Lumping and Splitting in Cardiovascular Risk
Lumping and Splitting in Cardiovascular Risk
The world is divided into 'lumpers' and 'splitters' i.e. those that aggregate data to yield the widest possible conclusions and those that seek to sub-divide groups into smaller more plausible subgroups. I have always had 'splittist' tendencies. In the field of cardiovascular disease (CVD) risk the tendency over the last few years has been to aggregate data across populations and then give general advice that relates to all based on this unitary view. Thus, we have CVD risk calculators e.g. QRISK and Framingham based on the core CVD risk factors identified in numerous epidemiological studies such as age, gender, smoking, blood pressure and total cholesterol: HDL-cholesterol ratio. At the simplest guidelines recommended assessing these and then treating with a single standard dose of a statin with no need for further lipid measurement or indeed any further assessment. While this may be justified at a population level, this does not deliver ideal care for patients as some awkward facts begin to rear their heads.
One of these awkward features is family history of CVD. This is discussed in more detail in the perspective article by A. Bannerjee published in this issue of the International Journal of Clinical Practice. Family history was found to be a CVD risk factor in the Framingham study on univariate analysis but dropped out of the overall multivariate analysis as though it might contribute significantly in some subgroups it did not add to risk prediction across the whole population. It is, however, one of the most reliable patient-derived estimates with individuals knowing the family history and often the onset date in both parents in 75–90% of cases for diabetes, hypertension and cholesterol. Family history can be extreme and diagnostic as is the case in monogenic hyperlipidaemia syndromes. In the limit case familial hypercholesterolaemia which has a prevalence of 1 in 400–500 and an excess age-dependent CVD risk of 2 to 20-fold the overall contribution to population risk is too small to be significant but there is no doubt that effective identification and treatment in individuals and affected families reduces CVD events by 75%. However, the degree of embarrassment caused by leaving out the second commonest genetic syndrome in man with its vast CVD risk consequences because of its autosomal dominant inheritance despite its low population-attributable risk meant that all CVD risk calculators have been modified to include family history even if as a footnote. The same considerations apply to the other less well known but commoner familial combined hyperlipidaemia syndromes whose genetics remain unclear.
However, this still underestimates the contribution made by family history to CVD risk. There are lipoprotein sub-fractions that show co-dominant inheritance for plasma levels. The best known of these is lipoprotein(a) [Lp(a)] whose levels are the co-dominant sum of expression at the two parental alleles and which is 95% genetically inherited based on larger expression from gene alleles with lesser numbers of Kringle (IV) repeats. Significant levels are present in only a few individuals and some ethnic subgroups (e.g. West Africans) but they lead to increased risks of pan-vascular atherosclerosis, increased progression of disease and worse prognosis which is particularly obvious when levels exceed 0.5 g/l. Not only is Lp(a) inherited but a specific treatment exists to reduce its levels – niacin, although other therapies in development may also have beneficial effects on it. Patients with elevated Lp(a) levels are often found amongst individuals that screen negative for autosomal dominant familial hypercholesterolaemia gene mutations [LDL receptor; apolipoprotein B3500 or pre-protein convertase serine kexin (PCSK)-9] yet LDL-cholesterol is elevated.
However, not all premature CVD is caused by lipoprotein-related abnormalities. One rather dated study identified only about 25% of cases of premature coronary heart disease as having a lipoprotein-associated abnormality which it identified as a result of a combination of familial hypercholesterolaemia, familial combined hyperlipidaemia and raised L(a). The rest of the cases remained to be accounted for. Despite the progress made in understanding lipid-related disorders as causes of premature CVD far less has been achieved in the fields of atherothrombosis/thrombophilia and inflammation although these processes are known to contribute to atherosclerosis. Although much still remains to be discovered, great interest has recently been found in a locus for CVD located on chromosome 9p21. The identity of the causative protein or gene regulatory sequence is unknown but the best supposition is that its effects relate to the regulation of inflammation, another key contributor to the process of atherosclerosis. Unfortunately, the lack of a specific marker for this locus has meant that specific screening tests have not as yet been developed or validated.
