Understanding the Effects of Genetic Exposure to Low LDL-C and Systolic Blood Pressure on Lifelong Cardiovascular Risk – An Increasing Role for Early Intervention?

For several decades, efforts in Preventive Cardiology have focused on early risk detection and treating high risk patients with lipid and blood pressure lowering therapies as well as trying to optimize lifestyle habits. However, despite these efforts, there is an exceedingly high prevalence of cardiovascular (CV) risk factors and suboptimal health behaviors that contribute to <1% of all adults and children meeting ideal health metrics.1

The recent 2019 ACC/AHA Guideline on Primary Prevention emphasizes adopting healthy lifestyle choices early in life and sustaining them over time.2 Recently, elegant studies done by Ference et al and Collet et al underscore the importance of recognizing and addressing atherosclerosis early on in young adults.3,4

Life-long Risk Factor Modification in Young Adults

In the study done by Ference et al, lifetime exposure to both lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) was associated with 39% lower cardiovascular disease (CVD) risk.3 More than 400,000 individuals in the UK Biobank were studied between 2006 and 2018. Researchers devised a genetic LDL score using 100 exome variants and a genetic SBP score using 61 exome variants.

Patients were randomized into four groups based on their genetic lifetime exposure. Compared with the reference group, individuals in the lower LDL-C group had a 15 mg/dL lower LDL-C and a 27% lower risk of major CV events (OR 0.73), while those in the lower SBP group had a 3 mmHg lower SBP and an 18% lower risk (OR 0.82). Those in the group with both lower LDL-C and SBP had 15 mg/dL lower LDL-C and 3 mmHg lower SBP and this was associated with a 39% lower risk of major CV events. Importantly, the effects of lower LDL-C and lower SBP on CV event risk were independent and additive.3

Implications for Sustained Lifestyle Improvements

This study has tremendous implications for lifestyle prevention. The authors show that even modest reductions in LDL-C and SBP can lead to substantial reductions in lifetime CVD risk, if maintained long-term. CVD risk begins in childhood, both physiologically and through adverse health habits. Fatty streaks start developing during teenage years, before reaching a critical point in mid-life where risk of atherosclerotic cardiovascular disease (ASCVD) grows exponentially. This is seen even with normal range LDL-C and SBP levels. Typically, patients and clinicians wait until dyslipidemia and hypertension are formally diagnosed to jumpstart their lifestyle habits. However, these patients will still have some risk of developing progressive plaque burden from a lifetime exposure to suboptimal lipid level. Prevention should start when individuals are in elementary school.

Lessons from the AFIJI Registry

In the JACC study published a month later by Collet et al, authors studied a cohort of 880 young adults in the AFIJI (Appraisal of risk Factors in young Ischemic patients Justifying aggressive Intervention) registry, who experienced symptomatic CAD <45 years of age and were followed for up to 20 years.4 The majority of the patients presented with obstructive stenosis (≥70%) causing an acute myocardial infarction (excluding myocarditis, Takotsubo cardiomyopathy, and vasospasm). In this mostly male cohort of smokers with a family history of CAD and an average age of 40 years, one-third had a recurrent major adverse cardiovascular event (MACE), and of these, 36% had at least a second recurrence.

The strongest predictors of a recurrent event were persistent smoking (adjusted HR, 2.32; p <0.01), ethnic origin (sub-Saharan African vs Caucasian; adjusted HR, 1.95; p = 0.02) and inflammatory disease (adjusted HR, 1.58; p = 0.03). Moreover, one in three who experienced multiple MACE eventually developed diabetes, compared to one in ten control patients without events.

The study identified one in three individuals as having cardiovascular events over the span of 20 years, suggesting that our current secondary prevention and adherence efforts are simply not strong enough. Smoking was the strongest prognostic factor for recurrent events. Moreover, 48% of patients with a first recurrence were not taking a high-intensity statin and 7% were not on a statin at all.

One of the challenges lies in identifying which young adults are at higher risk for early coronary artery disease (CAD), with limitations in risk calculators and limited data for this age group. In an excellent commentary by Michos and Choi, the authors illustrate the risk factors for CAD in young adults through a pyramid, including unhealthy lifestyle (diet, exercise, smoking), psychosocial, heritability, ethnicity, ASCVD 10-year risk of ≥5%, and sex-specific effects (early menopause, adverse pregnancy outcomes).5

Implications for Early Prevention

Together, these studies raise many interesting questions: given that a lifetime of low cholesterol and blood pressure is associated with few CV events, what lifestyle measures should we prescribe and when? Moreover, if these do not produce substantial reductions, at what point should early initiation of medication be considered? How can we design prevention programs that focus on promoting long-term exposure to lower LDL-cholesterol and lower SBP, with broader access and with minimal cost and side effects? Lastly, how do we improve secondary prevention efforts through existing programs for cardiac rehabilitation and smoking cessation?

Improvements in CVD mortality are plateauing and we suspect a large component of this is related to health disparities and suboptimal primordial prevention. Primordial prevention involves reducing onset of risk factors and improving health behaviors in otherwise healthy people.6 This involves focusing on diet, exercise, weight control, developing healthy childhood habits, smoking, and addressing socio-economic disparities.

