Heart disease risk begins in the womb, according to a new study.

A new research study published in PLOS Biology suggests that mothers can pass on “heart toxic” traits to their children through epigenetic changes that occur in the womb. These are chemical changes that don’t alter the underlying genetic material passed from mother to offspring, but do change gene expression. In other words, you could have inherited a risk* for heart disease from your parents, based not on the genes you inherited from them but based on prenatal conditions that affected your oxygen supply as a fetus. (Various lifestyle and environmental factors can reduce oxygen supply to the placenta, such as smoking, for example.)

What does this all mean? It means that we can transmit and inherit, across generations, detrimental traits that arise from our own and our parents’ health behaviors and environmental conditions. That’s the bad news. The good is that we can also transmit and inherit protective traits in the same way. For example, based on new research published in PLOS Biology, mothers at risk for hypoxia (low oxygen supply) who receive prenatal antioxidant supplementation may help reduce heart disease risk in future generations.

*Don’t worry – own health behaviors also modify your own risk of heart disease, despite cardiotoxic traits your parents may have passed to you.

Heart model.
Heart model.

The Science of Prenatal Origins of Heart Disease Risk

Dino A. Giussani, a researcher in the Department of Physiology, Development and Neuroscience at the University of Cambridge, and researchers in his lab have been studying the prenatal origins of heart disease for over 20 years. Dino’s lab uses various animal models for their preclinical studies of how heart disease can originate in the womb. They recently conducted a study in sheep to determine how hypoxia, a common complication during pregnancy, can cause stress to the developing cardiovascular system in unborn lambs that predisposes them to heart disease later in life.

Hypoxia, a condition in which a fetus isn’t getting enough oxygen for normal growth, can result from a variety of pregnancy complications and lifestyle factors including maternal obesity, preeclampsia (a pregnancy complication characterized by high blood pressure), maternal smoking, gestational diabetes and infection. Anything that increases placental vascular resistance will reduce blood flow and perfusion of oxygen to the baby, resulting in what is called chronic fetal hypoxia.

“We are interested in heart disease, but with a twist,” Dino said. “We are particularly interested in the early origins of heart disease, or what we call a prenatal origin or a fetal origin.”

When you think about your risk for heart disease, you might wonder how your genes are interacting with your environment to put you at risk. Maybe you have heart disease in your family, or genetic factors that can interact with environmental risk factors such as smoking, obesity or a sedimentary life to put you at high risk.

Most people understand this genetic component and gene-environment interaction effect to chronic disease. But in the last 20 years or so, Dino says, we’ve discovered that there is a very early gene-environment interaction, even before birth, that can raise or lower our risk for chronic diseases like heart disease.

“The genetic makeup of an unborn baby can interact with adverse environmental conditions during pregnancy to set up a risk of cardiovascular disease,” Dino said. “This interaction may be very important in setting up an increased risk of cardiovascular disease under adverse conditions.”

We have quite a lot of evidence from studies in animal models as well as human studies that the gene-womb interaction can contribute to cardiovascular disease risk. For example, researchers have previously found that children of obese mothers are more prone to heart disease. Medical professionals first interpreted these findings as being attributable to genetic predispositions inherited by the children of obese parents, or the fact that parents often pass on their “bad” health behaviors to their children. But we are now finally understanding that the reality may be more complicated and related to epigenetic changes.

This understanding came on the heels of studies showing that children born to once obese mothers who had received bariatric surgery were completely healthy, with no elevated risk of cardiovascular disease. However, children in the same family born pre-bariatric surgery did have elevated risk of heart disease.

“Babies of obese mothers were found to have signs of cardiovascular and cardiac dysfunction,” Dino said. “This suggested to me that there was something in the early [womb] environment that was modifying the development of the cardiovascular system.”

VERY Early Prevention

According to Dino, the laws of nature predict that the younger we are, the greater the impact our environment has upon us and our health. This makes sense because our physiology is incredibly plastic and malleable early in our life, particularly during embryonic development. This means that challenges we encounter as an embryo or fetus, during critical periods of development, may produce damage that is visible decades later.

