Faculty of Medicine

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Diet and sex inequities in ischemic heart disease mortality across Europe: findings from the global burden of disease study
(Oxford University Press (OUP), 2025-11)
Bugiardini, Raffaele
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Rahaman, Tania
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Manfrini, Olivia
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Maas, Angela
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Bergami, Maria
Aims Sex differences in ischemic heart disease (IHD) mortality remain underexplored from a population-level case fatality perspective. This study evaluates sex-specific disparities in IHD mortality and risk-attributable causes across 27 European Union (EU) countries using Global Burden of Disease (GBD) 2021 data. Methods and results We calculated age-standardized mortality rates (ASMRs), prevalence rates (ASPRs), and mortality-to-prevalence ratios (MPRs) as a proxy for population-level case fatality. To quantify mortality attributable to specific exposures among individuals with IHD, we derived a case fatality index (CFI) by normalizing risk-attributable ASMRs to ASPRs. Z-scores quantified the magnitude and statistical significance of sex differences in MPRs and CFIs (|Z| ≥ 1.96 = P < 0.05; |Z| ≥ 2.58 = P < 0.01). From 2011 to 2021, IHD ASMRs declined by 24.0% in men and 19.1% in women. In 2011, 12 countries showed significantly higher MPRs in women than men. By 2021, Austria (MPR 6.0% vs. 3.6%), Greece (9.4% vs. 5.3%), and Malta (9.3% vs. 4.2%) remained outliers, with Z-scores >2.58 (P < 0.01). CFIs showed that women in these countries faced 40 to 60% higher mortality burdens from hypertension, hyperglycemia, and poor dietary intake. Low intake of omega-3 fatty acids, fibers, vegetables, and nuts/seeds accounted for the largest dietary disparities. Conclusion Despite declining IHD mortality rates, Austria, Greece, and Malta continue to exhibit significant sex disparities, with women experiencing disproportionately higher case fatality. These disparities are largely driven by modifiable cardiometabolic and dietary risks, underscoring the need for sex-specific, regionally tailored prevention strategies.
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The Paradox of SMURF-less Outcomes and its Implication for Diabetes
(Oxford University Press (OUP), 2026-01-28)
Cenko, Edina
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Manfrini, Olivia
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Yoon, Jinsung
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Bergami, Maria
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Vasiljevic, Zorana
Individuals without standardized modifiable risk factors (SMuRF), which implicitly include those with diabetes, have been paradoxically reported to experience higher mortality following acute coronary syndromes (ACS). We aim to clarify the independent impact of diabetes on 30-day mortality after ACS and explore how grouping it with other SMuRF might obscure its true effect.
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Sex and gender differences in coronary pathophysiology and ischaemic heart disease
(Oxford University Press (OUP), 2026-01-23)
Manfrini, Olivia
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Tousoulis, Dimitris
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Antoniades, Charalambos
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Badimon, Lina
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Bugiardini, Raffaele
Ischaemic heart disease shows important differences between men and women, requiring an understanding of sex and gender dissimilarities to improve outcomes. This Scientific Statement provides an updated review of the current knowledge from risk factors to prognosis. It discusses the unequal impact of certain traditional risk factors between men and women, along with additional factors, such as hormonal changes and treatments (including those for transgender people and cancer), pregnancy-related complications, and autoimmune diseases, which contribute to the sex-specific risk profiles. Moreover, it outlines functional and structural sex differences in the pathophysiology (e.g. coronary atheroma plaques and burden, coronary dissection, vasospasm, and microvascular disease) with women being more prone to microvascular disease and endothelial dysfunction, while paradoxically experiencing less severe myocardial ischaemia at similar levels of coronary stenosis. The document further addresses the evaluation of diagnostic tools, which often have a male-centric bias, resulting in underdiagnosis in women who also tend to receive less guideline-recommended treatment. Additionally, women can have different responses and side effects to various preventive and therapeutic treatments, potentially contributing to the worse prognosis documented in acute coronary syndromes with obstructive coronary artery disease, particularly at a young age. Considering all these sex and gender differences and the low enrolment of women in randomized controlled trials, questions arise regarding the optimal treatment for women. Addressing sex differences requires conducting sex-specific research to close the knowledge gap. Overall, the Scientific Statement highlights all relevant sex- and gender-specific dissimilarities to advance clinical practice and identify directions for future research to improve guideline recommendations for equitable care.
