University of Minnesota

Evolution of CVD Epidemiology in Italy. A. Menotti

[ed. Alessandro Menotti, a pioneer Italian CVD epidemiologist, provides an intimate essay on development of the field in Italy in the context of its international evolution. With a 40-year perspective, letting it “all hang out,” it is rich in historical anecdote, opinion, and documentation.]

How CVD epidemiology started

After the second World War some “illuminated” persons in several countries realized that the decline in incidence and mortality from infectious diseases was accompanied by an upsurge of cardiovascular conditions, once rare and traditionally attributed to “aging”. This observation was only sporadically made by a few skilled people, and even fewer had the curiosity to provide numeric evidence of this and to search for causes. This curiosity occurred first in the USA, a little later in Europe and much later in other countries, reflecting the historical evolution in the decline of infectious disease and the appearance of other chronic conditions. In 1959 a full issue of the journal “Acta Cardiologica” (Brussels, vol. 14, suppl. VIII) was devoted to this problem with description of hospital and vital statistics data from several countries, which brought with them the errors of selection bias, or known limitations of mortality reporting.

Who influenced most CVD epidemiology at its beginning?

At the international level it is widely recognized that a landmark in the history of cardiovascular epidemiology research was set by the start of the Framingham Study, also because it became the most known, and quoted world-wide. However, the Minnesota Business and Professional Men Study started 2 years before Framingham and included many measurements which only later (or never) were considered in the Framingham study.

In Europe and in Italy the story was different. In Italy, for example, the first person to address the problem of cardiovascular diseases in the population was Prof. Vittorio Puddu, probably the first recognized cardiologist in this country. He was influenced by the experience in France where centers for social cardiology were operating in the late 1940’s. In Rome he founded the Center for Cardiovascular Disease, subsidized by the Ministry of Health, which was the first institution that organized systematic screening for cardiovascular diseases. The population samples were “school-children,” the conditions of study were congenital and rheumatic heart diseases, the latter common in the post-war era. However, this was the basis for understanding the problem of CVD epidemiology and to open the door to international cooperation starting a decade later in the field of coronary heart disease and other CVD conditions on an atherosclerotic basis.

A fundamental role in the development of CVD epidemiology in Italy was played by Prof. Ancel Keys, who landed in Naples in the 1950’s to explore whether this country would be suitable to demonstrate the hypothesized association between diet (and serum cholesterol) and coronary heart disease. He influenced the career and the cooperation of a (then) young physiologist –nutritionist, Prof. Flaminio Fidanza, who became the first and life-long nutritionist in the epidemiological field. However, Prof. Keys also needed the collaboration and support of a cardiologist. Prof. Vittorio Puddu was the right person, introduced by a common friend, Dr. Paul D. White.

Prof. Puddu was reached in relation with his international reputation, his role as Secretary General of the International Society of Cardiology, his “epidemiologically oriented” Center and his fluency in several languages. He was never an epidemiologist, as such, but he understood the problems, and collaborated with Prof. Keys in running the Italian section of the Seven Countries Study. He involved during the fist 10 years of the study at least 20 physicians (mostly cardiologists) in the field operations, although, at the end of the story, only one (myself) became really interested in CVD epidemiology and then became a full time epidemiologist.

The role of Prof. Keys in the development of CVD epidemiology in Italy was actually confined to the influence he had on the conduction of the Italian Section of the Seven Countries Study and on me (AM), who had the major responsibilities in this Italian action and developed a number of subsequent activities in this field. Beyond that, two other Italian physicians became students or fellows at the Laboratory of Physiological Hygiene, University of Minnesota, in Minneapolis, in the 1960’s and the 1970’s. In 40 years of collaborations with Prof. Keys, I always liked to consider him a patriarch running the study “with iron fist and velvet glove.”

