Breath of Life: Heart Disease Link to Developmental Hypoxia

Abstract

Heart disease remains one of the greatest killers. In addition to genetics and traditional lifestyle risk factors, we now understand that adverse conditions during pregnancy can also increase susceptibility to cardiovascular disease in the offspring. Therefore, the mechanisms by which this occurs and possible preventative therapies are of significant contemporary interest to the cardiovascular community. A common suboptimal pregnancy condition is a sustained reduction in fetal oxygenation. Chronic fetal hypoxia results from any pregnancy with increased placental vascular resistance, such as in preeclampsia, placental infection, or maternal obesity. Chronic fetal hypoxia may also arise during pregnancy at high altitude or because of maternal respiratory disease. This article reviews the short- and long-term effects of hypoxia on the fetal cardiovascular system, and the importance of chronic fetal hypoxia in triggering a developmental origin of future heart disease in the adult progeny. The work summarizes evidence derived from human studies as well as from rodent, avian, and ovine models. There is a focus on the discovery of the molecular link between prenatal hypoxia, oxidative stress, and increased cardiovascular risk in adult offspring. Discussion of mitochondria-targeted antioxidant therapy offers potential targets for clinical intervention in human pregnancy complicated by chronic fetal hypoxia.

Keywords: fetus; hypoxia; mitochondria; oxidative stress.

Figure 1.

Biological programming and age. Laws of nature predict that the younger we are, the greater the impact the environment has on us. This environmental impact has its maximum expression during embryonic or fetal life, and it diminishes progressively as we grow older. Equally important is that the opportunity for correction follows a similar trajectory, being greatest in early life and diminishing progressively as we grow older. Therefore, in medicine and public health today, there is a growing change in practice away from treatment, when we can do comparatively little, toward prevention, when we can do comparatively a lot. Clearly, there is no better form of preventative medicine than bringing this concept right back along the developmental trajectory, when the window of opportunity for correction is greatest, and try to halt the development of disease at its very onset, by bringing “preventative medicine back into the womb.”

Figure 2.

Cardiovascular defense to acute hypoxia. Values are mean±SEM for the change from baseline in perfusion pressure (arteriovenous difference), heart rate, carotid and femoral arterial blood flow, carotid vascular conductance (flow/pressure) and femoral vascular resistance (pressure/flow) during a 1-h period of acute hypoxia (box) in 14 intact (blue circles) and 12 carotid chemoreceptor denervated (red circles) fetal sheep in late gestation. The Darcy law of flow, which is the hydraulic equivalent of the Ohm law of electricity, was formulated in 1856 after his study of water flowing through gravel beds of the fountains of Dijon: flow in the steady state is linearly proportional to the pressure difference between 2 points and inversely proportional to the resistance across them. Vascular conductance and resistance can be calculated by applying the Darcy law to the circulation: blood flow is proportional to the arteriovenous pressure difference and inversely proportional to vascular resistance. Carotid chemoreceptor denervation attenuates the increase in fetal perfusion pressure, abolishes the fetal bradycardia, and delays the fall in femoral blood flow and the increase in femoral vascular resistance without affecting the increase in carotid blood flow or vascular conductance in response to acute hypoxia. *P<0.05, intact vs carotid chemoreceptor denervated by ANOVA. Redrawn from Giussani et al with permission. Copyright ©1993 The Physiological Society.

Figure 3.

Physiology underlying the fetal cardiovascular defense to acute hypoxia. Activation of a carotid chemoreflex by hypoxic blood triggers a fall in heart rate and vasoconstriction in the peripheral circulation in the fetus. The fall in heart rate is vagally mediated and the peripheral vasoconstriction is initiated by activation of the sympathetic nerves. Vasoconstrictor hormones, such as catecholamines and vasopressin are then released into the fetal circulation to maintain the neurally-triggered vasoconstriction. The neuroendocrine vasoconstriction is then supplemented by a vascular oxidant tone, which is promoted by an increase in the ratio of free radicals, such as the superoxide anion (O2^•-) relative to nitric oxide (NO), both of which are increased in the fetus during periods of oxygen deprivation. The magnitude of the peripheral vasoconstrictor response to acute hypoxia in the late-gestation fetus therefore depends on the partial contributions of chemoreflex, endocrine, and local vascular redox responses. Redrawn from Giussani with permission. Copyright ©2016, The Physiological Society.

Figure 4.

The role of oxygen in the regulation of embryonic and fetal growth. Studies in Bolivia have revealed that babies born in the high-altitude city of La Paz (top, red bars; ≈3600 meters above sea level) have lower birth weight compared with babies born at the sea-level city of Santa Cruz (top, yellow bar). However, babies born from Andean mothers in La Paz (top, red hatched bar) show protection against this effect, being significantly heavier than babies born from European mothers in La Paz (top, red solid bar). These discoveries have been replicated and extended by studies in the chicken embryo. Incubation in La Paz of fertilized eggs laid by sea-level hens (bottom, red solid bar) led to a significant reduction in embryo weight by the end of the incubation period when compared with incubation in Santa Cruz of fertilized eggs laid by sea-level hens (bottom, yellow solid bar). Incubation at high altitude in La Paz of fertilized eggs laid by highland hens which had lived in La Paz for generational times (bottom, red hatched bar) produced embryos that were heavier compared with incubation in La Paz of fertilized eggs laid by sea-level hens (bottom, red solid bar). This finding confirms the protection against the effects of high-altitude hypoxia on fetal growth by prolonged highland-residence ancestry discovered in humans. Incubation of fertilized eggs laid by high-altitude hens at sea level in Santa Cruz (bottom, blue hatched bar) prevented the expected reduction in embryo weight. In fact, this group of embryos not only recovered their growth potential, but grew heavier when compared with embryos from eggs laid in Santa Cruz by sea-level hens (bottom, yellow solid bar). This is despite high-altitude eggs being substantially smaller than sea-level eggs. Last, incubation of fertilized eggs laid by sea-level hens at high altitude with oxygen supplementation at rates to equate to sea-level Pao₂ (bottom, yellow hatched bar) prevented the high altitude–induced reduction in embryo weight, confirming an isolated effect mediated by hypoxia. Values are mean±SEM. n numbers shown in brackets. Significant letters are significantly (P<0.05) different (ANOVA plus Tukey test). HAHA indicates high-altitude hens at high altitude; HASL, high-altitude hens at sea level; SLHA, seal-level hens at high altitude; SLHAO₂, sea-level hens at high altitude with oxygen supplementation at rates to equate sea-level Pao₂; and SLSL, sea-level hens at sea level. Data from Giussani et al^, with permission (Copyright ©2001, Springer Nature; Copyright ©2007, The Physiological Society) and Soria et al (Copyright ©2013, Springer Nature). Photos reprinted from Itani et al with permission.