These findings show differences between men and women in the triggering mechanisms of the disease and open the door to the study of specific therapeutic targets that make personalized patient treatment possible.
 

Cardiovascular diseases are the main cause of mortality and disability worldwide and represent an increasing health expenditure due to the aging of the population. Specifically, severe degenerative or calcified aortic stenosis (CAD) is the most common form of heart valve disease, a narrowing that occurs in the valve and leads to its calcification and degeneration. Currently, there is no effective pharmacological treatment that alters the evolution of the disease, with aortic valve replacement surgery being the only way to improve symptoms and long-term survival.

The prevalence of CAD is estimated at around to 3.4% in patients over 75 years of age, and it increases noticeably with age. It is estimated that in Spain there are about 145,469 people with CAD only accounting for the group over 75 years old1.
With the aim of slowing down the evolution of the disease and avoid surgery, in 2016 the Navarra Biomedical Research Centre (Navarrabiomed) and the University Hospital of Navarra (HUN) began a study on mechanisms involved in the development of this pathology. The results of this research, published in Frontiers in Cardiovascular Medicine, conclude that the triggering factors of aortic valve disease are different in men and women and, therefore, open the door to personalized medicine through the study of sex-specific therapeutic targets that enable individualized patient treatment.

The authors of the work are Natalia López-Andrés, Principal Investigator of the Translational Cardiology Unit of Navarrabiomed; Lara Matilla, Mattie Garaikoetxea, Amaya Fernández-Celis, Alicia Gainza y Eva Jover, all researchers in this unit. On behalf of the HUN, the team includes Vanessa Arrieta, Amaia García-Peña and Adela Navarro, cardiologists of the Heart Area; Virginia Álvarez, Head of the Heart Area, and Rafael Sádaba, cardiac surgeon.  

Research with a gender dimension

Clinical studies prior to this one show that the valves of men and women are different, but then the causes and implications of those differences were not well known. For a same degree of severity of CAD, women have a lower degree of calcification and greater valve fibrosis than men. In addition, CAD is associated with other important diseases that aggravate the patient's prognosis, such as diabetes and chronic renal failure.
This information was decisive for considering the gender dimension in the project: “we confirmed the results that had been found in clinical trials analysing valves donated by patients undergoing surgery at the HUN whereby there was an increased calcified tissue in men compared to women”, explains Dr. López-Andrés, Principal Investigator of the Translational Cardiology Unit of Navarrabiomed, who stresses on the generosity of these people for donating their tissues for research and thus perhaps preventing other people from undergoing an intervention in the future. “We believe that if the aortic valves at the final stage, before surgery, seem different at a clinical level, perhaps they could also be different at a molecular and cellular level. And, indeed, they are.”

Study characteristics

The research has been developed between 2016 and 2021 financed by the Carlos III Health Institute in two Calls of the Health Research Fund (FIS) and has characterized for the first time sex-related cellular and molecular mechanisms of markers that cause valve damage and that lead to the onset of disease and valve replacement.
For this, a total of 238 patients with severe aortic stenosis referred to the HUN for surgical replacement of the aortic valve from June 2013 to October 2020 were recruited. Of those 238, 39.1% were women, an expected fact since women suffer less from aortic stenosis than men and also at an older age: specifically, the average is 77 years compared to 73 years in men. According to Dr. Natalia López-Andrés, "the analyses performed also confirm that the aortic valves of the women were in a better condition than those of the men.”

Personalized medicine: the patient-tailored approach

The research results suggest that the mechanisms involved in aortic disease are different in men and women, by providing new molecular and cellular knowledge for the development of sex-specific strategies aimed at differential disease-provoking processes that contribute to aortic stenosis.
The aortic valve tissue of women presented less calcification, inflammation, oxidative stress, apoptosis and improved remodelling of the extracellular matrix. Therefore, this is radically different from the tissue of men, which is much more calcified. These findings suggest that pharmacological treatments designed to slow the progression of the disease should be different. “If the valves are different, it is because the mechanisms that have triggered the disease are also different. If we intend to treat this disease at the origin so that the valve does not deteriorate and need not be replaced, the pharmacology to be used will also be different. We cannot look for a single treatment for everyone, because it may not be effective,” emphasizes Dr. López-Andrés. The results of this study have been presented in the Congress of the Heart Valve Society held in Miami between March 2 and 5, 2022. In addition, the research conducted by Dr. Natalia López-Andrés has been awarded best report in the categories of "Basic science” and "Aortic valve" at this congress for the progress made by research in aortic stenosis.
The next phase, which has already received financing by the Department of Health of the Government of Navarra, will focus on the search for pharmacological treatments that can block the onset of these differences and the development and progression of two very important associated diseases such as diabetes and chronic kidney damage, opening up new possibilities for the therapeutic management of these patients.
Overall, the research results show the importance of considering the gender dimension as a potential experimental variable to be taken into account when studying new therapeutic approaches that open the door to the development of more effective, specific and individualized treatments for patients.
 
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  1 Source: European Society of Cardiology