How Oxygen Hurts Our Hearts
By Adrienne Mueller, PhD
October 27, 2020
The Problem: Right Ventricular Failure
Congenital heart disease, a condition which approximately 1% of children in the US are born with, often causes a chamber of the heart called the right ventricle to fail. Currently, we do not understand the mechanism underlying this failure, which means we have a very hard time not only identifying which children will experience heart failure and when, but also treating it. The standard therapies we deploy for left heart failure—beta blockers, and ACE-inhibitors—do not work for right ventricular failure. We therefore need better therapies that target the underlying problem in these patients, which means we need a better understanding of the mechanisms causing our hearts’ right ventricles to fail.
Oxygen: Necessary but Harmful
Heart cells are extremely energy intensive. Every day, the heart uses oxygen to cycle up to 20 times its own weight of the energy-producing protein ATP. In order to generate the energy they need to contract, heart cells are packed with mitochondria: bundles of lipid membranes studded with oxygen-consuming ATP. However, oxygen is a reactive particle that can cause damage to cells. Because heart cells consume so much oxygen to produce energy, they are especially vulnerable to oxygen-induced stress (oxidative stress). First author HyunTae V. Hwang, PhD, and senior author Sushma Reddy, MD, of the Stanford Cardiovascular Institute therefore investigated how oxidative stress impacts heart cells.
In a paper recently published in Circulation, Hwang et al first showed that the heart cells of individuals with right ventricular failure do indeed exhibit oxidative stress, particularly of lipid membranes. When lipids are oxidated they create a product called 4HNE (4-Hydroxynonenal). Hwang et al next showed that there is more 4HNE being produced in patients with right ventricular failure and that mitochondria, which are extremely lipid-rich, are especially sensitive to 4HNE damage. In addition to mitochondrial damage, proteins that are important for the shape of our heart cells and their ability to contract were also damaged by 4HNE. In terms of a mechanism, this study suggests that when 4HNE reacts with mitochondrial proteins and damages their ability to consume oxygen, leading to reduced energy output of our heart cells and contributes to heart failure.
A Solution? Antioxidative Therapies
The remedy may seem obvious – reduce oxidative stress to heart cells. But, when the authors attempted to use a known antioxidative drug, Cardvedilol, to halt oxidative stress to heart cells, it had no effect. Encouragingly, however, even though Cardvedilol did not reverse existing mitochondrial damage, the authors did show that it helped prevent new 4HNE-related damage. Antioxidative therapies are therefore a promising avenue for preventing right ventricular failure in at-risk patients.
Hwang et al have shed light on an important new mechanism that helps explain right ventricular failure. Individuals with right ventricular failure have 4HNE-induced damage to heart cell mitochondria, which impairs energy generation by inhibiting the ability of those mitochondria to consume oxygen. New therapies that limit oxidative stress are therefore needed to help treat individuals with right ventricular failure. By improving energy generation, we can improve heart cell activity and survival, and have better functioning hearts.
Other Stanford Cardiovascular Institute-affiliated investigators who contributed to this work include Nefthi Sandeep, Sharon L. Paige, Sara Ranjbarvaziri, Dong-Qing Hu, Mingming Zhao, Ingrid S. Lan, Sean M. Wu, Giovanni Fajardo, and Daniel Bernstein.