Applying this theory to our risk of heart disease may seem fatalistic and depressing. But Dino approaches it with a more positive outlook. The theory also presents an incredible opportunity to improve the healthspan of generations to come.

“I work with people who truly believe that a paradigm shift is coming in the fields of medicine and public health, a shift in focus from treatment, when we can do very little, to prevention, when we can do comparatively a lot,” Dino said. “Even more, we believe there’s no better form of preventative medicine than tracking disease back to its origins in early development in order to halt disease before it starts.”

Bringing the Mountains to Cambridge

“Our aim was to identify whether pregnancies complicated by simulated chronic hypoxia could program heart disease in adult offspring, and if so, by what mechanisms.” – Dino A. Giussani

In order to produce human-relevant results, Dino’s group set out to answer their research questions using a sheep model. They choose this model because sheep typically only give birth to one or two babies at a time and because lambs are born relatively mature, similar to human babies but unlike mouse and rat offspring for example. In other words, the temporal development of the cardiovascular system in the prenatal environment is remarkably similar between humans and sheep.

“Our work shows that a component of programmed risk of heart disease later in life can be homed down to a reduction in oxygenation to the fetus,” Dino said. “We demonstrated this by placing pregnant sheep in a simulated high-altitude environment. At high altitude you have low barometric pressure, which reduces the partial pressure of all gases in air including that of oxygen, so you get hypobaric hypoxia.”

Studying the complications of high-altitude pregnancies is nothing new. In fact, fetal growth restriction is a well-known issue that affects both animal and human pregnancies in naturally high-altitude environments. There’s also a higher risk of cardiovascular disease in high-altitude countries. But such findings have largely been correlative with many confounding factors muddying the waters. (In other words, it’s very difficult to prove cause and effect, especially in human studies of heart disease.) High-altitude countries also tend to be impoverished, and babies born in these regions don’t just experience lower oxygen conditions before birth – these conditions persist after birth as well.

Dino’s study is the first to experimentally investigate the impacts of prenatal hypobaric hypoxia (chronic low oxygen conditions before birth) in a human-relevant animal model. Lambs in the study were born to mothers who experienced hypobaric hypoxia within a barometric chamber. However, after birth these lambs were raised in normal pastures around Cambridge, at normal atmospheric pressures.

Dino and his colleagues found that lambs that developed under hypoxic conditions in the womb were smaller when they were born than were lambs that developed under normal conditions. Both sets of lambs grew well once outside of the womb and were indistinguishable until they were about 9 months old. After 9 months, however, the lambs that developed under hypoxic conditions started to look a lot older within their cardiovascular systems.

Sheep are a good model for studying human-relevant pregnancy.
Sheep are a good model for studying human-relevant pregnancy.

“They had significantly increased blood pressure and stiffer blood vessels, hallmarks of and risk factors for cardiovascular disease,” Dino said. “These results were quite impactful. The magnitude of hypertension that we measured in these young adult offspring [born to mothers living in hypoxic conditions] was about twice the magnitude of hypertension that is typically induced by smoking. We also found evidence of fibrosis in the walls of the aorta,  vasoconstriction and thickening of major arteries in the offspring of sheep living in hypoxic conditions during pregnancy.”

But why did lambs born to sheep living in low oxygen pressure conditions develop high blood pressure and thick, dysfunctional arteries? The answer likely lies in epigenetic programming, or changes that can affect gene expression and tissue function without changing the genetic material itself. Lambs born to sheep living in hypoxic environments developed dysfunctional endothelial cells in their blood vessels while still in the womb. These changes persisted into adulthood. One of the underlying mechanisms for these changes appears to be oxidative stress in the fetus.

It’s All About Stress

“Free radicals such as the superoxide anion like to pair up with nitric oxide in the developing cardiovascular system,” Dino said. “Nitric oxide is normally a powerful vasodilator [widens blood vessels to allow more blood to travel through]. Oxidative stress decreases the bioavailability of nitric oxide and thus increases vascular resistance in the placenta and causes an aberrant development of the circulatory system.”