Starting Early: Primordial Prevention

Implementing lifestyle changes related to primary prevention during childhood holds unmatched potential for reducing lifetime CVD risk. Fewer than 1% of children and young adults have healthy dietary habits, and barely a third younger individuals reach ideal physical activity levels on a regular basis. With studies showing that atherosclerotic lesions are already present in the majority of individuals by the age of 15, beginning aggressive prevention efforts during young adulthood is already too late.7 If ideal health habits are established in childhood, individuals are given the greatest chance possible to live a heart healthy life with lower CVD risk.

For most of eternity, humans have lived a more active lifestyle. Compared to our ancestors, most adults now have sedentary lives, eat mostly processed meals, and society encourages these behaviors from a young age. In just children, between 2009 to 2015, there was a steady increase from 25% to 42% in the time spent ≥3hours/day on computers for purposes other than school.8 Research has shown that unhealthy diets at a young age can also contribute to CVD.9 In a prior study, researchers implemented a three-year healthy lifestyle intervention for 3 to 5 year-olds in Madrid with exposure to positive behavior modeling and achieved positive changes in body weight.10

Future population-wide programs should support healthier early patterns, with a special focus in schools. Comprehensive policy changes are needed related to prices of healthy foods, regulation of food marketing, and public health programs extending into childhood to truly advance prevention in an impactful and cost-effective manner across a lifetime. Young adulthood is another critical period in life when exposure to suboptimal BP or cholesterol is detrimental. Young adults frequently discount the importance of high BP and LDL-cholesterol compared with middle-aged and older adults.11,12 Findings from these recent studies suggest that investment in programs targeting modifiable risk factors during childhood and young adulthood is key to reducing incident burden of CVD.

Better Secondary Prevention

Beyond these strategies for primordial and primary prevention, further attention is needed for targeted secondary prevention efforts. Cardiac rehabilitation has been shown to reduce mortality, improve psychosocial well-being, and improve risk factor modification. However, it remains profoundly underutilized.13 Barriers include referral issues, poor support, transportation challenges, and limited resources/hours of operation due to poor reimbursement.

Recently, newer home-based and individualized programs have been introduced to increase access. Use of mobile applications and alternative methods of monitoring and surveillance may further help expand implantation of cardiac rehabilitation.

While smoking represented the strongest prognostic factor in recurrence of events in the study done by Collet et al, it is plausible that this number may under-represent smoking with the rise in vaping and e-cigarette use amongst young adults over recent years, given the study focused on cigarette use. Greater national concern and policy changes are needed to reduce the burden of tobacco use and, now, the e-cigarette rise. Lastly, with secondary prevention, more aggressive targeting of LDL-C reduction in younger patients at higher risk, such as those belonging to certain ethnic groups or with inflammatory disease, is needed.


In the past two years, the ACC/AHA guidelines for hypertension and cholesterol have increased awareness for both entities, encouraged lifestyle modification, and added more intensive initiation and intensification targets for US adults at increased CVD risk. More research is needed to investigate which groups may potentially benefit from earlier and larger reductions in LDL-C and SBP with medication for primary prevention.

Currently the ECAD (Eliminate Coronary Artery Disease) trial is investigating whether ASCVD events can be better prevented by early initiation of statin therapy in young and middle-aged adults, who are not candidates for guideline-based therapies for low ASCVD risk.14 Nonetheless, lifelong persistent exposures to elevated cholesterol and BP are linked with subclinical and clinical CVD. As clinicians, if we do not think about lifestyle and lifetime risk early, we simply miss the mark.


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  2. Arnett DK, Blumenthal RS, Albert MA et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:1376-14.
  3. Ference BA, Bhatt DL, Catapano AL, et al. Association of genetic variants related to combined exposure to lower low-density lipoproteins and lower systolic blood pressure with lifetime risk of cardiovascular disease. JAMA 2019;[Epub ahead of print]
  4. Collet JP, Zeitouni M, Procopi N, et al. Long-term evolution of premature coronary artery disease. J Am Coll Cardiol 2019;74:1868-78.
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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet, Exercise, Hypertension, Smoking

Keywords: Dyslipidemias, Cholesterol, LDL, Atherosclerosis, Biological Specimen Banks, Cardiac Rehabilitation, Cholesterol, LDL, Constriction, Pathologic, Diabetes Mellitus, Africa South of the Sahara, Africa, Northern, Cohort Studies, Body Weight, Diet, Electronic Nicotine Delivery Systems, Coronary Artery Disease, Blood Pressure, Ethnic Groups, Health Behavior, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Exome, Exercise, Hypertension, Life Style, Mobile Applications, Myocardial Infarction, Pregnancy Outcome, Menopause, Prevalence, Primary Prevention, Prognosis, Myocarditis, Referral and Consultation, Risk Factors, Secondary Prevention, Reference Values, Public Health, Smoking, Smoking Cessation, Takotsubo Cardiomyopathy, Registries, Tobacco Use, Transportation

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