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Cardiovascular Research 35 Ž1997. 200–201 Cardiovascular Mystery Series Series Editor: Karl T. Weber, University of Missouri-Columbia, Division of Cardiology, Room MA 432, Medical Sciences Building, Columbia, OH 65212, USA Dealing with a modern-day epidemic 1 Karl T. Weber July 7, 1992. It was now a year since resident in internal medicine, Nicole Saarinen, had begun her research studies in the Department of Medical Biochemistry at the University of Oulu ŽCardiovasc Res 1997;33:533.. Drawing on the pioneering work of Leila and Juha Ristelli, her project focused on serologic markers of collagen turnover to address extracellular matrix accumulation in diseased organs. Today, she eagerly looked forward to medical grand rounds and what would prove a standing-room-only session. Pekka Puska, Department of Epidemiology, National Public Health Institute in Helsinki, would review data gathered in North Karelia over the past 20 years. This work represented the first community- based prevention study of heart disease—a modern-day epidemic of worldwide proportions and a major cause of death and disability in this eastern province of Finland. Nicole arrived at the auditorium and carefully selected an aisle seat near the front so as to fully gather in Puska’s presentation and every detail of audience discussion. Perhaps she too would pose her own questions. Her plans would not go unrewarded. Puska began with a historical accounting. The Project had its beginnings in 1971 and arose after the results of a WHO-sponsored study were announced. The study suggested middle-aged men in North Karelia had the world’s highest mortality from cardiovascular disease. Representatives of this rural community petitioned the Finnish government for assistance with its public health problem. Approval followed. A baseline survey of 12 500 people living in North Karelia was carried out in the spring of 1972. It demonstrated that among young and middle-aged men: 54% smoked; mean cholesterol was 269 mgrdl; blood pressure ŽBP. 147r90; and incidence of myocardial infarction ŽMI. 13.8r1000 population. A federally spon1 A brief mystery which sets the stage for the accompanying mini-review, seeking to integrate basic laboratory and clinical sciences and diverse expressions of disease, while highlighting the role of the generalist Žthat is, the integrator.. 0008-6363r00r$17.00 Published by Elsevier Science B.V. PII S 0 0 0 8 - 6 3 6 3 Ž 9 7 . 0 0 1 1 0 - 7 sored program of primary and secondary prevention, known as the North Karelia Project, was officially initiated in 1972. In contrast to epidemiologic interventions of the 19th and early 20th centuries, the Project would not draw on quarantines and military bureaucracy to deal with miasmata and contagions. It would not confront, confine and penalize the population. Instead, it focused on the community’s entire population and its service structure and social organization—a mass community action based on education and persuasion. The main objective of primary prevention: to reduce overall rates of heart disease and other cardiovascular diseases and to improve health of the population. Objectives of secondary prevention: promote health and life style changes; reduce risk factors for heart disease; and promote early detection, treatment and rehabilitation. Program activities focused on education through dissemination of information, training of health educators, organization of health, school and social services, and implementation of environmental changes that addressed nutrition and behavior. Kuopio, a neighboring province, was selected as a reference area since it matched North Karelia in terms of its population, geography, occupational and socioeconomic features. Five-year results were presented in 1977. Total mortality in North Karelia had decreased by 5% and from cardiovascular disease among 30–64-year-old men and women by 13 and 31%, respectively. A decrease in risk factors was evident compared to the control area: 17% in men and 12% in women at risk for coronary artery disease. Incidence of acute MI fell by 16% in men and 5% in women. The reduction in the incidence of recurrent MI was greater than first MI, implicating the importance of secondary prevention. In hypertensive individuals reductions in systolic and diastolic BP translated into a net reduction in prevalence of hypertension among men and women by 44 and 49%, respectively. With improved screening techniques, the number of individuals receiving anti-hypertensive therapy likewise increased and the proportion of treated hypertensive individuals who became K.T. Weber r CardioÕascular Research 35 (1997) 200–201 normotensive increased by 150% in men and 340% in women. During the first 10 years of the project major changes in life styles and risk factors were seen, particularly smoking and dietary habits, and were associated with a major reduction in average serum cholesterol. The decline in risk