My initial involvement into CVD epidemiology is rather curious since I joined the Center of Prof. Puddu after an experience in Libya as hospital physician where I started elementary epidemiological studies. The origin of this was my curiosity trying to understand why, in the hospital wards of Tripoli, cases of myocardial infarction were so rare compared with my previous Rome experience, and again so rare among the Arab community compared to the Italian community with its very small denominator) and the Jewish community with a minimal denominator. Prof. Puddu gave me the label of epidemiologist, despite the absence of any formal knowledge or training, and introduced me to Prof. Keys, to join immediately in 1962 the field operations in the Seven Countries Study and starting a life-long career in this study and in CVD epidemiology in general.

The relationship of Prof. Keys with Italy helped him to develop the concept of the Mediterranean Diet which derived from dietary observations made mainly in the central and southern part of the country, together with those collected in Greece and in Dalmatia, former Yugoslavia.

Another person who influenced CVD epidemiology in Italy was Prof. Jeremiah Stamler since he, like Prof. Keys, found himself well acquainted with the Italian environment. In fact, both of them built a summer house on the shores of the Mediterranean Sea, south of Naples. Prof. Stamler was influential in relation to the International Teaching Seminar on CVD Epidemiology, the second edition being held in Italy in 1969. He organized other teaching courses in Italy but mainly offered formal teaching and training at Northwestern University in Chicago to a number of young doctors of the University of Naples, pushing them into epidemiological activities involving several groups in Italy in the Intersalt study and then becoming a member of the Steering Committee of the Gubbio Population Study devoted to problems of hypertension.

Which institutions worldwide were influential on CVD epidemiology?

The role of the NHLBI, even outside the USA, was largely known and acknowledged. Funding of US studies of an observational type, such as the Framingham Heart Study, the US Pooling Project, or trials such as the Hypertension Detection and Follow-up Program, the Lipid Clinic Project, the feasibility stage of the Diet Heart Study, the MRFIT, and others, plus the long series of recommendations and Guidelines is something which represents the basis for our knowledge. Many studies were funded abroad and for several European epidemiologists (in Finland, the Netherlands, Italy, former Yugoslavia, Greece) the funding of the first 10 years of the Seven Countries Study was the first direct impact with the action of the NHLBI. Moreover, from a personal point of view, the NHLBI funded in Italy a study on occupational physical activity and coronary heart disease in the personnel of the Italian Railroad industry (177,000 subjects) in the 1960’s and the 1970’s.

However, in Europe, and in Italy in particular, an important influence on CVD epidemiology was also received from the World Health Organization, both the headquarters in Geneva, Switzerland and the Regional Office for Europe in Copenhagen, Denmark. CVD officers such a Dr. Fejfar and Dr. Pisa, both Czech, and Dr. Lamm, from Hungary, were very active in stimulating research activities on a multinational scale, although usually WHO was unable to provide funding.

The inception of CVD epidemiology in Italy

In this country, but basically everywhere else, one of the major initial issues at the beginning of the story was the quantification of the disease of interest, initially mainly coronary heart disease. This prompted the start of rare population studies which, in the overwhelming majority, remained confined to the cross-sectional stage, limited to the estimate of prevalence rates. Longitudinal studies, based on prolonged follow-up, were considered boring, difficult, and expensive. Not even a follow-up for mortality was seriously considered. Until the early 1980’s the only study in Italy to provide incidence estimates for coronary heart diseases was the Italian section of the Seven Countries Study made of 3 cohorts of middle-aged men for a total of almost 2500 subjects.

Another open question was the need to confirm the relationship between individual characteristics measured at entry and new CVD events during follow-up. Beyond the rarity of proper studies, there were serious doubts, among experts of clinical medicine, that this relationship would have been the same as first shown in the US-based studies. Everything was later confirmed, and in 1969, for the first time, it was shown, in a formal publication, that blood pressure, serum cholesterol and smoking habits were risk factors for coronary hart disease also in Italy when the first analyses were made on the 5-year follow-data of the Italian rural cohorts of the Seven Countries Study.

However, most clinicians refused the idea that risk could be reversible and the start of operations organized in this direction was extremely complex, and seriously considered by a small group of early epidemiologists.

