Understanding Heart Disease Risk and Risk Factors in Familial Hypercholesterolemia

We are constantly bombarded with information about risk and risk factors for heart disease. The numbers are often confusing, sometimes they are big (50 or 100 times the risk), sometimes they are small, and sometimes they are in percent form (20% higher, 300% higher). What does this information mean for people with FH? The topic is complicated and I will try to make interpretation of risk more clear.

First, we should be clear on what is meant by heart disease. If you have FH, this primarily means a heart attack, angina, or the need for stents or bypass, or in medical terms, atherosclerotic cardiovascular disease (ASCVD). While patients with FH can have strokes, heart failure, and peripheral artery disease, these tend to occur later in life after a heart attack. If you look at risk evaluations, the ones about heart attacks are most relevant.

For each of these, subsequent research has shown that controlling the risk factor (e.g. lowering your cholesterol or blood pressure, controlling diabetes, increasing physical fitness, quitting smoking) lowers your risk. Each of these risk factors, if acquired by middle age and if untreated, increases the likelihood of having a heart attack 2-3 times compared to those without them. If you have more than 1, risk increases proportionately.

Risk factors should not be confused with biomarkers which are risk predictors but modifying them does not lower risk. HDL cholesterol and c-reactive protein are examples of biomarkers associated with heart disease risk, but clinical trials have not shown improvement in heart attack rates by improving biomarker status.

Age is a major risk factor, the older you are, the more likely having any form of heart disease becomes. People with risk factors have heart disease at earlier ages than those without risk. Having a heart attack before age 35 years is rare, even with many risk factors, but having a heart attack before 50 years of age typically occurs in those with many risk factors or severe risk.

FH is a risk factor, as a genetic condition, but not a disease itself.

Having FH means you are much more likely to have a heart attack for two reasons: your LDL cholesterol is very high and it has been high since birth. The higher your LDL cholesterol, the higher the risk. Lowering cholesterol levels in those with FH lowers risk. About 10% of untreated people with heterozygous FH do not have heart attacks (we do not always know why). However, 90% of those with FH, if untreated, will get a heart attack as compared to only 5% of people with normal cholesterol and no other major cardiovascular risk factors. If you have FH, the presence of any other major risk factors, and/or high lipoprotein (a) (Lp(a)) level further increases risk. This is why if you have FH, all other risk factors should be controlled.

The term “risk” has broader dimensions and, unfortunately in the medical literature, both “risk” and “risk factor” have been used in ways that create confusion rather than clarity. To provide a simple example, people who have already had a heart attack are much more likely to have a second one regardless of risk factor status. However, if you have had a heart attack and survived, you can no longer be at risk for heart disease because you actually have heart disease! Here understanding the distinction between controlling risk to prevent a heart attack and treating existing heart disease is critical in interpreting research data and making recommendations.

There are three categories of risk that should be understood. These are attributable risk, absolute risk, and relative risk. Unless you know what type of risk is being discussed, you cannot interpret the science.

Attributable Risk

Attributable risk refers to the percentage of events in a given population that can be assigned to a specific risk factor. For example, the attributable risk from smoking for lung cancer or abdominal aortic aneurysms is about 80%! Thus, if nobody smoked, or was exposed to smoke passively, 80% of the cases of these two diseases would disappear from society. If you think about FH and attributable risk, it becomes clear why FH gets short attention from people trying to prevent heart disease at the public health level. With a prevalence of 1:250 and a 90% likelihood of an event without treatment (and some of that explained by other risk factors), the highest possible attributable risk for FH in the larger population is only 0.3 to 0.4%.

Absolute Risk

This brings us to absolute risk which is your actual personal risk of having a heart attack. As I discussed above, someone with FH and no treatment has a 90% lifetime absolute risk of having a heart attack. Because atherosclerosis takes a long time to develop and reach the point where it can trigger a heart attack, your absolute risk changes as you get older. When someone with FH is young, absolute risk of an event in the next decade is very low; rates start to increase at age 35 years and continue to increase dramatically (faster for men than women) until age 70 years or so when they are not much higher than rates in the general population.

