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Filippo Crea, The risk of ‘hidden’ sodium and of low vitamin D levels, European Heart Journal, Volume 43, Issue 18, 7 May 2022, Pages 1687–1690, https://doi.org/10.1093/eurheartj/ehac203
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With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
For the podcast associated with this article, please visit https://dbpia.nl.go.kr/eurheartj/pages/Podcasts.
This Focus Issue on epidemiology and prevention contains the Clinical Research article ‘A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study’ by Xiangfeng Lu from the Chinese Academy of Medical Sciences and Peking Union Medical College, and colleagues.1 While the prevention of coronary artery disease (CAD) is currently guided by the severity of risk factors,2,3 a better knowledge of the individual susceptibility to risk factors might substantially improve risk stratification. The authors aimed to construct a polygenic risk score (PRS) for CAD and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. Using a meta-analytic approach and a large amount of results from genome-wide association studies (GWAS) for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. Individuals with a high PRS (the highest 20%) had about a three-fold higher risk of CAD than the lowest 20% [hazard ratio (HR) 2.91], with the lifetime risk of 15.9% and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in the C-statistic (1%) and net reclassification improvement (3.5%). Lu et al. observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk stratum (Figure 1).

The polygenic risk has a great potential to refine coronary artery disease (CAD) risk stratification within each guideline-recommended clinical risk category and inform clinical decision-making for primary prevention. Among individuals at intermediate clinical risk whose guideline-based recommendations are unclear, those with a high polygenic risk should be recommended to initiate lifestyle and pharmacological intervention. Individuals with both a high polygenic risk and a high clinical risk urgently need intensive prevention. Combination of polygenic risk and clinical risk could promote precision prevention of CAD and reduce the disease burden, particularly considering inadequate primary prevention or statins and antihypertensive treatment in China.1
The authors conclude that the PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk stratum, demonstrating a great potential to identify high-risk individuals for targeted interventions. The contribution is accompanied by an Editorial by Maryam Kavousi from the University Medical Center Rotterdam in the Netherlands, and Heribert Schunkert from the Deutsches Herzzentrum München in Germany.4 The authors conclude that meta-analyses of large CAD GWAS have allowed the identification of many common genetic variants with very small effects. In young people, in the absence of later life risk factors, a PRS might be the best tool for cardiovascular risk stratification, but indications of preventive treatment early in life still need a better definition. Likewise, when cardiovascular risk is high or a person has already suffered from an event, the CAD PRS offers little information for stratification of medical treatment. On the other hand, among middle-aged subjects with mild risk factors, a CAD PRS yields additional clinical benefit in ∼10% of those being tested. If a person decides to have a genetic test, such arrays also cover genes implicated in a variety of other common conditions including cancers of the prostate, breast, and colon, and thus may yield predictive information beyond CAD risk. This complex situation should be explained to the patient asking for genotyping.
The risk of recurrent atherosclerotic events is clinically relevant.5 The 10-year risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events in patients with established ASCVD can be estimated with the Secondary Manifestations of ARTerial disease (SMART) risk score and may help refine clinical management. In a Clinical Research article entitled ‘Estimation of recurrent atherosclerotic cardiovascular event risk in patients with established cardiovascular disease: the updated SMART2 algorithm’, Steven H.J. Hageman from the University Medical Center Utrecht in the Netherlands, and colleagues note that in order to broaden generalizability across regions, they updated the existing tool (SMART2 risk score), recalibrated it with regional incidence rates, and assessed its performance in external populations.6 Individuals with CAD, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms were included from the Utrecht Cardiovascular Cohort-SMART cohort (n = 8355) to derive a 10-year risk prediction model for recurrent ASCVD events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular mortality) using a Fine and Gray competing risk-adjusted model. The model was recalibrated to four regions across Europe, and to Asia (excluding Japan), Japan, Australia, North America, and Latin America using contemporary cohort data from each target region. External validation used data from seven cohorts and included 369 044 subjects. C-statistics ranged from 0.605 to 0.772. The clinical utility of the model was demonstrated across a range of clinically relevant treatment thresholds for intensified treatment options.
The authors conclude that the SMART2 risk score provides an updated, validated tool for the prediction of recurrent ASCVD events in patients with established ASCVD across European and non-European populations. The use of this tool could allow for a more personalized approach to secondary prevention based upon quantitative rather than qualitative estimates of residual risk. The contribution is accompanied by an Editorial by Naveed Sattar and Paul Welsh from the University of Glasgow, UK.7 The authors indicate that by providing a framework and an ‘objective’ identification of patients at highest residual risk, and who stand to benefit most from aggressive risk management, SMART2 provides an important basis for future clinical decisions. Whether this tool can be used to improve adherence or could be further improved over time with better quality data or statistical methods, or cost-effectively expanded to include new risk factors for prediction gains, requires ongoing work. These limitations will doubtless be worked on in the future so that secondary prevention risk scores will continue to mature over time. For now, however, most cardiovascular specialists would do well to familiarize themselves with SMART2 as its use has the potential to improve care.
Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs).8 Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD risk, a non-linear effect cannot be excluded. In a Clinical Research article entitled ‘Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk’, Ang Zhou from the South Australian Health and Medical Research Institute in Adelaide, Australia, and colleagues sought to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with CVD risk.9 The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac imaging-derived phenotypes were included as secondary outcomes. Zhou and colleagues also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was an L-shaped association between genetically predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at ∼50 nmol/L. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) BP. Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (Figure 2).

Non-linear Mendelian randomization analyses support an L-shaped association of serum 25-hydroxyvitamin D concentration with CVD risk, suggesting that with respect to cardiovascular health the benefits of improving vitamin D status are the strongest for those within the deficiency range.8
The authors conclude that the burden of CVD could be reduced by population-wide correction of low vitamin D status. This manuscript is accompanied by an Editorial by Stephen Burgess from the University of Cambridge and Kevin Vernooy from Imperial College in the UK.8 The authors conclude that this investigation strengthens the evidence base for vitamin D supplementation as a beneficial intervention to reduce CVD risk in individuals with low vitamin D levels.
Previous studies have found high sodium intake to be associated with increased risks of CVD and all-cause mortality, although the relationship is complex.10–13 In a Clinical Research article entitled ‘Sodium-containing acetaminophen and cardiovascular outcomes in individuals with and without hypertension’, Chao Zeng from Harvard Medical School in Boston, MA, USA, and colleagues aimed to compare the risks of incident CVD and all-cause mortality among initiators of sodium-containing acetaminophen with the risk of initiators of non-sodium-containing formulations of the same drug according to the history of hypertension.14 Using The Health Improvement Network, the authors conducted two cohort studies among individuals with and without hypertension. The outcomes were incident CVD (myocardial infarction, stroke, and heart failure) and all-cause mortality. Among individuals with hypertension, the average weighted HR to develop CVD was 1.59 in initiators of sodium-containing acetaminophen vs. initiators of non-sodium-containing formulations. Among individuals without hypertension, the average weighted HR was 1.45. Results of specific CVD outcomes and all-cause mortality were similar.
The authors conclude that the initiation of sodium-containing acetaminophen is associated with increased risks of CVD and all-cause mortality among individuals with or without hypertension. These findings suggest that individuals should avoid unnecessary excessive sodium intake through sodium-containing acetaminophen use. The contribution is accompanied by an Editorial by Aletta E. Schutte from the University of New South Wales in Sydney, Australia and Bruce Neal from the Imperial College London in the UK.15 The authors note that widespread use of effervescent medication in the general population, and the enormous doses of sodium that can be consumed inadvertently by unsuspecting consumers, requires urgent action. Particularly concerning is the observation in some surveys that up to 94% of uses of fizzy medications are self-medication using over-the-counter preparations. There is an immediate need for protection of consumers against these risks. The most plausible and effective strategy is likely to be the mandatory labelling of all medications containing significant quantities of sodium with a front-of-pack warning label. Information programmes that raise public and practitioner awareness of the hidden sodium in medications, and educate about the need to avoid effervescent, dispersible, and soluble medicines in all but essential circumstance should also be considered.
The prevalence of chronic limb-threatening ischaemia (CLTI) is increasing, and available data often derive from cohorts with various selection criteria. In a Clinical Research article entitled ‘Sex-related differences in treatment and outcome of chronic limb-threatening ischaemia: a real-world cohort’, Lena Makowski from the University Hospital Muenster, Germany, and colleagues included CLTI patients and studied sex-related differences in their risk profile, vascular procedures, and long-term outcome.16 The authors analysed 199 953 unselected patients of the largest public health insurance system in Germany (AOK: local healthcare funds), hospitalized between 2010 and 2017 for a main diagnosis of CLTI. Female CLTI patients were older (median 81 vs. 73 years in males; P < 0.001) and more often diagnosed with hypertension, atrial fibrillation, chronic heart failure, and chronic kidney disease. Male patients suffered more frequently from diabetes mellitus, dyslipidaemia, smoking, cerebrovascular disease, and chronic coronary syndrome (all P < 0.001). Within hospitalized CLTI patients, females represented the minority (43% vs. 57%; P < 0.001) and, during the index hospitalization, women underwent revascularization procedures less frequently (61 vs. 65%; both P < 0.001). Moreover, women less frequently received guideline-recommended drugs such as statins (35 vs. 43%) and antithrombotic therapy (48 vs. 53%; both P < 0.001). Interestingly, after including age and comorbidities in a Cox regression analysis, female sex was associated with increased overall survival and amputation-free survival (both P < 0.001).
The authors conclude that female patients with CLTI were older, underwent vascular procedures less often, and received guideline-recommended medication less frequently. Nevertheless, female sex was independently associated with better overall survival and amputation-free survival during follow-up. The manuscript is accompanied by an Editorial by David Kingsmore and Julie Brittenden from the University of Glasgow, UK.17 The authors note that separating out the facts of biological difference from treatment variation must remain a priority that is reflected in sex-based stratification in trials and thus treatment guidelines. This study does not aid this understanding, but further emphasizes that an aim of negating differences between sexes may therefore be simply detrimental to both if we do not understand the appropriateness to either.
Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.
The editors hope that readers of this issue of the European Heart Journal will find it of interest.