Longer and Greater Risk Factor Exposure, More CVD

The duration and intensity of exposure to common CV risk factors over decades cumulatively influence how likely a person is to develop coronary heart disease, stroke, and congestive heart failure after age 40, according to a new analysis.

Researchers used data from the CARDIA study, which enrolled young adults in the 1980s and then tracked them for 30 years, to calculate incident CVD rates as “a function of the time-varying course of independent risk factors operating simultaneously”: LDL cholesterol, HDL cholesterol, triglycerides, mean arterial pressure, and pulse pressure.

“The resulting quantitative relationships provide information that informs the design of primary prevention strategies and clinical trials to assess those strategies, and as a tool for formulating projections of the likely impact on public health of prevention strategies,” Michael J. Domanski, MD (University of Maryland School of Medicine, Baltimore), and colleagues write in their paper, published online this week in the Journal of the American College of Cardiology. The current study builds on prior work, also led by Domanski, looking at cumulative exposure to LDL cholesterol as a stand-alone risk factor.

Jean-Philippe Empana, MD, PhD (Université Paris Cité, INSERM, Paris, France), commenting on the new analysis for TCTMD, said that although it isn’t the first to focus on the concept of cumulative exposure, it is “still quite novel.”

“The usual method is to calculate risk by risk factors measured at one point in time. . . . Even in clinical practice, we still keep working on risks factors measured at a specific day,” he told TCTMD. “I think we should really move towards this approach, because it brings new findings, new [perspectives], and new predictions.”

CARDIA Data on Young Adults

The researchers developed models that estimated the risk of incident CVD (coronary heart disease, stroke, and congestive heart failure) based on the length and severity of exposure to LDL cholesterol, HDL cholesterol, triglycerides, mean arterial pressure, and pulse pressure. They analyzed data for 4,958 asymptomatic adults ages 18 to 30 years who enrolled in the CARDIA study between 1985 and 1986.

After age 40, participants’ median follow-up duration was 19 years, during which 316 people experienced their first CVD event (166 cases of nonfatal coronary heart disease, 108 strokes, and 81 cases of congestive heart failure).

The intensity and length of exposure to the risk factors, expressed as area under the curve (AUC), “were strongly, positively, and independently associated with incident CVD risk after age 40 years,” the investigators report.

Patients in quartile 4 of LDL-exposure level and duration, for example, had a 12.6% CVD event rate at age 60, as compared with rates of 4.3%, 5.7%, and 8.4%, in quartiles 1 through 3, respectively. Rates based on exposure to triglyceride level and duration, meanwhile, ranged from as low as 3.3% in quartile 1 to as high as 12.6% in quartile 4. Similar patterns were seen for mean arterial and pulse pressure.

For HDL, there was a trend toward less CVD with greater cumulative exposure.

When looking at the individual components of incident CVD, each of the risk factors had a different impact. LDL exposure significantly predicted coronary heart disease but not congestive heart failure or stroke, for example. Mean arterial pressure was significant linked to all three endpoints, but only marginally so for congestive heart disease.

Another factor that raised the risk of incident CVD, congestive heart failure, and stroke was Black (versus white) race, which “suggests that self-declared Black race is a phenotypic marker for unexplained significant racial differences in CVD susceptibility,” the researchers note. Male sex, meanwhile, was linked to congestive heart failure.

The determinants of health are starting early in life, even in the womb. Jean-Philippe Empana

The team has created an online app that uses patients’ test results for lipid and blood pressure levels, collected over years, to estimate their personal risk of incident CVD. This tool enables their models to “make the risk prediction calculations simple and practical in any setting, including in an individual physician’s office, by simply entering the severity of each of the risk factors at various points in time,” they say.

In the longer term, Domanski et al urge, “Controlled clinical trials are needed to assess the utility of optimizing risk factors in early adulthood or sooner to reduce cumulative exposure.”

Empana, whose research has long focused on prevention, said that at first his work’s emphasis was on the adult population, then turned to older patients. “But at the end of this journey, [we decided] we should go back to where everything starts, meaning early childhood,” he said, adding that he, too, hopes that the methods applied here can be applied to a younger population than CARDIA’s. “The determinants of health are starting early in life, even in the womb.”

One project to keep an eye on, he noted, is the European Union-funded LongITools, a research program that’s studying the interplay between environmental exposure, socioeconomic and psychosocial factors, lifestyle, and biology and their effects on chronic CV and metabolic diseases.

For the idea of cumulative exposure to be useful, however, Empana stressed it’s important that patients’ risk factor measurements are recorded not just once, but repeatedly by their cardiologist or general practitioner. To ensure this happens, there’s a “need to educate physicians, because it takes almost 10 years from one discovery to its implementation in the field,” he added.

Hector O. Ventura, MD, Andrew Elagizi, MD, Carl J. Lavie, MD (all from John Ochsner Heart and Vascular Institute, New Orleans, LA), in an accompanying editorial agree the study already has implications for today’s practice and “changes how we view and embark on primary prevention strategies going forward.”

“The results from the CARDIA cohort indicate the need to prevent and treat elevated triglycerides, with reduced intake of simple sugars, carbohydrates, and alcohol; preventing weight gain and eventual overweight/obesity; and increased levels of physical activity and exercise, which should start long before age 40,” they write.

“Likewise, reducing LDL cholesterol by reducing high intakes of cholesterol and saturated fats with a more Mediterranean-style diet should begin early in life, especially to reduce progression of atherosclerosis and coronary heart disease,” the editorialists urge. Lowering of blood pressure also should begin early, with lower sodium and alcohol intake, higher potassium and calcium intake, a healthy body weight, and physical activity.