Chest pain triage: do genetics have a role?

Over the past few decades, the advent of ultrasensitive troponin has changed the scope of chest pain triage.1,2 The assay is so sensitive that virtually no acute coronary syndrome (ACS) can falsely be ruled out by a negative dosage.3 However, this excellent predictive value is mechanically compensated by a deep fall in specificity and the positive predictive value. As a result, more patients are likely to be incorrectly diagnosed with ACS.4 The challenge is now to select efficiently the patients who will require hospitalisation, aggressive antithrombotic and invasive therapy, and to rule out or to readdress the patients with elevated troponin due to non-coronary disease. In that respect, instead of making clinical evaluation obsolete, the improvement of troponin detection gave it even more critical importance. The better the pre-test probability, the easier the interpretation. Although risk scores for chest pain assessment usually include traditional cardiovascular risk factors, the added value of a family history of coronary artery disease (CAD) in diagnosing ACSs among patients with chest pain has been questioned.5,6 In the present issue of the European Heart Journal: Acute Cardiovascular Care, Wahrenberg et al. present a retrospective analysis from patients who presented with chest pain between 1 January 2013 and 31 December 2016. The data were crossed-linked with a nationwide registry, including the Swedish Multi-Generation Register. This extensive observational database gathers information on millions of people in Sweden and their biological parents since 1962. A family history of CAD was defined as a history of myocardial infarction or coronary revascularisation in a first-degree relative and a history of early CAD if the coronary events were before the age of 55 years in male and 65 years in female relatives. The outcomes were, at 30 days, ACS for patients admitted in-hospital and ACS or mortality for patients discharged. A multivariable model was constructed, and analysis was stratified by age (<65 and ⩾65 years), gender and initial levels of troponin (<5 ng/L, 5–14 ng/L and >14 ng/L). A total of 28,188 patients with analysable data were identified. The authors found an association between a family history of CAD and the outcome at 30 days (odds ratio (OR) 1.40, 95% confidence interval (CI) 1.40–1.57), especially in patients younger than 65 years (OR 1.62, 95% CI 1.35–1.95). In patients with a history of early ACS, the association was even more potent (OR 1.62, 95% CI 1.35–1.94), especially in patients younger than 65 years (OR 2.00, 95% CI 1.58–2.52) or with a negative initial value of troponin (OR 4.41, 95% CI 1.98–9.82). The retrospective observational data suggest that a family history of CAD and early CAD is valuable information in the identification of patients with ACS. The retrospective nature of the analysis and the amount of missing parental data are certainly limitations. But the main value of this analysis lies in the size of the dataset, as this appears to be the largest study of its kind. The Swedish Multi-Generation Register is a dedicated database for the investigation of the transmission of disease, ensuring the reliability of the information pertaining to family history.7 Of note, a previous meta-analysis of seven studies on the subject only gathered 8717 patients.6 The association between a family history of premature CAD and myocardial infarction is well known.8,9 Studies have identified that the risk of CAD can be transmitted by genetic or lifestyle factors, and often by both.10 The genetic determinism of CAD has been widely studied.10,–12 First, some rare mutations linked with familial dyslipidemia have been recognised for driving this genetic risk.12,13 But recent whole-genome studies have identified about 60 common genetic loci associated with CAD.14,15 When these variants are combined, the resulting polygenic score can be as much as 10 times more frequent than the single-allele mutation and is associated with a similar three to four-fold increased risk of early myocardial infarction.16 Whether these polygenic scores provide an additional benefit for the identification of patients at risk of ACS in the emergency department remains unknown. However, the strength of the association between early CAD in a relative and ACS in young patients suggests that it could probably be the case. Despite the mounting evidence for the importance of the genetic predisposition to CAD,17 genetic risk scores are notably underused, possibly because of the assumption that inherited genetic risk cannot be overcome. However, the adoption of a healthy lifestyle and aggressive treatment of associated risk factors can largely mitigate this risk.18 In the future, the widespread use of genetic screening for CAD may allow improved triage of chest pain and, more importantly, personalised management of patients with CAD.