New inflammatory predictors of cardiovascular events and the role of Mendelian randomizations

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on epidemiology, prevention, and healthcare policies contains the co-publication ‘COP27 Climate Change Conference: urgent action needed for Africa and the world’.1 The 2022 report of the Intergovernmental Panel on Climate Change paints a dark picture of the future of life on earth, characterized by ecosystem collapse, species extinction, and climate hazards such as heatwaves and floods. These are all linked to physical and mental health problems, with direct and indirect consequences of increased morbidity and mortality. To avoid these catastrophic health effects across all regions of the globe, there is broad agreement—as 231 health journals argued together in 2021—that the rise in global temperature must be limited to <1.5°C compared with pre-industrial levels. Large-scale genome-wide association studies conducted over the last decade have uncovered numerous genetic variants associated with cardiometabolic traits and risk factors. In a State of the Art Review article entitled ‘Mendelian randomization for cardiovascular diseases: principles and applications’, Susanna Larsson from Uppsala University in Sweden, and colleagues note that these discoveries have enabled the Mendelian randomization (MR) design, which uses genetic variation as a natural experiment to improve causal inferences from observational data.2 By analogy with the random assignment of treatment in randomized controlled trials, the random segregation of genetic alleles when DNA is transmitted from parents to offspring at gamete formation is expected to reduce confounding in genetic associations.3–7 MR analyses make a set of assumptions that must hold for valid results. Provided that the assumptions are well justified for the genetic variants that are employed as instrumental variables, MR studies can inform on whether or not a putative risk factor is likely to have a causal effect on the disease. MR has been increasingly applied over recent years to predict the efficacy and safety of existing and novel drugs targeting cardiovascular risk factors and to explore the repurposing potential of available drugs. This review article describes the principles of the MR design and some applications in cardiovascular epidemiology. In a State of the Art Review article entitled ‘Potassium intake: the Cinderella electrolyte’, Martin O’Donnell from the University of Galway in Ireland, and colleagues point out that dietary guidelines recommend intake targets for some essential minerals, based on observational and experimental evidence relating mineral intake levels to health outcomes.8 For prevention of cardiovascular disease, reducing sodium intake and increasing potassium intake are the principal tools.9–14 While reducing sodium intake has received the greatest public health priority, emerging evidence suggests that increasing potassium intake may be a more important target for cardiovascular prevention. Increased potassium intake reduces blood pressure and mitigates the hypertensive effects of excess sodium intake, and the recent large Phase III SSaSS trial reported that increasing potassium intake (and reducing sodium intake) in populations with low potassium intake and high sodium intake, through salt substitution (25% KCl, 75% NaCl), reduces the risk of stroke in patients at increased cardiovascular risk. As key sources of potassium intake include fruit, vegetables, nuts, and legumes, higher potassium intake may be associated with healthy dietary patterns. The current review makes the case that increasing potassium intake might represent a more advantageous dietary strategy for prevention of cardiovascular disease. Future research should focus on addressing the independent effect of potassium supplementation in populations with low or moderate potassium intake, and determine effective strategies to increase potassium intake from diet. Chronic inflammation and autoimmunity contribute to cardiovascular disease.15–18 Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. In a Clinical Research article entitled ‘Autoantibodies against the chemokine receptor 3 predict cardiovascular risk’, Felix Müller from the University Medical Center of the Johannes Gutenberg-University Mainz in Germany, and colleagues note that the role of anti-CXCR3 aAbs for cardiovascular risk and disease is unclear.19 Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in the population-based Gutenberg Health Study. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcomes. Additionally, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(−/−) mice for pre-clinical validation. The analysis sample included 4195 individuals (48% female, mean age 55 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional cardiovascular risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima–media thickness, left ventricular mass, and N-terminal probrain natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) 1.25, P = .029], driven by excess cardiac mortality (HR 2.51, P = .014). A trend towards a higher risk for major adverse cardiac events (HR 1.42, P = .05) along with increased risk of incident heart failure (HR per standard deviation increase of anti-CXCR3 aAbs: 1.26, P = .03) may contribute to increased mortality. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine–cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(−/−) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared with non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model (Figure 1). The schematic overview of the study including description of the analysis sample, cross-sectional analyses, and data on clinical outcome, expressed by hazard ratios derived from Cox regression analysis with corresponding 95% confidence intervals and P-values, as well as experimental data on anti-CXCR3 autoantibodies and murine atherosclerosis. aAbs, autoantibodies; ApoE, apolipoprotein E; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; CVRF, cardiovascular risk factors; CXCR3, CXC-motif-chemokine receptor 3; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MACE, major adverse cardiac events (comprising coronary artery disease, myocardial infarction, and cardiac death); ME, membrane extract; NT-proBNP, N-terminal probrain natriuretic peptide; pct, percentile; SD, standard deviation; WTD, western-type diet.19 The authors conclude that in individuals free of autoimmune disease, anti-CXCR3 aAbs were related to cardiovascular end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis. The manuscript is accompanied by an Editorial by Wai Hong Wilson Tang from the Cleveland Clinic in Ohio, USA.20 Tang highlights that while Muller et al. provide excellent and promising data supporting the link between anti-CXCR3 aAb generation and adverse long-term cardiovascular consequences, the complex interpretations of such autoimmune processes underscore the challenge of navigating their therapeutic potential. Indeed, unravelling the intricate relationship between aAbs against CXCR3 (or other immune pathways) and cardiovascular health holds the promise of unveiling novel mechanistic insights that can inform potentially new therapeutic avenues, albeit necessitating judicious considerations to strike the balance between benefit and risk. Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. In a Clinical Research article entitled ‘Neutrophil counts and cardiovascular disease’, Jiao Luo from the Copenhagen University Hospital-Rigshospitalet in Denmark, and colleagues investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches.21 Observational analyses were conducted in the Copenhagen General Population Study. Genetic studies were firstly performed using one-sample MR with individual-level data from the UK Biobank; secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium. Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. Observational analyses showed associations between neutrophil counts and risks of all outcomes. In the UK Biobank, odds ratios per 1 – SD higher genetically predicted neutrophil counts were 1.15 for ischaemic heart disease, 1.22 for myocardial infarction, and 1.19 for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 for ischaemic heart disease and 1.11 for myocardial infarction. Multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes. Luo et al. conclude that observational and genetically determined high blood neutrophil counts are a causal risk factor for atherosclerotic cardiovascular diseases. The contribution is accompanied by an Editorial by Oliver Soehnlein from the University of Münster in Germany and Yvonne Döring from the University of Bern in Switzerland.22 The authors conclude that the findings from Luo et al. have the potential to influence recommendations regarding inflammation and cardiovascular monitoring. Since determining blood neutrophil counts is a straightforward laboratory test, it is suggested that evaluating neutrophil counts could be added to standard practice in cardiovascular disease assessment. Evidence on the link between sleep patterns and cardiovascular disease in the community essentially relies on studies that investigated one single sleep pattern at one point in time. In the Clinical Research article entitled ‘Healthy sleep score changes and incident cardiovascular disease in European prospective community-based cohorts’, Aboubakari Nambiema from the Université Paris Cité in France and colleagues examined the joint effect of five sleep patterns at two time points with incident cardiovascular disease events.23 A healthy sleep score (HSS; range 0–5) combining five sleep patterns (early chronotype, sleep duration of 7–8 h/day, never/rarely insomnia, no sleep apnoea, and no excessive daytime sleepiness) was calculated at baseline and follow-up using data from two prospective studies. The study sample included >11 000 participants free of cardiovascular disease aged 53–64 years (45% women). A total of 499 first cardiovascular disease events occurred during a median follow-up of 8.9 years. In multivariate Cox analysis, the risk of cardiovascular disease decreased by 18% (HR 0.82) per one-point increment in the HSS. A total of 262 first cardiovascular disease events occurred after the second follow-up; after adjusting for baseline HSS and covariates, the risk of cardiovascular disease decreased by 16% (HR 0.84) per unit of increment of the follow-up HSS. Nambiema et al. conclude that higher HSS and improvement in HSS over time are associated with a lower risk of cardiovascular disease and stroke in the community. The contribution is accompanied by an Editorial by Dominik Linz and Sevasti-Maria Chaldoupi from the Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht in the Netherlands.24 The authors conclude that one remaining challenge in addition to the development of new technology and validation of algorithms is the implementation of these new approaches in clinical workflows. A virtual management pathway may allow remote sleep assessment and fast implementation of new future longitudinal sleep tracking approaches, which is the subject of ongoing research projects. Until then, it appears that working towards a high level of HSS and maintaining a high HSS may be the best advice a clinician can provide in this regard. In a Clinical Research contribution entitled ‘Acquired risk factors and incident atrial fibrillation according to age and genetic predisposition’, Ningjian Wang from the Shanghai JiaoTong University School of Medicine in China, and colleagues remind us that atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Investigations of risk factor profiles for AF according to age and genetic risk groups are essential to promote individualized strategies for the prevention and control of AF.25 A total of ∼410 000 participants (mean age, 56 years; 46% men) free of AF at baseline and with complete information about risk factors were included from the UK Biobank cohort. The HR and population-attributable risk (PAR) percentages of incident AF associated with 23 risk factors were examined, comprising