Full development of CVD epidemiology in Italy

The start of CVD epidemiology in Italy was bound to the participation of Italian groups into the Seven Countries Study. The initial role of principal investigator was by Prof. Flaminio Fidanza, nutritionist of the University of Naples and then of the University of Perugia, and by Prof. Vittorio Puddu, chief cardiologist of the St. Camillo Hospital in Rome. Of the four cohorts enrolled in Italy (3 rural and one occupational), only three fully entered the long term study, since the rural area of Nicotera in Southern Italy was abandoned after the pilot examination due to logistic difficulties.

Within a few years the full responsibility for the conduction of the study, except for the nutritional aspects, fell on me (AM), who, at the same time was co-opted into the central staff of the study, becoming Research Associate of the Laboratory of Physiological Hygiene, University of Minnesota, Minneapolis between the mid 1960’s and 1975. In the 1960’s, I received formal training in Epidemiology and Medical Statistics at the London School of Hygiene, with a fellowship of the WHO, under the guidance of Professors Geoffrey Rose, Donald Reid, Peter Armitage and Richard Remington. During the late 1960’s and 1970’s, I became responsible for the field operation in Europe, for coding clinical diagnoses and causes of death and, after the retirement of Prof. Keys I ran a coordinating role for the whole study.

In this way I became the first full time CVD epidemiologist in Italy, with formal positions first at the Center for Cardiovascular Diseases of the St. Camillo Hospital (1975-1979) and then at the Istituto Superiore di Sanità (the Italian National Institute of Public Health), Laboratory of Epidemiology and Biostatistics (1979-1994), both located in Rome. In the latter site epidemiology did not exist (except traces of infectious disease epidemiology) and the job was to construct a unit of Chronic Diseases Epidemiology – mostly dedicated to CVD. This was done by transforming an heterogeneous and reluctant group of mathematicians, statisticians, physicists and biologists (a few physicians came later) into “epidemiologists”. This was the slow and difficult start of 15 years of productive work in that Institute.

Beyond continuing a central role in the Seven Countries Study, I started a number of other studies involving several new Italian groups, persons and institutions, creating and implementing an informal network of centers that, later, continued by themselves in epidemiological and preventive activities. In the 1970’s, the 1980’s and the early 1990’s, this brought to the conduction of studies, such as the Rome Project of CHD Prevention, as part of the WHO European Multifactor Preventive Trial of CHD; the Nine Community Study (initially observational then intervention) subsidized by the CNR (Italian National Research Council); the Rifle (Risk Factor and Life Expectancy) Pooling Project, involving 52 centers spread all over the country with a denominator of over 70,000 individuals, with risk factors measurement and mortality follow-up data; the participation of three centers in Italy to the WHO MONICA Project; of several more in the WHO ERICA Project; and other activities including teaching courses, production of guidelines for prevention, and manuals, charts and software for CVD risk prediction.

Later on, for seven years between 1994 and 2000, my interest for the Seven Countries Study prompted me to leave my position at the Italian National Institute of Public Health and to become part-time professor at the Division of Epidemiology, University of Minnesota, Minneapolis. There, I carried out analyses of the 25-year data of the Seven Countries Study, and in cooperation with Prof. Daan Kromhout of the Netherlands, prepared the extended data-bank of the same study, up to 40-years of follow-up.

My legacy in CVD epidemiology in Italy fell on other people who continued, mainly from the coordinating site of the Italian National Institute of Public Health. A role in the field operations and data collection is now being played also by the National Association of Hospital Cardiologists.

In the early days of CVD epidemiology in Italy, other initiatives started in a scattered way during the late 1960’s, early 1970’s. In the 1960’s, Prof. Luigi Checcacci, from his chair of Hygiene at University of Pavia, started systematic cardiovascular risk factor screening in occupational groups and later in the general population of the tiny Republic of S. Marino. Prof. Mario Mancini, Professor of Internal Medicine at the University of Naples and former fellow of the Laboratory of Physiological Hygiene, University of Minnesota, started a similar operation in the Olivetti typewriter factory near Naples.

In the early 1970’s, Prof. Sergio Lenzi, and his assistant Prof. Giancarlo Descovich, both Professors of Internal Medicine at the University of Bologna, started the Brisighella Study, an observational survey in a small village not far form Bologna, later transformed by Prof. Descovich into an intervention “demonstration project.”