Yet, again this underestimates the complexity of family history as factor for CVD. The family history can relate to conditions that accelerate atherosclerosis in their own right rather act directly to cause atherosclerosis. One example of this would be type 2 diabetes, which often shows strong familial inheritance with up to 30–80% of the variance being familial. With its slow onset and association with the metabolic syndrome this non-CVD family history actually can contribute strongly to atherogenesis by promoting the presence of the atherogenic small dense particle phenotype. Similarly, tendencies to dys-regulation of inflammation are inherited most commonly as part of the HLA-DR3 linked cluster of autoimmune diseases. Thus, autoimmune hypothyroidism, rheumatoid arthritis, vitiligo and to the greatest extent systemic lupus erythematosus all are associated with increased risk of CVD because of their roles in raising background inflammation rates and/or because of direct effects (e.g. secondary hypercholesterolaemia in hypothyroidism) or by promoting the generation of autoantibodies to multiple antigenic targets including those in the vasculature or plasma lipoproteins. Reducing inflammation by reducing disease flare episodes e.g. with anti-tumour necrosis factor-alpha antibodies or other treatments reduces CVD events. Type I diabetes, although it shows a different HLA association also can be familial and strongly contributes to atherogenesis.
But family history again comprises more than these genetic factors. It includes shared environment throughout childhood and adolescence where many behavioural and diet patterns are set. This is such a significant effect that even monozygotic twin studies are corrected for these effects of shared nurture if possible. The effects extend beyond the post natal period as there is increasing evidence that epigenetic changes in pregnancy may contribute to long-term CVD risks. This is best known in the field of diabetes where the epidemiological Barker hypothesis of intra-uterine growth retardation allied with post natal catch-up and excess adiposity now seems to be gaining an increasing evidence base in the form of epigenetic changes occurring in the placenta and foetal liver. It also seems to relate to the pathogenesis of pre-eclampsia and later offspring hypertension and there is some evidence to suggest that it may also relate to atherosclerosis occurring up to 50 years later.
Family history remains one of the most important though often neglected cardiovascular risk factors. It can be protean and many individual family disease histories are relevant to the assessment of cardiovascular risk. However, although genetics play a significant part in the underlying basis of family history it should not be forgotten that both shared parental environment and increasingly epigenetic changes may be relevant to the adult presenting with potential atherosclerotic disease.
Abstract and Introduction
Introduction
The world is divided into 'lumpers' and 'splitters' i.e. those that aggregate data to yield the widest possible conclusions and those that seek to sub-divide groups into smaller more plausible subgroups. I have always had 'splittist' tendencies. In the field of cardiovascular disease (CVD) risk the tendency over the last few years has been to aggregate data across populations and then give general advice that relates to all based on this unitary view. Thus, we have CVD risk calculators e.g. QRISK and Framingham based on the core CVD risk factors identified in numerous epidemiological studies such as age, gender, smoking, blood pressure and total cholesterol: HDL-cholesterol ratio. At the simplest guidelines recommended assessing these and then treating with a single standard dose of a statin with no need for further lipid measurement or indeed any further assessment. While this may be justified at a population level, this does not deliver ideal care for patients as some awkward facts begin to rear their heads.
One of these awkward features is family history of CVD. This is discussed in more detail in the perspective article by A. Bannerjee published in this issue of the International Journal of Clinical Practice. Family history was found to be a CVD risk factor in the Framingham study on univariate analysis but dropped out of the overall multivariate analysis as though it might contribute significantly in some subgroups it did not add to risk prediction across the whole population. It is, however, one of the most reliable patient-derived estimates with individuals knowing the family history and often the onset date in both parents in 75–90% of cases for diabetes, hypertension and cholesterol. Family history can be extreme and diagnostic as is the case in monogenic hyperlipidaemia syndromes. In the limit case familial hypercholesterolaemia which has a prevalence of 1 in 400–500 and an excess age-dependent CVD risk of 2 to 20-fold the overall contribution to population risk is too small to be significant but there is no doubt that effective identification and treatment in individuals and affected families reduces CVD events by 75%. However, the degree of embarrassment caused by leaving out the second commonest genetic syndrome in man with its vast CVD risk consequences because of its autosomal dominant inheritance despite its low population-attributable risk meant that all CVD risk calculators have been modified to include family history even if as a footnote. The same considerations apply to the other less well known but commoner familial combined hyperlipidaemia syndromes whose genetics remain unclear.
