Download Dealing with a modern

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.