Prof. Giorgio Feruglio, Chief Cardiologist at the Regional Hospital in Udine, the main city of the Region of Friuli in the extreme north-east of the country, became impressed by the official death rates from CVD, which, during those times in the 1960’s, were the highest in the country. This prompted him to start several epidemiological operations including the Martignacco Project, a small trial of coronary prevention in two small rural communities (one treatment and one control) and later to join the MONICA Project.

Starting in the late 1970’s for almost two decades, an important role in the development of CVD epidemiology and prevention was run by the CNR (the Italian National Research Council) with a number of initiatives An important coordinating role are was played by Prof. Giorgio Ricci, Professor of Internal Medicine at the University La Sapienza, of Rome, while most of the technical responsibilities fell on me.

Several new university and hospital centers approached CVD epidemiology for the first time and contributed to a number of studies which allowed to improve the knowledge of CVD epidemiology in Italy and to spread interest and culture about prevention. Many of those studies were finally incorporated into the Rifle (Risk Factor and Life Expectancy) Pooling Project.

More recently the number of scattered and non-coordinated population studies became greater since many big bosses in clinical medicine (or cardiology) have realized that having his/her own epidemiological study represents a big source of recognition. [Sometimes these operations run without precise objectives, following poor methodology and reaching intriguing findings due to bias.]

Major contributions of CVD epidemiology and prevention

CVD epidemiology has provided major contributions to the understanding of causality of cardiovascular diseases bound to hypertension and atherosclerosis. It has broken the old-fashioned attitude to search causes only among patients, expanding the search among people still in apparent good health. It has introduced the concept of risk factors and of risk in general in medical research, opening the way for a better understanding of complex phenomena where the deterministic approach does not work or, for the moment, cannot be better handled. It has shown how diseases are not only an individual problem but also a population and cultural problem. It has posed the basis for prevention, despite the great difficulties in translating scientific knowledge into daily practice and success.

Finally, CVD epidemiology must be considered as the major responsible for the substantial decline in CVD incidence-mortality that, starting in the late 1960’s, occurred in most countries of the Western World, including Italy.

Lessons from the history of CVD epidemiology

There are other lessons from CVD epidemiology that go beyond findings and direct fall-out. The discipline contributed in a substantial way to develop theory and practice in quantitative medicine, in posing the need for standardization of measurements in both research and clinical practice, and in producing theory and tools on the principles of measurement, in pushing the role of statistics and numerical evaluation in research and practice, and in expanding scientific procedures in medicine. Among these, a basic achievement was bound to the structuring of clinical trials.
In Italy, after these advances in the field of cardiovascular diseases, many other medical “specialties” were affected, including fields such as pneumology, gastroenterology, nephrology, ophthalmology, etc, with the possible exception of oncology which developed parallel by itself. In other words, CVD epidemiology represented a kind of vanguard in many of the scientific accomplishments of the second part of the past century.

Personal reflections

One of the peculiar experiences of those who started these activities in the early days was to witness “live” the development and the evolution of CVD epidemiology while the discipline itself was constructed. Historically there was no trace until the end of the 1940’s, except sporadic observations of “geographical pathology”; methodology did not exists; statistics was little known and of difficult use before the computer era, or when computers were expensive, slow and difficult to use. In other words, methodology and conceptuality, beyond factual data, were constructed during the first three decades after the second World War; the up-date was parallel to the construction of the discipline. In those times to be a good epidemiologist meant to have or to acquire at least elementary competence in several fields, many of them not strictly medical. It was not only the case to know epidemiology, whose doctrine was in full development, but also clinical medicine and the use of some instruments such as an electrocardiographic machine or a spirometer; some biochemical knowledge was also needed, together with notions is nutrition science, mathematics, statistics, computer use, all this possibly complemented with interests in demography, psychology and sociology, plus curiosity in geography, history, culture and languages, mainly when the field work was run in other countries.

All this has rendered this activity quite attractive, due to its complexity, to the need to spread in many disciplines and at the end to feel more complete and not being a super-specialist.

