Family History of Premature Cardiovascular Disease
Family History of Premature Cardiovascular Disease
In this study of a large cohort of treated hypertensive patients with long follow-up, P-FH was associated with an earlier presentation to the clinic, a lower burden of traditional CV risk factors, and similar longitudinal BP reduction compared with P-FH. However, this did not translate into improved long-term CV outcomes, rather we show despite active management of CV risk factors in a tertiary care centre, P-FH had a higher 35-year CV mortality compared with those without. The results were consistent in both FDR-FH and in the propensity score-matched analyses. A positive parental history of CVD failed to substantially improve the discriminatory power of the risk models over and above traditional risk factors, but there was a slight improvement in risk reclassification.
P-FH individuals presented earlier to clinic, and this may be due to greater awareness, shorter referral time, or earlier onset of hypertension. However, P-FH also had lower BP at presentation along with lower cholesterol and less renal disease, indicating better awareness of future CV risk as a probable reason for referral. In a subset of patients in whom accurate data on prescription refill were available for at least 5 years, similar patterns of drug adherence were observed for antihypertensive, lipid-lowering, or antiplatelet drugs. Moreover, only 48–50% of subjects were taking antiplatelet drugs. There is evidence that awareness of a family history of CVD can result in positive changes in behavioural and lifestyle. It is to be expected that earlier adoption of healthier lifestyle and early risk factor intervention should lead to significant mitigation of risk over the long term. While our results are surprising, it needs to be interpreted taking into consideration all the positive features observed—early referral and no difference in longitudinal reduction in BP, which may have partially mitigated the excess risk. In our population, we do not have data to assess what the true risk would have been, had individuals with positive family history not been referred to the clinic. Moreover, while competing risks may have influenced our results for 35-year mortality risk, we show that CV mortality is still significantly higher over the long follow-up period. Interestingly, the Cooper Center Longitudinal Study showed findings similar to ours, albeit in a low-risk population cohort, where the presence of positive family history of premature vascular disease was associated with a 5% absolute and 50% relative difference in the lifetime risk for CVD and CVD mortality, and this risk was consistent across the short term (<10 years) and long term (>20 years) of follow-up. Taken together, the implication is that the presence of family history of premature CVD represents a clinically significant sustained increase in CHD and CVD risk across the lifespan, and the pathological processes determining this increased risk must start long before the traditional risk factors are identified and treated. Also, current risk reduction strategies may need to be optimized to minimize the excess lifetime risk posed by a positive family history.
There is unequivocal evidence that even relatively low burden of traditional risk factors translates into markedly higher lifetime risks of CVD across the lifespan. To our knowledge, we are the first to show that current primary prevention strategies do not completely abolish the excess risk from a positive parental history. There are three possible explanations for our findings. A positive family history may reflect (i) genetic factors that affect known risk factors like PSCK9 non-sense mutation, which can result in sustained exposure from birth and hence significant cumulative lifetime CV risk; (ii) novel mechanisms unrelated to traditional risk factors—if this is the case, there would be evidence of considerable improvement in discrimination and re-classification of short-term risk. But this is not observed in either our study or the Framingham and EPIC-Norfolk studies; (iii) onset of sustained damage to the vascular system much earlier than presentation—epidemiological evidence supporting this include the presence of significant subclinical atherosclerosis in one-third of asymptomatic women with a sibling history of early-onset CVD, children of hypertensive parents show a more rapid rise in BP, higher arterial stiffness, and greater left ventricular mass than those of normotensive parents. It is likely that family history can reflect a combination of these factors resulting in early vascular injury that is not effectively reversed with later interventions.
The strengths of the current study include the large cohort size, long follow-up, longitudinal clinic and laboratory measurements, and mortality outcomes. Our study has limitations which include its observational nature and the study subjects derived from a predominantly urban hypertension clinic. We have no data on diet or physical activity within our study. Although we had drug prescription data only from 2004, our metrics of drug adherence are reliable as the data are from at least 5 years of prescription refill data and more representative of current population. Almost all our subjects were Caucasians, so our results may not be applicable to other ancestries. Confounding may be an issue when assessing the relationship between family history and mortality outcomes. Although the GBPC is the only specialist hypertension clinic in the catchment area, patients with mild hypertension are usually not referred to the clinic. However, as the primary hypothesis is related to patients with premature CVD who are all referred to the clinic, this may not have a major impact, but a residual issue with differential selection cannot be completely excluded. Risk factor clustering occurs in families and sharing of higher levels of CV risk factors may lead to inflated risk estimates from a positive family history. In order to record a case as having a premature history of CVD in one of their siblings, families need to include a minimum of one proband. Larger families will be more likely to have a first-degree relative with a positive history, and therefore, it is possible that our analysis was disproportionately driven by an increased number of recorded events in larger families. Another type of bias we cannot exclude is survivorship bias. This refers to the possibility that individuals with more severe phenotypic disease expression may have died prior to clinic attendance. Patients included in our study may therefore have had less severe disease which may have diluted the results of our study. Self-report data have the potential to introduce recall bias; however, studies have found these methods of data collection are reliable with respect to family history of CVD.