factors also became evident in the reference area after 1977 as a program of prevention was initiated throughout Finland based on the success of the North Karelia Project. Over the course of 20 years, age-adjusted mortality rate among men aged 35–64 years in North Karelia had fallen for all cardiovascular diseases to 56% and for ischemic heart disease to 46%. Observed changes in risk factors predicted a decline in mortality from ischemic heart disease of 44% in men and 49% in women. The observed decline was 55 and 68%, respectively. These findings demonstrated that a community and indeed an entire country could enact behavioral modification that favorably influenced public health. The impact of the Project was also evident on Finland’s economy. Pension disability payments for cardiovasculardisease-related disabilities in 1977 was 10% lower than Kuopia, a 15% net savings corresponding to approximately 4 million marks. Compared to the 0.7 million marks invested in the Project, this suggests public health is a wise investment. A lively discussion followed Puska’s presentation. Nicole wondered what new directions the Project might take relative to cardiovascular disease prevention and in particular hypertensive heart disease. So did a cardiologist seated in front of her. He rose to make the observation that left ventricular hypertrophy ŽLVH., detected by echocardiographic determination of LV mass or by less sensitive electrocardiographic voltage criteria, is of even greater prognostic value than traditional risk factors, including elevated serum cholesterol. In patients with uncomplicated hypertension, LVH stratified risk independently of and more strongly than blood pressure or other potentially reversible traditional risk factors and was independent of ventricular systolic function or the presence of coronary artery disease. In hypertensive heart disease, the presence of ventricular arrhythmias and sudden death has been linked with LVH. Electrocardiographic evidence of LVH is associated with a risk of sudden death in excess of the risk attributable to hypertension alone. In the absence of coronary artery disease, LVH is associated with an increased frequency and complexity of ventricular arrhythmias and the relation between LVH and ventricular arrhythmias is graded and continuous. The relationship between LVH and increased risk of adverse cardiovascular events is therefore compelling. 201 But LVH per se could not be responsible for adverse risk, thought Nicole. Consider the world-class Finnish athlete, Paavo Nurmi, for example. During his career Nurmi won a total of 40 world records, including every race from 1500 meters to 20 kilometers. At the Paris Olympics in 1924 this supremely gifted athlete won the finals in the 1500 and 5000 meters on the same evening with just one hour’s rest in between races. Certainly Nurmi, a trained athlete, would have LVH that contributed to his success. Why would LVH prove detrimental in patients, particularly those with hypertension? Perhaps it was not the quantity but rather the quality of the hypertrophied myocardium, thought Nicole. As a medical student, Nicole was aware from her reading of pathology textbooks that the myocardium in hypertensive heart disease is not simply expressed as cardiac myocyte hypertrophy. There exists an adverse remodeling of its microscopic structure that includes an abundance of fibrous tissue presenting as a perivascular and interstitial fibrosis. It is this fibrous tissue, consisting largely of type I and III collagens, she thought, that must adversely affect tissue behavior contributing to ventricular dysfunction and enhancing arrhythmogenic potential. If this were the case, then should the Project not next focus on preventing pathologic LVH to thereby reduce risk for adverse cardiovascular events, such as MI and sudden cardiac death? Clinicians deal with patients, epidemiologists with populations. Both parties must harness their resources toward this common goal in a spirit of mutual cooperation and common purpose. She rose to make these comments and to pose several questions. How could the accumulation of fibrous tissue in the myocardium be non-invasively monitored in a large population? Furthermore, could fibrosis, once present, be regressed and how could this be monitored? Her research experience prompted her to propose the use of serologic markers of collagen turnover under such circumstances where prevention and treatment are targeted objectives. Answer Studies by Diez and co-workers have recently demonstrated the utility of monitoring the amino-terminal propeptide for type III collagen and carboxy-terminal propeptide for type I collagen as markers of fibrous tissue formation in hypertensive heart disease. This was demonstrated in untreated hypertensive individuals and rats with genetic hypertension. Moreover, this approach has been used to address a regression in fibrosis that appears in response to an angiotensin converting enzyme inhibitor.