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Changing clinical perspectives on sex and healthcare disparities in ischaemic heart disease
(Elsevier BV, 2025-09)
Maas, Angela
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Cenko, Edina
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Vaccarino, Viola
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Göttgens, Irene
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Bergami, Maria
Ischaemic heart disease (IHD) has historically been under-researched in women, leading to significant gaps in understanding sex-specific risk factors and outcomes. To address this issue, The Lancet Regional Health–Europe convened experts from a broad range of countries to evaluate sex-related cardiovascular inequalities and propose recommendations to address these disparities. Despite developing IHD a decade later than men, women experience higher mortality rates. Global Burden of Disease data highlight persistent sex differences in IHD mortality, with women showing higher mortality despite lower prevalence. Factors such as psychosocial stress, reproductive health, and physical inactivity disproportionately impact women's cardiovascular health, while caregiving responsibilities and delayed healthcare access further exacerbate these disparities. There is an urgent need to recognize chest pain symptoms in women and to reduce the time lag between symptom onset and hospital presentation. Addressing these gaps requires targeted public health interventions, expanded research, and improved clinical practices, emphasizing equitable healthcare access and greater inclusion of women in clinical trials. Tailoring treatment guidelines to account for sex differences in outcomes could significantly improve survival rates for women with IHD.
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Age and sex differences in the efficacy of early invasive strategy for non-ST-elevation acute coronary syndrome: A comparative analysis in stable patients
(Elsevier BV, 2025-06)
Cenko, Edina
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Bergami, Maria
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Yoon, Jinsung
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Vadalà, Giuseppe
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Objective: Previous works have struggled to clearly define sex-specific outcomes based on initial management in NSTE-ACS patients. We examined whether early revascularization (<24 h) versus conservative strategy impacts differently based on sex and age in stable NSTE-ACS patients upon hospital admission. Methods: We identified 8905 patients with diagnosis of non-ST elevation acute coronary syndromes (NSTE-ACS) in the ISACS-TC database. Patients with cardiac arrest, hemodynamic instability, and serious ventricular arrhythmias were excluded. The final cohort consisted of 7589 patients. The characteristics between groups were adjusted using inverse probability of treatment weighting models. Primary outcome measure was all-cause 30-day mortality. Risk ratios (RRs) with their 95 % CIs were employed. Results: Of the 7589 NSTE-ACS patients identified, 2450 (32.3 %) were women. The data show a notable reduction in mortality for the older women (aged 65 years and older) undergoing early invasive strategy compared to those receiving an initial conservative (3.0 % versus 5.1 %; RR: 0.57; 95 % CI: 0.32 - 0.99) Conversely, younger women did not exhibit a significant association between early invasive strategy and mortality reduction (2.0 % versus 0.9 %; RR: 2.27; 95 % CI: 0.73 - 7.04). For men, age stratification did not markedly alter the observed benefits of an early invasive strategy over a conservative approach in the overall population, with reduced death rates in both older (3.1 % versus 5.7 %; RR: 0.52; 95 % CI: 0.34 - 0.80) and younger age groups (0.8 % versus 1.7 %; RR: 0.46; 95 % CI: 0.22 - 0.94). These age and sex-specific mortality patterns did not significantly change within subgroups stratified by the presence of NSTEMI or a GRACE risk score>140. Conclusion: Early coronary revascularization is associated with improved 30-day survival in older men and women and younger men who present to the hospital in stable conditions after NSTE-ACS. It does not confer a survival advantage in young women. Further studies are needed to more accurately risk-stratify young women to guide treatment strategies.
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Early coronary revascularization among 'stable' patients with non-ST-segment elevation acute coronary syndromes: the role of diabetes and age
(Oxford Academic, 2024-12-14)
Fabin, Natalia
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Cenko, Edina
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Bergami, Maria
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Yoon, Jinsung
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Vadalà, Giuseppe
To investigate the impact of an early coronary revascularization (<24 h) compared with initial conservative strategy on clinical outcomes in diabetic patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) who are in stable condition at hospital admission.
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Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial
(Ovid Technologies (Wolters Kluwer Health), 2024-06)
Pracoń, Radosław
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Spertus, John A.
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Broderick, Samuel
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Bangalore, Sripal
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Rockhold, Frank W.
ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14–2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78–12.86] and 2.63 [95% CI, 1.51–4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23–3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34–2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46–0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS:Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease.
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Evaluating the Appropriate Use Criteria for Coronary Revascularization in Stable Ischemic Heart Disease Using Randomized Data From the ISCHEMIA Trial
(Ovid Technologies (Wolters Kluwer Health), 2025-03)
Slater, James
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Maron, David J.
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Jones, Philip G.
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Bangalore, Sripal
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Reynolds, Harmony R.
