in Framingham between 1950 and 1999. And in that time, coronary mortality was reduced 64%. Now, you know, we didn't do anything at all because we avoided trying to do anything in the community because of our need to be careful observers and to not interfere with routine medical care in the community. So, this occurred despite that lack of any intent to do anything about it, other than refer patients to their physician or at least make the information about their problem available to them and their physician. And Ford in the New England Journal, in 200711 pointed out that half the reduction in coronary mortality since 1980 is attributable to risk factor reduction of population. I think we can say that correction of risk factors as covered by Framingham can substantially reduce coronary mortality in the population because it stimulated many national programs in the US against hypertension, programs, against blood lipids, programs against obesity, programs that increase physical fitness, programs against smoking. Just the fact that we laid this out as being an important contributor to cardiovascular morbidity and mortality and others showed that by treating these things you actually benefited outcome

convinced the government to implement these campaigns against risk factors. Dr Greenberg: I think that puts it quite nicely. The barriers are still pretty immense around the world. Even the concept of taking medicines for asymptomatic disease is a huge issue in many parts of the world. We have been doing it in this country probably for 50 or 60 years with hypertension and I suspect that that cultural barrier was breached because of the data from Framingham that made people understand the need to take antihypertensive medications even though there was no symptoms that you could point to that you were treating. Dr Kannel: As you point out, we in this country and abroad as well need to swim upstream against our culture. Patterns of behavior are pretty hard to change. And it has to be changed by evolution, not revolution. Also, as you well know, there are powerful vested interests and this even happened, I think, in North Karelia when they tried to implement programs to change diet, to get people to eat less butter and cheese. I'm sure there are industries there that complained about it, didn't they? Dr Greenberg: I think they did. One of the unpublicized virtues of North Karelia was that the Finns developed a cold climate rapeseed so they could produce their own canola oil, and therefore, there was no expenditure of hard currency to buy something from abroad that replaced something that they produced locally, like animal fat. And that sort of win/win relationship gets very little publicity but I think was probably profoundly important. Dr Kannel: Oh, yes. Vested interest is an important consideration. In this country, particularly as you see from the current status, our economy runs on 3 things—greed, waste, and confidence that everything is going to turn out okay. Dr Wilson: Well, any further final comments, Dr Greenberg, to Dr Kannel? Dr Greenberg: No. This has been a great treat for me, since we have never sat down and chatted, yet I've been a fan for all of my career. I've just had an absolutely wonderful morning. I'm going to get a brief of this out to the contributors to this symposium on the Global Impact of the Framingham Study. I think this will be a good stimulus for our participants to get their manuscripts done. Peter Wilson Emory University School of Medicine and Rollins School of Public Health at Emory University Atlanta, GA 30322 Henry Greenberg Columbia University College of Physicians and Surgeons St. Luke's Roosevelt Hospital New York, NY 10019

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References 1. Kannel W, Dawber T, Kagan A, et al: Factors of risk in the development of coronary heart disease—six-year follow-up experience, the Framingham Study. Ann Intern Med 1961;55:33-48. 2. Stamler J, Lindberg HA, Berkson DM, et al: Prevalence and incidence of coronary heart disease in strata of the labor force of a Chicago industrial corporation. J. Chronic Dis 1960;11:405-420. 3. Butter WJ, Ostrander LP, Carman WJ, et al: Mortality from coronary heart disease in the Tecumseh Study. Am J Epidemiol 1985; 121:541-547. 4. Vartiainen E, Jousilahti P, Alfhtan G sundvall J, et al: Cardiovascular risk factor changes in Finland, 1972-1997. Int J Epidemiol 2000;29: 49-56 [North Karelia]. 5. García-Palmieri MR, Feliberti M, Costas Jr R, et al: An epidemiological study on coronary heart disease in Puerto Rico: the Puerto Rico Heart Health Program. Bol Asoc Med PR 1969;61: 174-179.

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6. Kagan A, Rhoads GG, Zeegen PD, et al: Coronary heart disease among men of Japanese ancestry in Hawaii: the Honolulu Heart Study. Israel J Med Sci 1971;7:1573-1577. 7. Kozarevic D, Pirc B, Dawber TR, et al: The Yugoslavia cardiovascular disease study. 1. The incidence of coronary heart disease by area. J Chronic Dis 1976;29:405-414. 8. Bengtsson L: Ischemic heart disease in women: a study based on a randomized sample of women and women with myocardial infarction in Goteborg Sweden. Acta Medica Scan 1973;549:1-128. 9. Wilson PW, D'Agostino RB, Levy D, et al: Prediction of coronary heart disease by using risk factor categories. Circulation 1998;97: 1837-1847. 10. Fox C, Evans JC, Larson MG, et al: Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999: the Framingham Heart Study. Circulation 2004;110:522-527. 11. Ford ES, Ajani UA, Croft JB, et al: Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. New Engl J Med 2007; 356:2388-2398.