Numerous genetic variants correlate with either lower LDL cholesterol or lower blood pressure. Some of these have been shown to result in greatly reduced risk of cardiovascular disease, such as variants in APOB, DSCAML1, ANGPTL4, and ASGR1. Researchers here adopt the position that one can use data on the health of individuals with these and other variants from a large population database as a way to model the outcome should a non-variant individual diligently control LDL cholesterol and blood pressure through lifestyle choices throughout life. This is probably a fair assumption, though it is also fair to suggest that not all of the relevant mechanisms touched on by these genetic variants are fully understood.
As one might expect, based on the results from earlier studies of specific variants and risk of cardiovascular disease, the data here shows a large reduction in risk for people who have one or more of these variants. This can then be associated with the level of reduction in LDL cholesterol and blood pressure needed for a non-variant individual to achieve the same outcome. Assuming, of course, that cholesterol levels and blood pressure are the only relevant mechanisms, or at least the dominant mechanisms. They are undoubtedly influential, given that higher LDL cholesterol accelerates atherosclerosis and higher blood pressure results in all sorts of tissue damage, but they are not the only influential processes in aging.
In this study, researchers studied 438,952 participants in the UK Biobank, who had a total of 24,980 major coronary events - defined as the first occurrence of non-fatal heart attack, ischaemic stroke, or death due to coronary heart disease. They used an approach called Mendelian randomisation, which uses naturally occurring genetic differences to randomly divide the participants into groups, mimicking the effects of running a clinical trial.
People with genes associated with lower blood pressure, lower LDL cholesterol, and a combination of both were put into different groups, and compared against those without these genetic associations. Differences in blood LDL cholesterol and systolic blood pressure (the highest level that blood pressure reaches when the heart contracts), along with the number of cardiovascular events was compared between groups.
A long-term reduction of 1 mmol/L low-density lipoprotein (LDL), or 'bad' cholesterol, in the blood with a 10 mmHg reduction in blood pressure led to an 80 percent lower lifetime risk of developing heart and circulatory disease. This combination also reduced the risk of death from these conditions by 67 percent. The team found that even small reductions can provide health benefits. A decrease of 0.3 mmol/L LDL cholesterol in the blood and 3 mmHg lower blood pressure was associated with a 50 percent lower lifetime risk of heart and circulatory disease.
Numerous randomized trials have demonstrated that treatment for up to 5 years with therapies that reduce low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) reduce the risk of cardiovascular events. In addition, mendelian randomization studies suggest that the benefit of exposure to lower LDL-C levels and lower SBP may accumulate over time. Because the biological effects of LDL-C and SBP may be cumulative, long-term exposure to the combination of both could potentially substantially reduce the lifetime risk of cardiovascular disease. However, the association of combined lifetime exposure to both lower LDL-C and lower SBP with the risk of cardiovascular disease has not been reliably quantified.
Ideally, this question would be addressed by conducting a randomized trial to minimize the effect of confounding that can occur in observational studies. However, a randomized trial evaluating the association between maintaining prolonged exposure to both lower LDL-C levels and lower SBP with the risk of cardiovascular disease would take several decades to complete, and therefore is unlikely to ever be conducted.
In an attempt to fill this evidence gap, this study used genetic variants associated with lower LDL-C levels and SBP as instruments of randomization to divide participants into groups with lifelong exposure to lower LDL-C levels, lower SBP, or both; and then compared the differences in plasma LDL-C, SBP, and cardiovascular event rates in each group to estimate the association of combined lifetime exposure with the lifetime risk of cardiovascular disease in a manner analogous to a long-term randomized clinical trial. The primary objective of this study was to assess and quantify the association of prolonged exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease.