Ageing, Menopause, and Ischaemic Heart Disease Mortality
Ageing, Menopause, and Ischaemic Heart Disease Mortality
Objectives To use changes in heart disease mortality rates with age to investigate the plausibility of attributing women’s lower heart disease mortality than men to the protective effects of premenopausal sex hormones.
Design Modelling study of longitudinal mortality data with models assuming (i) a linear association between mortality rates and age (absolute mortality) or (ii) a logarithmic association (proportional mortality). We fitted models to age and sex specific mortality rates in the census years 1950 to 2000 for three birth cohorts (1916-25, 1926-35, and 1936-45).
Data sources UK Office for National Statistics and the US National Center for Health Statistics.
Main outcome measure(s) Fit of models to data for England and Wales and for the US.
Results For England-Wales data, proportional increases in ischaemic heart disease mortality fitted the data better than absolute increases (improvement in deviance statistics: women, 58 logarithmic units; men, 37). We identified a deceleration in male mortality after age 45 years (decreasing from 30.3% to 5.2% per age-year, P=0.042), although the corresponding difference in women was non-significant (P=0.43, overall trend 7.9% per age-year, P<0.001). By contrast, female breast cancer mortality decelerated significantly after age 45 years (decreasing from 19.3% to 2.6% per age-year, P<0.001). We found similar results in US data.
Conclusions Proportional age related changes in ischaemic heart disease mortality, suggesting a loss of reparative reserve, fit longitudinal mortality data from England, Wales, and the United States better than absolute age related changes in mortality. Acceleration in male heart disease mortality at younger ages could explain sex differences rather than any menopausal changes in women.
The relative delay in the onset of ischaemic heart disease in women compared with men, on a population level, has been attributed largely to the putative protective effects of the premenopausal hormonal milieu, but little epidemiological or clinical evidence supports this. Circulating lipids have been shown to change levels during the menopausal transition, but interpretation of these changes is made complex by discrepant changes in the levels of cholesterol and apolipoprotein. Ischaemic heart disease mortality increases with age, but cross sectional analyses of age specific mortality have not shown any sudden proportional acceleration at the age of menopause in women, either in data from England and Wales, the United States, By contrast, the proportional increase in breast cancer mortality with age abruptly decelerates at menopausal age among women.
Two issues need resolution with respect to previous cross-sectional analyses. Firstly, it is not known why age related mortality should be examined on the proportional (or logarithmic) scale for ischaemic heart disease mortality, rather than an absolute age related increase in mortality, which accelerates throughout adult life in both men and women. By contrast, the accumulation of multiple injuries has been suggested as a mechanistic explanation for a proportional increase in cancer related mortality with age. Secondly, ischaemic heart disease has a long latency period before death, and in view of changing lifestyles and treatment environments over a person’s lifetime, it is difficult to interpret cross sectional associations between age and mortality.
The dual goal of this analysis was to challenge existing paradigms regarding causality attribution to menopause as it relates to the risk of ischaemic heart disease in women, by providing a mechanistic hypothesis for proportional increases in mortality, and applying it to longitudinal vital statistics data. To do this, we aimed to show that a proportional change in mortality is biologically and numerically meaningful, possibly representing a constant probability of the failure of tissue reparative cells across a lifetime. Indeed, the length of telomeres in circulating leucocytes, which can be taken as a proxy for other bone marrow cells that replenish the circulatory system, reduces linearly during adult life. Because telomere length shortens linearly with every cell division, the linear loss of telomere length over adult life indicates that, on average, cells divide at a constant rate over time. Loss of telomere length limits a cell’s capacity to replicate. Therefore, regeneration of bone marrow cells is limited in a linear fashion with increasing age. This explanation is a generalisation of the cancer specific process proposed by Pike and colleagues to all senescent chronic disease, and is based on age related heart disease mortality among birth cohorts (born 1916-45) in England and Wales and the United States.
Abstract
Objectives To use changes in heart disease mortality rates with age to investigate the plausibility of attributing women’s lower heart disease mortality than men to the protective effects of premenopausal sex hormones.
Design Modelling study of longitudinal mortality data with models assuming (i) a linear association between mortality rates and age (absolute mortality) or (ii) a logarithmic association (proportional mortality). We fitted models to age and sex specific mortality rates in the census years 1950 to 2000 for three birth cohorts (1916-25, 1926-35, and 1936-45).
Data sources UK Office for National Statistics and the US National Center for Health Statistics.
Main outcome measure(s) Fit of models to data for England and Wales and for the US.
Results For England-Wales data, proportional increases in ischaemic heart disease mortality fitted the data better than absolute increases (improvement in deviance statistics: women, 58 logarithmic units; men, 37). We identified a deceleration in male mortality after age 45 years (decreasing from 30.3% to 5.2% per age-year, P=0.042), although the corresponding difference in women was non-significant (P=0.43, overall trend 7.9% per age-year, P<0.001). By contrast, female breast cancer mortality decelerated significantly after age 45 years (decreasing from 19.3% to 2.6% per age-year, P<0.001). We found similar results in US data.
Conclusions Proportional age related changes in ischaemic heart disease mortality, suggesting a loss of reparative reserve, fit longitudinal mortality data from England, Wales, and the United States better than absolute age related changes in mortality. Acceleration in male heart disease mortality at younger ages could explain sex differences rather than any menopausal changes in women.
Introduction
The relative delay in the onset of ischaemic heart disease in women compared with men, on a population level, has been attributed largely to the putative protective effects of the premenopausal hormonal milieu, but little epidemiological or clinical evidence supports this. Circulating lipids have been shown to change levels during the menopausal transition, but interpretation of these changes is made complex by discrepant changes in the levels of cholesterol and apolipoprotein. Ischaemic heart disease mortality increases with age, but cross sectional analyses of age specific mortality have not shown any sudden proportional acceleration at the age of menopause in women, either in data from England and Wales, the United States, By contrast, the proportional increase in breast cancer mortality with age abruptly decelerates at menopausal age among women.
Two issues need resolution with respect to previous cross-sectional analyses. Firstly, it is not known why age related mortality should be examined on the proportional (or logarithmic) scale for ischaemic heart disease mortality, rather than an absolute age related increase in mortality, which accelerates throughout adult life in both men and women. By contrast, the accumulation of multiple injuries has been suggested as a mechanistic explanation for a proportional increase in cancer related mortality with age. Secondly, ischaemic heart disease has a long latency period before death, and in view of changing lifestyles and treatment environments over a person’s lifetime, it is difficult to interpret cross sectional associations between age and mortality.
The dual goal of this analysis was to challenge existing paradigms regarding causality attribution to menopause as it relates to the risk of ischaemic heart disease in women, by providing a mechanistic hypothesis for proportional increases in mortality, and applying it to longitudinal vital statistics data. To do this, we aimed to show that a proportional change in mortality is biologically and numerically meaningful, possibly representing a constant probability of the failure of tissue reparative cells across a lifetime. Indeed, the length of telomeres in circulating leucocytes, which can be taken as a proxy for other bone marrow cells that replenish the circulatory system, reduces linearly during adult life. Because telomere length shortens linearly with every cell division, the linear loss of telomere length over adult life indicates that, on average, cells divide at a constant rate over time. Loss of telomere length limits a cell’s capacity to replicate. Therefore, regeneration of bone marrow cells is limited in a linear fashion with increasing age. This explanation is a generalisation of the cancer specific process proposed by Pike and colleagues to all senescent chronic disease, and is based on age related heart disease mortality among birth cohorts (born 1916-45) in England and Wales and the United States.