However, this still underestimates the contribution made by family history to CVD risk. There are lipoprotein sub-fractions that show co-dominant inheritance for plasma levels. The best known of these is lipoprotein(a) [Lp(a)] whose levels are the co-dominant sum of expression at the two parental alleles and which is 95% genetically inherited based on larger expression from gene alleles with lesser numbers of Kringle (IV) repeats. Significant levels are present in only a few individuals and some ethnic subgroups (e.g. West Africans) but they lead to increased risks of pan-vascular atherosclerosis, increased progression of disease and worse prognosis which is particularly obvious when levels exceed 0.5 g/l. Not only is Lp(a) inherited but a specific treatment exists to reduce its levels – niacin, although other therapies in development may also have beneficial effects on it. Patients with elevated Lp(a) levels are often found amongst individuals that screen negative for autosomal dominant familial hypercholesterolaemia gene mutations [LDL receptor; apolipoprotein B3500 or pre-protein convertase serine kexin (PCSK)-9] yet LDL-cholesterol is elevated.
However, not all premature CVD is caused by lipoprotein-related abnormalities. One rather dated study identified only about 25% of cases of premature coronary heart disease as having a lipoprotein-associated abnormality which it identified as a result of a combination of familial hypercholesterolaemia, familial combined hyperlipidaemia and raised L(a). The rest of the cases remained to be accounted for. Despite the progress made in understanding lipid-related disorders as causes of premature CVD far less has been achieved in the fields of atherothrombosis/thrombophilia and inflammation although these processes are known to contribute to atherosclerosis. Although much still remains to be discovered, great interest has recently been found in a locus for CVD located on chromosome 9p21. The identity of the causative protein or gene regulatory sequence is unknown but the best supposition is that its effects relate to the regulation of inflammation, another key contributor to the process of atherosclerosis. Unfortunately, the lack of a specific marker for this locus has meant that specific screening tests have not as yet been developed or validated.
Yet, again this underestimates the complexity of family history as factor for CVD. The family history can relate to conditions that accelerate atherosclerosis in their own right rather act directly to cause atherosclerosis. One example of this would be type 2 diabetes, which often shows strong familial inheritance with up to 30–80% of the variance being familial. With its slow onset and association with the metabolic syndrome this non-CVD family history actually can contribute strongly to atherogenesis by promoting the presence of the atherogenic small dense particle phenotype. Similarly, tendencies to dys-regulation of inflammation are inherited most commonly as part of the HLA-DR3 linked cluster of autoimmune diseases. Thus, autoimmune hypothyroidism, rheumatoid arthritis, vitiligo and to the greatest extent systemic lupus erythematosus all are associated with increased risk of CVD because of their roles in raising background inflammation rates and/or because of direct effects (e.g. secondary hypercholesterolaemia in hypothyroidism) or by promoting the generation of autoantibodies to multiple antigenic targets including those in the vasculature or plasma lipoproteins. Reducing inflammation by reducing disease flare episodes e.g. with anti-tumour necrosis factor-alpha antibodies or other treatments reduces CVD events. Type I diabetes, although it shows a different HLA association also can be familial and strongly contributes to atherogenesis.
But family history again comprises more than these genetic factors. It includes shared environment throughout childhood and adolescence where many behavioural and diet patterns are set. This is such a significant effect that even monozygotic twin studies are corrected for these effects of shared nurture if possible. The effects extend beyond the post natal period as there is increasing evidence that epigenetic changes in pregnancy may contribute to long-term CVD risks. This is best known in the field of diabetes where the epidemiological Barker hypothesis of intra-uterine growth retardation allied with post natal catch-up and excess adiposity now seems to be gaining an increasing evidence base in the form of epigenetic changes occurring in the placenta and foetal liver. It also seems to relate to the pathogenesis of pre-eclampsia and later offspring hypertension and there is some evidence to suggest that it may also relate to atherosclerosis occurring up to 50 years later.
Family history remains one of the most important though often neglected cardiovascular risk factors. It can be protean and many individual family disease histories are relevant to the assessment of cardiovascular risk. However, although genetics play a significant part in the underlying basis of family history it should not be forgotten that both shared parental environment and increasingly epigenetic changes may be relevant to the adult presenting with potential atherosclerotic disease.
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