[This article proposes an alternative causation for the emergence and decline of the coronary heart disease "epidemic" experienced by many developed countries. A consistent explanation by the authors addressing the emergence of CHD in developing countries would be that many populations of developing countries have had high prevalence of infectious diseases and malnutrition which has created a vulnerability to CHD when these people later in their lives are exposed to tobacco smoking and other risky behaviors.]
Title: Coronary Heart Disease (CHD)--One or Several Diseases?
Author: MI Azambuja, R Levins
Reference: Perspectives in Biology and Medicine 2007; 50(2): 228,
http://muse.jhu.edu/journals/perspectives_in_biology_and_medicine/toc/pbm50.2.html
Reviewer: Carlos Mendoza Montano, PhD, APRECOR, Guatemala, ProCOR contributing editor, e-mail: projhouse@intelnet.net.gt
The current article presents an interesting perspective about the causation of CHD. It revisits evidence that may have been overlooked or misinterpreted during the heights of the CHD epidemic in the United States and other developed countries due to the prevalent framework of multicausality, and the hegemony of the lipid over alternative hypotheses to CHD causation. The authors of the article propose a fresh look at some old evidence which leads to new ways of thinking about CHD, its trends and its causes, and new ways of thinking about chronic disease occurrence in general.
According to the multifactorial model of causality, CHD is conceived as resulting from possible alternative and interconnected chains of exposures component causes) that would eventually become sufficient to initiate the disease in an individual. Azambuja and Levins argue that, 40 years after its introduction, we still lack a sound biologic theory to explain the development of CHD and its progression to death, which allows them to question both this causal model and the degenerative idea behind it.
The article pointed out that during the rise in CHD mortality (1931-1935), the odds of finding hypertensive disease among cases of CHD was 5:1. In 1951-1955, the degree of atherosclerosis in males from all age categories was considerably greater, but the odds of finding hypertensive disease among cases had reversed to 1:2.5. Since there is no reason for assuming that the incidence of hypertensive disease had significantly decreased over this period, the authors felt justified in concluding that these findings indicate a considerable increase in CHD that is independent of hypertension as a factor in its pathogenesis. During the 20th century, then, the profile of the CHD cases varied from the pre-epidemic period (until the 1920s and 1930s) to the height of the epidemic period (1950s and 1960s), and again during the decline in CHD mortality (1980s to date). Cases described during the pre- and post-epidemic periods were mostly associated with "inflammation" and an individual phenotype suggestive of insulin-resistance (obesity, diabetes), hypertension, and/or smoking. During the epidemic period, hypercholesterolemia became the hallmark of CHD cases. The authors wondered how these trends should be interpreted.
Azambuja and Levins conceive CHD as encompassing different diseases associated with vulnerabilities and triggers with varying distributions over time and space. Therefore, they suggest that changes in CHD features accompanying the changes in CHD occurrence resulted from expansions and retractions of sub-populations of CHD cases over time. According to them, the steep rise in CHD mortality seen after the 1920s resulted from a huge expansion of a particular subpopulation of cases, characterized by high cholesterol levels and high case fatality.
While individual vulnerability is routinely considered in modeling infectious diseases, it is frequently ignored with respect to chronic diseases. Vulnerability to chronic "degenerative" diseases is usually conceived as a genetic attribute and, as such, not subject to short-term variation. Over the past years, different pathways have been postulated that could change individuals phenotypically and favor vulnerability to chronic diseases and CHD, including autoimmunity upon infection, metabolic reprogramming upon infection, and metabolic reprogramming associated with nongenomic mechanisms of inheritance. An alternative explanation of the huge expansion of a specific subpopulation of CHD cases occurring from the 1920s to the 1960s could depend not as much on changes in exposure to CHD risk factors as on an acquired window of vulnerability to the disease opened in the middle of the 20th century.
The article pointed out that during the rise in CHD mortality (1931-1935), the odds of finding hypertensive disease among cases of CHD was 5:1. In 1951-1955, the degree of atherosclerosis in males from all age categories was considerably greater, but the odds of finding hypertensive disease among cases had reversed to 1:2.5. Since there is no reason for assuming that the incidence of hypertensive disease had significantly decreased over this period, the authors felt justified in concluding that these findings indicate a considerable increase in CHD that is independent of hypertension as a factor in its pathogenesis. During the 20th century, then, the profile of the CHD cases varied from the pre-epidemic period (until the 1920s and 1930s) to the height of the epidemic period (1950s and 1960s), and again during the decline in CHD mortality (1980s to date). Cases described during the pre- and post-epidemic periods were mostly associated with "inflammation" and an individual phenotype suggestive of insulin-resistance (obesity, diabetes), hypertension, and/or smoking. During the epidemic period, hypercholesterolemia became the hallmark of CHD cases. The authors wondered how these trends should be interpreted.
Azambuja and Levins conceive CHD as encompassing different diseases associated with vulnerabilities and triggers with varying distributions over time and space. Therefore, they suggest that changes in CHD features accompanying the changes in CHD occurrence resulted from expansions and retractions of sub-populations of CHD cases over time. According to them, the steep rise in CHD mortality seen after the 1920s resulted from a huge expansion of a particular subpopulation of cases, characterized by high cholesterol levels and high case fatality.