At those times, classic epidemiology was something innovative in the research field: it needed the identification of a clear question to be answered, usually linked to the possible causality of a disease; a longitudinal study was needed; statistical pre-conditions were the basis for this approach, including population sampling and the principles of measurement; it was based on multi-disciplinary team work where almost all members were able to do almost everything; it included a component of field work in close contact with data collection; it imposed the hard work of manual data coding and checking; it compelled the use of slow and little-powerful computers; it imposed running complex (for those times) statistical analyses to reach biostatistical conclusions; and everything required a high degree of enthusiasm. All this was unusual and largely unknown in traditional clinical or laboratory research.

Nowadays things have largely changed, for the good and for the bad. Many epidemiologists are not physicians, most of them have never seen a single case of the disease or condition under study, or have ever examined a single subject of the study population, nor have taken a single measurement of the study variables, which – on the other hand- they analyze with friendly statistical packages.

However, I am convinced that computer science gave an extraordinary contribution to the development of CVD epidemiology, as well as of many other scientific disciplines. This is particularly felt by those, as myself, who started to use punch cards, card sorters and the first slow, noisy and incredibly un-powered computers, such as the first Italian Olivetti desk computer that had a “memory” of 120 positions!

In the early 1970’s, with the complicity of Prof. Keys, I imported from the USA (probably illegally) a computer program to solve the multiple logistic function. It was a suitcase weighing more than 30 kg, full of punch cards. Then I found the most powerful computer available in Rome in those times, in the same Italian National Institute of Public Health that I joined a few years later. It was a huge IBM 1340 that could solve the equation in about 50 minutes. Presently a portable computer weighing 2 Kg, using a very friendly program, solves the same equation in less than 10 seconds. This compares to covering a distance of about 5 km walking (about 50 minutes) or using a supersonic plane (about 10 seconds).

Several times I have asked myself why one becomes an epidemiologist and which kind of mental attitude he/she must have. Be sure there must be a substantial scientific curiosity stimulated by sporadic observations. There should be an interest for general problems, such as that difference in the amount of disease between or among populations and cultures may have hidden information of the cause of diseases; that mass diseases should be explained by mass phenomena; the fascination of prediction and the hope for prevention.

To reach formal recognition on the part of “official” medicine, of the “academic environment” and even of public health has not been easy and it took years. Still at the beginning of the 1980’s, some people with high reputation and high position in the medical field thought that epidemiologists were studying in a complex way some obvious facts and that they reached conclusions of no interest. Several “scientists” engaged in other disciplines, expressed the view that epidemiologists followed questions of no use which, in any case, did not deserve any answer and that, basically, they did everything except research.

A child, son of an epidemiologist, questioned by a friend about his father’s profession, said that his activity consisted in “counting the deaths”: at least he was not too far from the truth.

The joining of epidemiology with clinical science has been slow and tormented in the area of CVD. It is curious that many clinicians have been enemies of the discipline, attributing to it no value. Only recently something has been slowly changing. Some super-specialists, such as lipidologists, hypertensiologists, diabetoligists, obesiologists, etc are now “discovering” what observational epidemiology had documented long ago, that is the rough principle of “the lower the better “which is true for many risk factors. But when observational epidemiology gave that suggestion, it was considered nonsense.

During my career, I have been living this progressive consensus starting from the 1960’s when high cholesterol started from 300 mg/dl plus, or hypertension did not exist below 180 mm Hg of systolic blood pressure. Now they (the clinicians) demand to teach us about the concept that having 180 mg/dl of serum cholesterol is better than having 200, etc. Similarly the present widespread interest in CVD risk prediction is offered as a new idea while most problems in this area (apart the availability of powerful desk computers) were solved 80% some 25 years ago.

Despite difficulties and misunderstandings my life in CVD epidemiology has been a great adventure, full of satisfactions and enrichment for every aspect of life. (Alessandro Menotti)

[ed. The full version of this essay is available to scholars upon request at the History of Cardiovascular Disease Epidemiology Archive at the University of Minnesota. (Henry Blackburn)]