Our study has important implications in clinical practice and underlines the importance of screening and prevention strategies to be adopted in primary and secondary care settings. Our finding that individuals with family history of premature CVD are referred earlier for primary prevention is encouraging; however, this may not be the case in general. There is evidence that despite higher prevalence of modifiable risk factors among relatives of probands with premature CVD and guideline recommendations, in practice they are not actively targeted for treatment. In a subgroup analysis, we observed similar rates of prescription of lipid-lowering and antiplatelet drugs and did not see an increase in drug adherence among those with a positive family history. This is potentially an aspect of clinical practice to be addressed, especially in terms of increasing take-up of antiplatelet and lipid-lowering therapy, and improving adherence to all CV medications in those with a strong family history of premature CVD. Current treatment guidelines are based on risk scores which interpret an individual's risk using a population-based model which may not pick individuals in the lower- or medium-risk groups that account for the majority of CVD events. The identification of a CV risk factor or the occurrence of a CV event in an individual before the age of 60 should necessitate active intervention in their children, even if they do not manifest abnormal findings, to reduce future CV risk. Very few studies have evaluated the impact of interventions on family members of patients with CVD, and most of them focused on lifestyle interventions. But all these studies showed promising positive effects of the intervention on traditional risk factors among family members. Additionally, targeted dietary and exercise interventions need to be encouraged as there is evidence that the benefits of exercise on BP and outcomes may be intensity dependent. Smoking cessation is an important aspect of risk reduction measures and we find the presence of any family history of premature CVD had no impact on smoking status in our patients. Scotland's tobacco control strategy is one of the most comprehensive in Europe and includes smoke-free legislation along with well-developed smoking cessation services and nicotine replacement therapy prescribing provided by the National Health Service. However, after the initial increase in smoking cessation attempts when smoke-free legislation was implemented, this has not been sustained, suggesting the need for additional tobacco control measures and ongoing support. Our study suggests that despite earlier referral and treatment of individuals with a positive family history of premature CVD, excess risk persists, indicating the need for continued and sustained efforts to reduce risk factors and drug adherence in these individuals. Additional prospective research is required to assess the utility and cost-effectiveness of primary prevention strategies in first-degree relatives of individuals with CVD or primordial prevention strategies for relatives of individuals who manifest a CV risk factor.
Discussion
In this study of a large cohort of treated hypertensive patients with long follow-up, P-FH was associated with an earlier presentation to the clinic, a lower burden of traditional CV risk factors, and similar longitudinal BP reduction compared with P-FH. However, this did not translate into improved long-term CV outcomes, rather we show despite active management of CV risk factors in a tertiary care centre, P-FH had a higher 35-year CV mortality compared with those without. The results were consistent in both FDR-FH and in the propensity score-matched analyses. A positive parental history of CVD failed to substantially improve the discriminatory power of the risk models over and above traditional risk factors, but there was a slight improvement in risk reclassification.
P-FH individuals presented earlier to clinic, and this may be due to greater awareness, shorter referral time, or earlier onset of hypertension. However, P-FH also had lower BP at presentation along with lower cholesterol and less renal disease, indicating better awareness of future CV risk as a probable reason for referral. In a subset of patients in whom accurate data on prescription refill were available for at least 5 years, similar patterns of drug adherence were observed for antihypertensive, lipid-lowering, or antiplatelet drugs. Moreover, only 48–50% of subjects were taking antiplatelet drugs. There is evidence that awareness of a family history of CVD can result in positive changes in behavioural and lifestyle. It is to be expected that earlier adoption of healthier lifestyle and early risk factor intervention should lead to significant mitigation of risk over the long term. While our results are surprising, it needs to be interpreted taking into consideration all the positive features observed—early referral and no difference in longitudinal reduction in BP, which may have partially mitigated the excess risk. In our population, we do not have data to assess what the true risk would have been, had individuals with positive family history not been referred to the clinic. Moreover, while competing risks may have influenced our results for 35-year mortality risk, we show that CV mortality is still significantly higher over the long follow-up period. Interestingly, the Cooper Center Longitudinal Study showed findings similar to ours, albeit in a low-risk population cohort, where the presence of positive family history of premature vascular disease was associated with a 5% absolute and 50% relative difference in the lifetime risk for CVD and CVD mortality, and this risk was consistent across the short term (<10 years) and long term (>20 years) of follow-up. Taken together, the implication is that the presence of family history of premature CVD represents a clinically significant sustained increase in CHD and CVD risk across the lifespan, and the pathological processes determining this increased risk must start long before the traditional risk factors are identified and treated. Also, current risk reduction strategies may need to be optimized to minimize the excess lifetime risk posed by a positive family history.