While individual vulnerability is routinely considered in modeling infectious diseases, it is frequently ignored with respect to chronic diseases. Vulnerability to chronic "degenerative" diseases is usually conceived as a genetic attribute and, as such, not subject to short-term variation. Over the past years, different pathways have been postulated that could change individuals phenotypically and favor vulnerability to chronic diseases and CHD, including autoimmunity upon infection, metabolic reprogramming upon infection, and metabolic reprogramming associated with nongenomic mechanisms of inheritance. An alternative explanation of the huge expansion of a specific subpopulation of CHD cases occurring from the 1920s to the 1960s could depend not as much on changes in exposure to CHD risk factors as on an acquired window of vulnerability to the disease opened in the middle of the 20th century.
The article postulates that both hypercholesterolemia and coronary thrombosis reported frequently among the CHD cases registered from the 1920s to the 1960s were secondary to an autoimmune response to influenza (re)infection developed among a specific subgroup of vulnerable individuals (those 15 to 45 years old in 1918) marked by the 1918 influenza pandemic virus. This vulnerability may be due to autoimmune disruption of low-density lipoprotein-receptor interactions.
One subgroup of CHD cases, however, has grown since the 1980s: that associated with inflammation and insulin resistance. The growth of this subtype of CHD cases does not seem to be merely relative or secondary to the impressive fall in the number of hypercholesterolemic cases. We need to ask what caused the emergence of the vulnerable (insulin-resistant) phenotype underlying the rising rates of obesity, diabetes, and their associated pool of CHD cases in the population. An important contribution may come from Barker\'s hypothesis and from other theories of nongenetic inheritance of vulnerability across generations. Evidence suggests that the interaction of genes and the pre- and postnatal environments, against a heterogeneous background of vulnerability, could operate to produce metabolic programming effects across generations and result in obesity, diabetes, and cardiovascular diseases later in life.
Comments: This article proposes an alternative causation for the emergence and decline of the CHD "epidemic" experienced by many developed countries during the 20th century. The authors of the article did not address the emergence of CHD currently observed in most developing countries, although a consistent explanation with their argument would be that many populations of developing countries have had high prevalence of infectious diseases and malnutrition which has created a vulnerability to CHD when these people later in their lives are exposed to tobacco smoking and other risky behaviors.
Another issue not addressed in the article is the implications of the proposed theory of CVD causation on the prevention of CHD. The cornerstone of CHD prevention and control is the reduction of traditional risk factors such as blood cholesterol and hypertension. These prevention strategies have proved to be very effective to prevent or delay the onset of CVD outcomes in diverse populations of the world and many studies have indicated that the reduction of CHD mortality rates observed in many countries was associated to the reduction of mean cholesterol levels, fat consumption and other risk factors of populations. It would be interesting that Azambuja and Levins discuss these issues to reconcile their theory with the large evidence regarding effective CHD prevention.
The article postulates that both hypercholesterolemia and coronary thrombosis reported frequently among the CHD cases registered from the 1920s to the 1960s were secondary to an autoimmune response to influenza (re)infection developed among a specific subgroup of vulnerable individuals (those 15 to 45 years old in 1918) marked by the 1918 influenza pandemic virus. This vulnerability may be due to autoimmune disruption of low-density lipoprotein-receptor interactions.
One subgroup of CHD cases, however, has grown since the 1980s: that associated with inflammation and insulin resistance. The growth of this subtype of CHD cases does not seem to be merely relative or secondary to the impressive fall in the number of hypercholesterolemic cases. We need to ask what caused the emergence of the vulnerable (insulin-resistant) phenotype underlying the rising rates of obesity, diabetes, and their associated pool of CHD cases in the population. An important contribution may come from Barker's hypothesis and from other theories of nongenetic inheritance of vulnerability across generations. Evidence suggests that the interaction of genes and the pre- and postnatal environments, against a heterogeneous background of vulnerability, could operate to produce metabolic programming effects across generations and result in obesity, diabetes, and cardiovascular diseases later in life.
Comments: This article proposes an alternative causation for the emergence and decline of the CHD "epidemic" experienced by many developed countries during the 20th century. The authors of the article did not address the emergence of CHD currently observed in most developing countries, although a consistent explanation with their argument would be that many populations of developing countries have had high prevalence of infectious diseases and malnutrition which has created a vulnerability to CHD when these people later in their lives are exposed to tobacco smoking and other risky behaviors.
Another issue not addressed in the article is the implications of the proposed theory of CVD causation on the prevention of CHD. The cornerstone of CHD prevention and control is the reduction of traditional risk factors such as blood cholesterol and hypertension. These prevention strategies have proved to be very effective to prevent or delay the onset of CVD outcomes in diverse populations of the world and many studies have indicated that the reduction of CHD mortality rates observed in many countries was associated to the reduction of mean cholesterol levels, fat consumption and other risk factors of populations. It would be interesting that Azambuja and Levins discuss these issues to reconcile their theory with the large evidence regarding effective CHD prevention
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