three social factors, seven health behaviours, six cardiometabolic factors, six clinical comorbidities, and the genetic risk score (GRS), across three age groups (40–49, 50–59, and 60–69 years) and three genetic risk groups (low, moderate, and high GRS). After a follow-up of 5 027 587 person-years, 23 847 participants developed AF. Most cardiometabolic factors and clinical comorbidities showed a significant interaction with age, whereby the associations were generally strengthened in younger groups (Pinteraction < .002). However, only low LDL cholesterol, renal dysfunction, and cardiovascular disease showed a significant interaction with genetic risk, and the associations with these factors were stronger in lower genetic risk groups (Pinteraction < .002). Cardiometabolic factors consistently accounted for the largest number of incident AF cases across all age groups (PAR 36.2%–38.9%) and genetic risk groups (34.0%–41.9%), with hypertension and overweight/obesity being the two leading modifiable factors. Health behaviours (PAR 11.5% vs. 8.7%) and genetic risk factors (19.1% vs. 14.3%) contributed to more AF cases in the 40–49 years group than in the 60–69 years group, while the contribution of clinical comorbidities remained relatively stable across different age groups. The AF risk attributable to overall cardiometabolic factors (PAR 41.9% in the low genetic risk group and 34.0% in the high genetic risk group) and clinical comorbidities (24.7% and 15.9%) decreased with increasing genetic risk. The impact of social factors on AF was relatively low across the groups by age and genetic risk (Figure 2). Age-specific and genetic predisposition-specific associations of risk factor profiles with atrial fibrillation (AF). Population-attributable risk percentages of AF risk factors were presented for different age and genetic risk population groups.25 Wang et al. conclude that this study provides comprehensive information about age- and genetic predisposition-related risk factor profiles for AF in a cohort of UK adults. Prioritizing risk factors according to age and genetic risk stratifications may help to achieve precise and efficient prevention of AF. The contribution is accompanied by an Editorial by Adrian Elliott and Melissa Middeldorp from the University of Adelaide in Australia, and Emelia Benjamin from the Boston University Chobanian and Avedisian School of Medicine in Massachusetts, USA.26 The authors reinforce the notion that this work strengthens the demand for population-wide initiatives that address modifiable factors promoting the development of AF, particularly hypertension and obesity. As with the secondary prevention of AF, which benefits from weight loss and aggressive risk factor reduction, the primary prevention of AF demands the prioritization of those factors most responsible for its development. The issue continues with a Rapid Communications article entitled ‘Changes in physical activity and incident cardiovascular events in cancer survivors’ by Hyeok-Hee Lee from Yonsei University College of Medicine in Korea, and colleagues.27 Lee et al. utilized a nationwide, single-provider database of the Korean National Health Insurance Service, which covers the entire Korean population, to identify 515 261 adults aged ≥20 newly diagnosed with cancer. Physical activity was assessed using a modified International Physical Activity Questionnaire. The primary outcome was a cardiovascular disease event, defined as a composite of first hospitalization for myocardial infarction, first hospitalization for stroke, or cardiovascular death by 31 December 2019. Over a median follow-up of 4.4 years from the index date, 1874 new cardiovascular disease events occurred. Both pre- and post-diagnosis physical activities were inversely associated with cardiovascular disease risk, with the association being stronger for post-diagnosis physical acivity. Each increasing category of post-diagnosis physical activity was significantly associated with a lower cardiovascular disease risk in every pre-diagnosis physical activity category. In an exploratory continuous analysis, an inverse dose–response relationship was observed between physical activity change and cardiovascular disease risk. The authors conclude that an increase in physical activity after a cancer diagnosis is associated with a reduced cardiovascular disease risk, whereas a decrease in physical activity is associated with a higher cardiovascular disease risk. In a Viewpoint article entitled ‘Long COVID and its cardiovascular implications: a call to action’, Ziyad Al-Aly from the VA Saint Louis Health Care System in Saint Louis, MO, USA indicate that long COVID represents the constellation of post-acute and long-term health effects of severe acute respiratory syndrome coronavirus infection which can affect nearly every organ including the cardiovascular system.28 Long COVID can affect people across race, ethnicity, sex, gender, and age groups. While the risk of long COVID is highest among those who had severe acute COVID-19, the risk is non-trivial among people with mild COVID-19. It is estimated that at least 65 million people worldwide are impacted by long COVID. Work to deepen our understanding of the biology and epidemiology of long COVID, how to best prevent it and treat it, and how to optimize care for the people affected by its long-term sequelae must be prioritized. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Early identification of oesophageal lesions after atrial fibrillation ablation to prevent atrio-oesophageal fistula’, Mauricio Scanavacca, Esteban Rivarola, and Cristiano Pisani from the University of São Paulo Medical School in Brazil and colleagues comment on the recent publication ‘A worldwide survey on incidence, management, and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: the POTTER-AF study’ by Roland Richard Tilz from the University Hospital Schleswig-Holstein in Germany.29,30 Tilz et al. respond in a separate comment.31 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, the to and Martin for help with of this