There is unequivocal evidence that even relatively low burden of traditional risk factors translates into markedly higher lifetime risks of CVD across the lifespan. To our knowledge, we are the first to show that current primary prevention strategies do not completely abolish the excess risk from a positive parental history. There are three possible explanations for our findings. A positive family history may reflect (i) genetic factors that affect known risk factors like PSCK9 non-sense mutation, which can result in sustained exposure from birth and hence significant cumulative lifetime CV risk; (ii) novel mechanisms unrelated to traditional risk factors—if this is the case, there would be evidence of considerable improvement in discrimination and re-classification of short-term risk. But this is not observed in either our study or the Framingham and EPIC-Norfolk studies; (iii) onset of sustained damage to the vascular system much earlier than presentation—epidemiological evidence supporting this include the presence of significant subclinical atherosclerosis in one-third of asymptomatic women with a sibling history of early-onset CVD, children of hypertensive parents show a more rapid rise in BP, higher arterial stiffness, and greater left ventricular mass than those of normotensive parents. It is likely that family history can reflect a combination of these factors resulting in early vascular injury that is not effectively reversed with later interventions.
The strengths of the current study include the large cohort size, long follow-up, longitudinal clinic and laboratory measurements, and mortality outcomes. Our study has limitations which include its observational nature and the study subjects derived from a predominantly urban hypertension clinic. We have no data on diet or physical activity within our study. Although we had drug prescription data only from 2004, our metrics of drug adherence are reliable as the data are from at least 5 years of prescription refill data and more representative of current population. Almost all our subjects were Caucasians, so our results may not be applicable to other ancestries. Confounding may be an issue when assessing the relationship between family history and mortality outcomes. Although the GBPC is the only specialist hypertension clinic in the catchment area, patients with mild hypertension are usually not referred to the clinic. However, as the primary hypothesis is related to patients with premature CVD who are all referred to the clinic, this may not have a major impact, but a residual issue with differential selection cannot be completely excluded. Risk factor clustering occurs in families and sharing of higher levels of CV risk factors may lead to inflated risk estimates from a positive family history. In order to record a case as having a premature history of CVD in one of their siblings, families need to include a minimum of one proband. Larger families will be more likely to have a first-degree relative with a positive history, and therefore, it is possible that our analysis was disproportionately driven by an increased number of recorded events in larger families. Another type of bias we cannot exclude is survivorship bias. This refers to the possibility that individuals with more severe phenotypic disease expression may have died prior to clinic attendance. Patients included in our study may therefore have had less severe disease which may have diluted the results of our study. Self-report data have the potential to introduce recall bias; however, studies have found these methods of data collection are reliable with respect to family history of CVD.
Our study has important implications in clinical practice and underlines the importance of screening and prevention strategies to be adopted in primary and secondary care settings. Our finding that individuals with family history of premature CVD are referred earlier for primary prevention is encouraging; however, this may not be the case in general. There is evidence that despite higher prevalence of modifiable risk factors among relatives of probands with premature CVD and guideline recommendations, in practice they are not actively targeted for treatment. In a subgroup analysis, we observed similar rates of prescription of lipid-lowering and antiplatelet drugs and did not see an increase in drug adherence among those with a positive family history. This is potentially an aspect of clinical practice to be addressed, especially in terms of increasing take-up of antiplatelet and lipid-lowering therapy, and improving adherence to all CV medications in those with a strong family history of premature CVD. Current treatment guidelines are based on risk scores which interpret an individual's risk using a population-based model which may not pick individuals in the lower- or medium-risk groups that account for the majority of CVD events. The identification of a CV risk factor or the occurrence of a CV event in an individual before the age of 60 should necessitate active intervention in their children, even if they do not manifest abnormal findings, to reduce future CV risk. Very few studies have evaluated the impact of interventions on family members of patients with CVD, and most of them focused on lifestyle interventions. But all these studies showed promising positive effects of the intervention on traditional risk factors among family members. Additionally, targeted dietary and exercise interventions need to be encouraged as there is evidence that the benefits of exercise on BP and outcomes may be intensity dependent. Smoking cessation is an important aspect of risk reduction measures and we find the presence of any family history of premature CVD had no impact on smoking status in our patients. Scotland's tobacco control strategy is one of the most comprehensive in Europe and includes smoke-free legislation along with well-developed smoking cessation services and nicotine replacement therapy prescribing provided by the National Health Service. However, after the initial increase in smoking cessation attempts when smoke-free legislation was implemented, this has not been sustained, suggesting the need for additional tobacco control measures and ongoing support. Our study suggests that despite earlier referral and treatment of individuals with a positive family history of premature CVD, excess risk persists, indicating the need for continued and sustained efforts to reduce risk factors and drug adherence in these individuals. Additional prospective research is required to assess the utility and cost-effectiveness of primary prevention strategies in first-degree relatives of individuals with CVD or primordial prevention strategies for relatives of individuals who manifest a CV risk factor.