In this expert commentary, Professor Alaide Chieffo, principal investigator of the Italian Gender, Diversity and Inclusion – Acute Coronary Syndromes study, provides insight into how it is redefining the understanding and management of acute coronary syndrome in women, paving the way for truly personalised cardiovascular care.

For decades, acute coronary syndrome (ACS) has been studied and managed from a predominantly male-centric perspective, leaving substantial gaps in the understanding of how the disease presents in women.

Despite cardiovascular disease being the leading cause of death among women, they remain significantly under-represented in cardiovascular clinical trials and registries, which has led to an incomplete characterisation of sex-specific pathophysiology, risk factors and outcomes, ultimately contributing to disparities in diagnosis, treatment and prognosis.

Complex risk profile of ACS in women

Women present with a unique ACS risk profile that extends beyond traditional cardiovascular factors. Sex-specific factors, including pregnancy-related complications, menopause, hormonal therapies and conditions such as polycystic ovary syndrome, play a significant role but are rarely captured in standard registries.

In addition, autoimmune diseases and reproductive history further contribute to cardiovascular risk yet remain insufficiently studied.

At the same time, women have a higher prevalence of conditions such as myocardial infarction with non-obstructive coronary arteries (MINOCA), which continues to be poorly understood and often underdiagnosed.

Equally important are the social and behavioural determinants of health, which disproportionately affect women, such as low socioeconomic status, reduced health literacy, unemployment and domestic violence.

These dimensions are often overlooked in traditional cardiovascular research, despite their clear impact on outcomes. As a result, women frequently experience delays in diagnosis and treatment, which may translate into worse short- and long-term prognosis.

Addressing critical knowledge gaps through GEDI-ACS

The EU-funded Gender, Diversity and Inclusion – Acute Coronary Syndromes (GEDI-ACS) registry was specifically designed to address these critical gaps by adopting a comprehensive and multidimensional approach.

Integrating clinical, biological and social data within a dedicated female cohort, the registry aims to provide a more accurate and holistic understanding of ACS in women.

This approach is intended to improve diagnostic accuracy, enable personalised treatment strategies, and ultimately promote more equitable and effective cardiovascular care tailored to women.

GEDI-ACS represents a fundamental departure from traditional ACS registries, which historically have enrolled predominantly male populations and treated women as a subgroup.

This leads to a limited ability to identify and understand sex-specific mechanisms, often masking important differences in disease presentation, progression and response to treatment.

GEDI-ACS enables a much deeper and more accurate characterisation of female-specific disease patterns.

The decision to focus solely on women was not only methodological but also strategic, allowing researchers to generate robust hypotheses without the confounding influence of male-dominated datasets. This exclusive focus enhances the ability to identify distinct phenotypes, risk profiles and predictive factors that are unique to women.

By combining biological and social determinants within a single framework, GEDI-ACS moves beyond traditional registry design and adopts a more holistic investigative model. This innovative approach not only improves the depth and quality of data but also lays the foundation for developing targeted prevention and treatment strategies.

Ultimately, it represents a shift toward precision medicine tailored specifically to women, addressing a long-standing gap in cardiovascular research.

Integrating multiomics and machine learning in ACS

What further distinguishes GEDI-ACS is its multidimensional architecture. Alongside standard clinical and imaging data, the registry incorporates biochemical, molecular and psychosocial variables, providing a comprehensive dataset that reflects the complexity of ACS in women.

It also integrates advanced multiomics profiling and machine learning with detailed assessments of health literacy, socioeconomic status and quality of life.

The integrative approach is one of the most innovative and promising aspects of GEDI-ACS. By simultaneously analysing genomics, transcriptomics, proteomics and metabolomics, the study captures multiple layers of biological information.

When integrated, these data can reveal complex interactions and previously unrecognised pathways involved in ACS, providing an unprecedented opportunity to explore the molecular landscape of ACS in women in a highly detailed and systematic manner.

Machine learning plays a crucial role in making sense of these high-dimensional datasets. Traditional analytical methods are often insufficient to capture the complexity of multiomics data, whereas machine learning algorithms can detect subtle patterns, correlations and predictive signatures that would otherwise remain hidden.

Through this approach, GEDI-ACS aims to identify molecular fingerprints associated with disease severity, recovery trajectories and specific ACS subtypes.

A key objective is to uncover distinct biological phenotypes within ACS, moving beyond conventional classifications based solely on clinical presentation. This may include identifying clusters of patients with shared molecular characteristics who may respond differently to specific therapies. Additionally, the study may shed light on mechanisms such as microvascular dysfunction or reperfusion injury, which are particularly relevant in women.

Ultimately, this integrated strategy is expected to support the development of predictive biomarkers and enable a more personalised, data-driven approach to cardiovascular care.

Social determinants and biological factors of ACS

Understanding ACS in women requires investigation beyond biological mechanisms to consider the broader context in which health and disease occur. Social determinants play a critical role in shaping health behaviours, accessing care and influencing clinical outcomes. However, these factors have historically been underrepresented in cardiovascular research and are rarely included in clinical registries.

GEDI-ACS recognises that a woman’s ability to interpret symptoms, seek timely medical attention, adhere to prescribed therapies and implement lifestyle changes is deeply influenced by the social environment.