Oxidative stress doesn’t just decrease the bioavailability of nitric oxide – it can promote a range of cellular stress signaling and inflammatory pathways such as the unfolded protein response. Oxidative stress in the prenatal environment may also reduce the expression of cardioprotective genes such as PRKCE. This gene produces a protein called protein kinase C epsilon (PKC epsilon) that protects the heart from injury. Oxidative stress triggers DNA methylation (an often long-lasting epigenetic change) that can silence the expression of particular genes such as PRKCE.

“This means that offspring of hypoxic pregnancies might grow up with less of a cardioprotective reserve,” Dino said. “When superimposed on a challenge later in life such as a sedentary lifestyle, an obesogenic diet or simply aging, this lack of cardioprotection gets expressed as disease.”

Dino’s group is currently testing this theory by investigating the impacts of hypoxic pregnancies on not just first but also second-generation offspring.

Antioxidants to the Rescue

If oxidative stress is responsible for causing the downstream impacts of prenatal hypoxia, including heart disease risk in offspring, there is one obvious potential treatment: Antioxidants.

Dino’s team tested their oxidative stress theory in sheep using Vitamin C. If Vitamin C could soak up the free radical products of hypoxic oxidative stress in the prenatal environment, it could possibly prevent the epigenetic or gene expression changes leading to cardiovascular dysfunction in the adult offspring. Dino’s team chose to study Vitamin C because of its human relevance, as a substance commonly supplemented in the human diet.

They found that Vitamin C not only acted as a classic antioxidant, soaking up free radicals that would otherwise inactivate nitric oxide, but it also activated other antioxidant pathways in the developing lamb fetus. Vitamin C modified the maternal hemoglobin (an oxygen-carrying compound) to help it more efficiently transfer oxygen from the mother sheep to its fetus.

“We find that Vitamin C may be beneficial in pregnancies complicated by hypoxia in many ways; it increases placenta blood flow and enables more efficient delivery of oxygen to the developing fetus. This can help prevent fetal growth restriction, which is a major killer,” Dino said. “The magnitude of the protective effect of Vitamin C in our study surprised us.”

There are limitations in terms of treating complicated human pregnancies with high concentrations of Vitamin C, however. Previous human clinical trials have found Vitamin C to be ineffective in improving the negative impacts of fetal hypoxia, but Dino believes this is because the Vitamin C doses used in these studies were not high enough. It turns out that Vitamin C is a relatively weak antioxidant. On the other hand, extremely high doses of Vitamin C can cause kidney stone and other side effects.

“We consider our study to be a proof of principle that antioxidants can be useful, but Vitamin C may not be the antioxidant of choice for clinical translation,” Dino said. “We are trying to identify other antioxidants that may be useful at doses appropriate for human clinical translation.”

Other antioxidants that Dino and colleagues are studying include melatonin.

“The real message of this work is that we need to change our philosophy, from thinking of how we are going to reduce the prevalence of heart disease in adults to how we are going to prevent heart disease in future generations,” Dino said.

Mothers Get a Bad Rap

Based on Dino’s study, you might fault obese or smoking mothers for passing “heart toxic” traits to their children. But this is far from the whole truth – mothers actually have an incredible power to also pass protective traits to their children. Mothers who experience hypoxic pregnancies may even pass on cardioprotective traits to future generations through genetic material located within their mitochondria. Mitochondria are cellular energy powerhouses that you inherit from your mother but typically not your father.

Under conditions of stress, mitochondria may respond and adapt to this stress by developing traits that can benefit future generations. This mitochondrial adaptation to stress is one of the underlying reasons that exercise, and even intermittent fasting, help to prevent chronic diseases of aging.

Let’s Not Burn the Toast

The overall message of Dino’s study is that when it comes to heart disease risk, an ounce of prevention may be worth a pound of treatment, even down to the prenatal environment. In the same way that we can’t unburn toast, antioxidant supplementation and other therapies applied later in life for those who have inherited cardiotoxic traits from their parents cannot currently reverse cardiovascular dysfunction. However, preventing oxidative stress in the prenatal environment may lead to future generations that have much lower risks for heart disease in the first place.

Of course, early and even late life healthy behaviors including exercise and an anti-inflammatory diets are key to delaying and preventing the onset of heart disease on an individual level.