Here we can begin to understand the difference between public health approaches and personalized approaches to risk. For the US population, stopping people from smoking had a big impact on heart disease rates as did clean indoor air legislation. Taking trans fats out of the diet likely lowered cholesterol levels. Those with FH benefited from these public health approaches but they did not benefit enough to lower absolute risk from high cholesterol. Unless elevated cholesterol is recognized and treated, those with FH will continue to be at high risk.

Relative Risk

This brings us to relative risk, which is the most commonly reported risk statistic. Here a percent difference in risk in comparison to another population is reported. Alternatively reported is an odds ratio for having an event compared to a comparison population. If it is stated that those with the FH gene have three times the risk for a heart attack at any given cholesterol level, this comparison is between two populations that seem about the same except one group has the FH gene and one does not. However, to fully interpret what this means for yourself, you need to know a number of additional facts, the most important of which is absolute risk. In this particular study, heart attack rates in this study for those with the FH gene and LDL cholesterol < 130 mg/dl were lower than those for people without the FH gene and LDL cholesterol above 160 mg/dl. Thus, there are two lessons from this data: having the FH gene and lifelong higher cholesterol increases your risk and having high LDL cholesterol is even worse.

Another key factor in interpreting relative risk is time. The duration of follow up is important as epidemiological studies typically go on for 5 to 10 years and the percent difference in risk refers to that time frame. The risk equations used in current guidelines are reliable for a 10 year interval.Someone with a predicted absolute risk of a heart attack of 10% in the next 10 years is considered high risk. However, this risk equation is not applicable for people with FH, who are already considered high risk. In the new 2018 AHA/ACC cholesterol management guidelines, and in several settings, having FH, or an LDL cholesterol over 190 mg/dL even if that’s not due to FH, elevates you to high risk status independent of other risk factors because of the lifelong exposure to higher cholesterol.

In shorter studies and in younger populations, heart attack risk ratios tend to be much higher. This is because event rates are lower at younger ages, but people with risk factors are much more likely to have those events. The very high odds ratios for heart disease risk for FH come from studies of people below 40-45 years of age. That is because heart attack rates are very low in this age range and FH causes a lot of these heart attacks. In fact, the most common age for someone to have a heart attack with FH is over 40 years, but compared to the general population, the relative risk is highest in young adulthood.

At the other end of the age spectrum, let us say over 70 years, heart attack risk ratios related to FH are much lower, typically around 2:1 or even lower. This is because heart disease is a common cause of death in the world and as the population ages those without FH begin to have events. Also, the small group of people with FH who will never have a heart attack form an increasingly large percentage of the total group of people alive with FH over the age of 70 years. This further diminishes the risk ratio but has no impact on the absolute risk or attributable risk.

To make this clearer we can do some simple math. If a 40 year old with FH has 10 times the risk as in the general population and the rate in the general population is 2 events at age 40, then those with FH will have 20 events. However, at age 70 if the population rate is 100 events and the FH risk ratio is 2:1, then those with FH will have 200 events. Even though the ratio is lower at age 70, the absolute number of events is much higher

Relative risk must always be interpreted in the context of absolute event rates. If the absolute risk of an event is very rare, say 1 out of 100,000 even a relative risk of 100:1 lowers the likelihood to 1:1000, still very rare. However, if an event is common, with an absolute risk of 10%, an increase in relative risk of 50% will increase the event rate to 15%, a large proportion of the population.

Understanding this concept is important for interpreting risk reduction in treatment trials. A statistically significant reduction in relative risk in a clinical trial might or not be a meaningful reduction in absolute risk for an individual.

Conversely, results from an observational study might show opportunities for a meaningful reduction in absolute risk, such as maintaining lifelong low cholesterol that cannot be achieved in a short-term clinical trial.

To summarize, both FH and high cholesterol are risk factors for having a heart attack. To interpret research and understand specific risk related to your personal situation you need to know many factors about the study: the type of risk reported, the age of the group studied, how the group was selected, the length of follow-up, and how other risk factors and treatment are managed in the analysis.