Therefore, the registry systematically incorporates validated measures of health literacy, such as the Brief Health Literacy Screening and the Single Item Literacy Screener, alongside detailed assessments of socioeconomic status, including income, education, employment and housing conditions.

Evidence suggests that a substantial proportion of women with ACS have low health literacy and socioeconomic vulnerability, which can lead to delayed diagnosis, difficulties navigating healthcare systems and reduced treatment adherence. Psychological factors such as anxiety and depression further complicate recovery and long-term management.

By integrating these variables with clinical and biological data, GEDI-ACS adopts a truly holistic approach to patient assessment. This allows researchers to explore how social disadvantage interacts with biological vulnerability, influencing both disease presentation and outcomes.

Importantly, it also enables the identification of barriers to effective care and supports the development of targeted interventions, such as educational programmes and support strategies, to improve equity and overall quality of care.

Clarifying variability in symptom presentation

A key challenge in managing ACS in women is the variability in how their symptoms present. Chest pain is common, but women tend to undervalue their symptoms and may, in some cases, show atypical signs such as dyspnoea, fatigue, nausea or back pain more frequently than men. These differences can cause both patients and healthcare providers to misinterpret symptoms, leading to diagnosis and treatment delays.

GEDI-ACS addresses this issue by systematically collecting detailed information on symptom characteristics, distinguishing between typical and atypical presentations. In addition, the registry captures key timing variables across the entire care pathway, including the interval from symptom onset to first medical contact, the time to diagnostic evaluation and the time to coronary angiography.

By linking these data to clinical outcomes, the study aims to quantify the extent to which under-recognition of chest pain as cardiac pain and atypical presentations contribute to diagnostic delays and to determine their impact on both short- and long-term prognosis. Furthermore, the integration of psychosocial data may help explain why delays occur more frequently in women.

This comprehensive analysis will provide robust evidence to inform clinical practice and support the development of strategies to improve early recognition of ACS in women. Ultimately, it may help reduce the long-standing diagnostic gap and ensure more timely and accurate management.

Addressing MINOCA via GEDI-ACS

MINOCA is one of the most complex and least understood presentations of ACS, particularly in women, in whom it is significantly more prevalent. Despite its frequency, MINOCA encompasses a heterogeneous group of conditions with diverse underlying mechanisms, and distinguishing between these mechanisms in clinical practice is often difficult, making diagnosis and management particularly challenging.

Potential causes include coronary vasospasm, microvascular dysfunction, spontaneous coronary artery dissection, coronary embolism and Takotsubo syndrome.

GEDI-ACS aims to address this complexity through a comprehensive and structured diagnostic approach, in line with current guidelines. This includes the use of intracoronary imaging techniques, physiological assessments and provocative testing, as well as non-invasive modalities such as cardiac magnetic resonance imaging and coronary computed tomography when appropriate.

By combining clinical, imaging and molecular data, the study seeks to achieve a more precise classification of MINOCA, moving beyond a single diagnostic label toward a spectrum of biologically defined subtypes.

This improved characterisation is essential for guiding therapeutic decisions and avoiding inappropriate management.

Ultimately, the goal is to develop tailored diagnostic and treatment strategies that reflect the underlying pathophysiology, thereby improving outcomes in this challenging patient population.

Looking to the future with GEDI-ACS

Multidisciplinary collaboration is one of GEDI-ACS’s greatest strengths. This collaborative approach ensures that all relevant dimensions of the disease are captured. The involvement of multiple centres across Italy further enhances the robustness and generalisability of the findings, while fostering a shared research framework that can be applied across different healthcare settings.

Importantly, this integration of disciplines strengthens the translational potential of the study, increasing the likelihood that its findings will be effectively translated into clinical practice and public health policy.

If successful, GEDI-ACS has the potential to fundamentally reshape the way ACS in women is understood and managed over the next decade.

At the biological level, the discovery of molecular signatures and genetic predispositions may allow for earlier diagnosis and more targeted therapeutic interventions, particularly for complex conditions such as MINOCA, where current strategies remain inadequate.

At the clinical level, a better understanding of symptom recognition and variability, as well as diagnostic delays, could improve recognition of ACS in women, reducing disparities in care and improving outcomes. Insights into social determinants may also support targeted interventions to improve health literacy, treatment adherence, and access to care.

In the longer term, the findings from GEDI-ACS could contribute to the development of clinical strategies that incorporate sex-specific differences in cardiovascular disease to a greater extent, while also serving as a model for more inclusive and gender-sensitive research in cardiovascular medicine.

Ultimately, GEDI-ACS represents a paradigm shift toward a more holistic, equitable and data-driven model of care – one that has the potential to significantly improve survival, quality of life, and overall cardiovascular health in women worldwide.

Note

The GEDI-ACS research was funded by the European Union – Next Generation EU – National Recovery and Resilience Plan (PNRR) M6C2. Investment 2.1: Enhancement and strengthening of biomedical research in the NHS. Project Code: PNRR-MCNT2-2023-12377431 – C43C24000290007.

Author

Professor Alaide Chieffo MD FESC
Professor of cardiology at Vita Salute San Raffaele University, and research director of interventional cardiology, IRCCS San Raffaele Hospital, Milan, Italy