The appropriate use criteria for revascularization of stable ischemic heart disease have not been evaluated using randomized data. Using data from the randomized ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; July 2012 to January 2018, 37 countries), the health status benefits of an invasive strategy over a conservative one were examined within appropriate use criteria scenarios. METHODS:Among 1833 participants mapped to 36 appropriate use criteria scenarios, symptom status was assessed using the Seattle Angina Questionnaire-7 at 1 year for each scenario and for each of the 6 patient characteristics used to define the scenarios. Coronary anatomy and SYNTAX(Synergy between percutaneous coronary intervention with Taxus and cardiac surgery) scores were measured using coronary computed tomography angiography. Treatment effects are expressed as an odds ratio for a better health status outcome with an invasive versus conservative treatment strategy using Bayesian hierarchical proportional odds models. Differences in the primary clinical outcome were similarly examined. RESULTS:The mean age was 63 years, 81% were male, and 71% were White. Diabetes was present in 28% and multivessel disease in 51%. Most clinical scenarios favored invasive for better 1-year health status. The benefit of an invasive strategy on Seattle Angina Questionnaire angina frequency scores was reduced for asymptomatic patients (odds ratio [95% credible interval], 1.16 [0.66–1.71] versus 2.26 [1.75–2.80]), as well as for those on no antianginal medications. Diabetes, number of diseased vessels, proximal left anterior descending coronary artery location, and SYNTAX score did not effectively identify patients with better health status after invasive treatment, and minimal differences in clinical events were observed. CONCLUSIONS: Applying the randomization scheme from the ISCHEMIA trial to appropriate clinical scenarios revealed baseline symptoms and antianginal therapy to be the primary drivers of health status benefits from invasive management. Consideration should be given to reducing the patient characteristics collected to generate appropriateness ratings to improve the feasibility of future data collection.
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The no-reflow phenomenon in the young and in the elderly
(Elsevier BV, 2016-11-01)
Cenko, Edina
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Ricci, Beatrice
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Câlmâc, Lucian
Background The objectives of this study were to evaluate the incidence of no-reflow as independent predictor of adverse events and to assess whether baseline pre-procedural treatment options may affect clinical outcomes. Methods Data were derived from the ISACS-TC registry (NCT01218776) from October 2010 to January 2015. No-reflow was defined as post-PCI TIMI flow grades 0–1, in the absence of post-procedural significant (≥25%) residual stenosis, abrupt vessel closure, dissection, perforation, thrombus of the original target lesion, or epicardial spasm. The outcome measure was in-hospital mortality. Results No-reflow was identified in 128 of 5997 patients who have undergone PCI (2.1%). On multivariate analysis, patients with no-reflow were more likely to be older (OR: 1.20, 95% CI: 1.01–1.44), to have a history of hypercholesterolemia (OR: 1.95, 95% CI: 1.31–2.91) and to be admitted with a diagnosis of STEMI (OR: 2.96, 95% CI: 1.85–4.72). Angiographic characteristics associated with no-reflow phenomenon were: stenosis ≥50% of the right coronary artery, presence of multivessel disease and pre-procedural TIMI blood flow grades 0–1. No-reflow was highly predictive of in-hospital mortality (17.2% vs. 4.2%; adjusted OR: 4.60, 95% CI: 2.61–8.09). Administration of pre-procedural unfractioned heparin or 600mg clopidogrel loading dose was associated with less incidence of no-reflow (OR: 0.65, 95% CI: 0.43–0.99 and 0.61, 95% CI: 0.37–1.00, respectively). Aspirin, enoxaparin, and 300mg clopidogrel loading dose, did not significantly impact the occurrence of the no-reflow. Conclusions We found that pre-procedural administration of 600mg loading dose of clopidogrel and/or unfractioned heparin is associated with reduced incidence of no-reflow.
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Acute Coronary Syndrome: The Risk to Young Women
(Wiley-Blackwell, 2017-12-22)
Ricci, Beatrice
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Cenko, Edina
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Vasiljevic, Zorana
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Stankovic, Goran
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Background Although acute coronary syndrome (ACS) mainly occurs in patients >50 years, younger patients can be affected as well. We used an age cutoff of 45 years to investigate clinical characteristics and outcomes of “young” patients with ACS. Methods and Results Between October 2010 and April 2016, 14 931 patients with ACS were enrolled in the ISACS‐TC (International Survey of Acute Coronary Syndromes in Transitional Countries) registry. Of these patients, 1182 (8%) were aged ≤45 years (mean age, 40.3 years; 15.8% were women). The primary end point was 30‐day all‐cause mortality. Percentage diameter stenosis of ≤50% was defined as insignificant coronary disease. ST‐segment–elevation myocardial infarction was the most common clinical manifestation of ACS in the young cases (68% versus 59.6%). Young patients had a higher incidence of insignificant coronary artery disease (11.4% versus 10.1%) and lesser extent of significant disease (single vessel, 62.7% versus 46.6%). The incidence of 30‐day death was 1.3% versus 6.9% for the young and older patients, respectively. After correction for baseline and clinical differences, age ≤45 years was a predictor of survival in men (odds ratio, 0.24; 95% confidence interval, 0.10–0.58), but not in women (odds ratio, 1.35; 95% confidence interval, 0.50–3.62). This pattern of reversed risk among sexes held true after multivariable correction for in‐hospital medications and reperfusion therapy. Moreover, younger women had worse outcomes than men of a similar age (odds ratio, 6.03; 95% confidence interval, 2.07–17.53). Conclusion ACS at a young age is characterized by less severe coronary disease and high prevalence of ST‐segment–elevation myocardial infarction. Women have higher mortality than men. Young age is an independent predictor of lower 30‐day mortality in men, but not in women.

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