When the heart is put under stress during exercise, it is considered healthy. Yet stress due to high blood pressure is bad for the heart. Why? And is this always the case?
Why is Heart Stress Bad?
Researchers of the German Center for Cardiovascular Research (DZHK) and of Heidelberg University Hospital obtained new findings which indicate that a previously undetected heart signal pathway can cause or protects from heart failure. But whether it causes or protects from heart failure depends on the type of stress.
The researchers examined the heart signal pathway that has histone deacetylase 4 (HDAC4), an epigenetic switch. Epigenetics is the study of gene expression and investigates how environmental influences regulate genes. The chain reaction within the pathway can be increased or decreased depending on the stress. The researchers identified this, because at the end of the signal pathway, a fragment of HDAC4 is more prevalent in healthy mouse hearts after physiological stress, such as exercise. Yet the mouse hearts that were subjected to pathological stress, such as permanent stress due to increased blood pressure, did not generate this fragment.
Does HDAC4 Combat Heart Stress?
The researchers conducted a second study to investigate the effect of HDAC4 more closely and produced genetically modified mice that are not able to generate the HDAC4 fragment. The animals were subjected to physiological stress (intense exercise) and, surprisingly, exercise no longer had the healthy effect on them. Instead, they developed temporary heart failure after the intensive workout which led to a distinctly reduced performance and temporary heart failure.
“We found temporary cardiac fatigue,” says DZHK Professor Johannes Backs of Heidelberg University Hospital, Director of the newly established Department of Molecular Cardiology and Epigenetics (Internal Medicine VIII) since 2015. The syndrome is also found in patients, but is underestimated according to Dr. Lorenz Lehmann, the lead author of the study from the Department of Cardiology (Internal Medicine VIII) at Heidelberg University Hospital. Lehmann states that this is because it can only be detected if the cardiac function is examined during or in the minutes immediately after exercise.
Rest During Exercise Makes a Difference
The HDAC4 fragment can thus protect the heart from damage caused by temporary physiological stress. Yet why not also from stress caused by high blood pressure or other kinds of morbid stress? “The breaks make all the difference,” says Backs. During exercise, there are frequently rest periods for the heart. An enzyme called protein kinase A recovers during these periods and then ensures that the healthy heart pathway with HDAC4 is used instead of the one without.
During permanent stress caused by severe high blood pressure, the signals in the heart cells trigger a different pathway. The protein kinase A’s activity eventually wanes under the permanent stress and the HDAC4 fragment disappears. This means that the cell doesn’t have the rest breaks to recover from the stress. This cell’s metabolism then uses more sugar than fat for producing energy. This increased use of sugar causes excess sugar residues that can attach to proteins. Some of these proteins altered by the sugar residue eventually inhibit the metabolism and the cell’s function, which leads to a deficiency in the heart’s pumping power.
“These findings are novel and change the way we think about how a myocardial cell can fail. We were able to demonstrate that there is a link from epigenetics via the metabolism through to contractility, i.e., through to cardiac function,” says Backs. The researchers also demonstrate that a gene therapy with the HDAC4 fragment protects against this pumping power deficiency in mice. This entirely new therapeutic principle is now being intensively investigated.
Extreme Endurance Sports Can Damage the Heart
Even from an evolutionary perspective, the mechanism seems plausible to the researchers. Our ancestors, the gatherers and hunters, often had to be physically active for many hours to find food and bring it home. The newly discovered signal pathway could have protected the heart in this case. The results also explain why extreme endurance sports without rest periods can damage the heart. “We all intuitively know that breaks are important. Perhaps we have now found the molecular causes for this,” states Backs.
That prolonged stress on the heart leads to changes in the signal pathway may also be the cause of the broken heart syndrome (Takotsubo cardiomyopathy), in which temporary heart failure is brought on, in particular, by emotional stress. The researchers led by Johannes Backs are currently putting this phenomenon under the microscope.
