Hypertension increases heart damage due to oncological drug

A team of Carlos III National Center for Cardiovascular Research (CNIC) has discovered how high blood pressure increases susceptibility to heart damage caused by anthracyclines, one of the most used cancer treatments for decades.

Anthracyclines have been one of the most used chemotherapy groups in oncology for more than 30 years. Their effectiveness against numerous solid and hematological tumors has meant that, even today, they continue to be considered first-line drugs, administered alone or in combination with other therapies. Among the cancers where anthracyclines continue to be the cornerstone of treatment are lymphomas, leukemias, sarcomas, gastric cancer and various subtypes of breast cancer.

Despite their therapeutic value, anthracyclines have a adverse effect known: they can cause cardiotoxicity, a type of heart damage that appears in a small percentage of people treated. This damage can progress to chronic heart failure, affecting approximately 5% of cancer survivors who receive these therapies.

Epidemiological studies have shown that those who have previous cardiovascular conditions, such as high blood pressure, diabetes, obesity or hypercholesterolemia, have a significantly higher risk of developing cardiotoxicity after receiving anthracyclines. Of all these conditions, high blood pressure is the one that has most consistently been associated with increased risk.

“We have known for years that high blood pressure clearly increases the risk of cardiotoxicity due to anthracyclines, but we were completely unaware of the underlying mechanism. This lack of understanding prevented the development of specific prevention strategies,” he explained. Borja Ibanezscientific director of the CNIC, cardiologist at the Jiménez Díaz Foundation, group leader at the CIBERCV, and principal investigator of this study.

perfect storm

In this new work, carried out at the CNIC in an experimental model highly similar to that of humans, the team induced a chronic pressure overload on the heart –equivalent to high blood pressure– for months before administering an anthracycline regimen comparable to that used in clinical oncology.

The results, published in European Heart Journalwere conclusive: subjects with previous pressure overload developed heart failure much more frequently than those exposed only to anthracyclines. Besides, They had higher mortality and worse general evolutionfaithfully reproducing human epidemiological observations.

“We have been able to observe that neither hypertension nor anthracyclines are sufficient on their own to generate severe heart damage. But when they coincide, they trigger a perfect storm. What is truly novel is that we identified a previous, silent metabolic vulnerability, which becomes evident only when the heart suffers the added stress of anthracyclines,” he reported. Carlos Galan-Arriolafirst author of the study and researcher at the Translational Laboratory for Cardiovascular Imaging and Therapy.

At a mechanistic level, the team demonstrated that chronic hypertension produces a latent energy fragility: alters the heart’s ability to adapt to metabolic demands, reduces energy flexibility, and generates a state of “limited reserve”, even compensated by apparently normal mitochondrial function.

When anthracyclines are administered – which directly damage the mitochondria – this compensation is broken, precipitating functional deterioration of the heart. In a final phase, the study explored a possible preventive strategy through the use of mavacamtena selective myosin inhibitor used in hypertrophic cardiomyopathy. In in vitro experiments, mavacamten managed to prevent heart damage induced by anthracyclines under pressure overload conditions.

“If these results are confirmed in clinical studies, we could be facing the first therapy specifically aimed at preventing this serious complication in individuals with hypertension,” he points out. Ibanez.

Cardio-oncology and preventive cardiology

The study has direct implications for cardio-oncology and preventive cardiology. According to the researchers, it has been carried out using highly translational techniques such as advanced MRI, MR spectroscopy, PET and molecular analyses, allowing rapid transfer to the clinical setting.

“This work represents a fundamental advance: identifying vulnerability before clinical damage is the type of anticipatory medicine towards which we must move. Personalized prevention based on mechanisms is the future of modern cardiology”, pointed out the director general of the CNIC, Valentin Fuster.

The research has been funded by the European Commission (ERC); the Ministry of Science and Innovation of Spain; the la Caixa Foundation and the Community of Madrid through the Madrid Network of Nanomedicine in Molecular Imaging.