Editor’s presentation

The 15th issue of the journal is particularly dedicated to cardiovascular risk prediction issues. Risk assessment is a major challenge in clinical practice.1 Several proteins are involved in the biological response following an acute ischaemic event and in the process of repair and remodelling. Therefore, it is no surprise that several studies have investigated the association between numerous biomarkers and prognosis, and two prospective studies are here presented. The first study evaluated the prognostic significance of the multiplex Proximity Extension Assay (PEA) proteomics chip (which provides a large-scale analysis of 92 biomarkers linked to cardiovascular disease).2 The PEA chip was applied to 847 patients with an acute myocardial infarction. GDF-15 and TRAIL-R2 resulted as the two most powerful biomarkers predicting all-cause long-term mortality. When combined with established risk factors and biomarkers, GDF-15 and TRAIL-R2 showed a discriminating accuracy of separating survivors from non-survivors with a cross-validation area under the receiver operating characteristic curve of 0.88. However, the PEA chip technique did not permit an absolute quantification of the target proteins, so translation into clinically relevant cut-off values is not possible. Also, in a second study, which was a population-based longitudinal experience of older individuals but free from previous cardiovascular events, GDF-15 and N-terminal pro-brain natriuretic peptide each provided prognostic capabilities extending beyond that of traditional cardiovascular risk factors and echocardiography.3 When used in combination, both biomarkers remained significantly associated with the outcome, but did not offer a significantly greater improvement in discriminative ability than that provided by each biomarker alone. Strengths of the study included the concurrent examination of multiple biomarkers, inclusion of detailed echocardiographic parameters, and an average follow-up interval exceeding eight years. However, these findings are to be considered hypothesis-generating and need confirmation in larger cohorts. Although sometimes externally and extensively validated, the original cardiovascular risk score models may fail in correctly estimation of the absolute cardiovascular disease (CVD) risk in single specific populations, such as aging4 or ethnic minority ones. The recalibrated 2008 Framingham model showed good performance on predicting five-year CVD risk in an Australian Indigenous population and was used to calculate the first risk chart based on empirical validation using long-term follow-up data from a remote Australian Indigenous population.5 In specific populations, instead of trying more CVD risk models, which were built based on other populations, it is important to generate/recalibrate a prediction tool based on local data. Differential association of exercise testing related parameters with cardio-metabolic risk factors, including diabetes, obesity, hypertension, as well as smoking, was investigated in the first large-scale study. The authors display numerous correlations between cardiovascular risk factors and exercise testing parameters that reflect inotropic and chronotropic response and functional capacity; these factors included blood pressure and heart-rate reaction during exercise and recovery, exercise duration and peak metabolic equivalents achieved. Patients in high-risk groups reveal different haemodynamic responses when undergoing treadmill stress testing, reflecting independent pathophysiological pathways, which may have significant prognostication value for future cardiovascular events.6 It is well known that the prognostic significance of stress testing extends beyond functional capacity, as underlined in a related commentary.7 Overall, studies have shown that there is a graded continuum of risk and additive prognostic effect with the increase in the number and different combinations of abnormal exercise testing parameters and heart-rate-related measures.8,9 The current study raises the hypothesis, but does not provide the underlying evidence, that differential haemodynamic responses during exercise testing reflect independent pathophysiological pathways. VO2peak is strongly related to walking capacity among heart failure patients with low and preserved ejection fraction.10 The walking speed maintained during a submaximal 1-km treadmill walk (1 k-TWT) has been demonstrated to be a valid and simple tool for VO2peak estimation, and is inversely related to survival, and hospitalization, in outpatients with CVD and preserved ejection fraction.11 The association between VO2peak estimated by the 1 k-TWT and all-cause mortality has been confirmed in men with middle-range ejection fraction, recently defined as a distinct clinical entity.12 These results may have practical implications in the context of transitioning from clinically based and supervised training programmes to fitness facilities or self-guided exercise programmes. The prognostic role of CHA2DS2-VASc was investigated in a Caucasian community population of 11,159 patients with arterial hypertension and sinus rhythm.13 After 37 months’ follow-up, an increasing CHA2DS2-VASc corresponded to a higher rate of thromboembolic events, and the predictive accuracy of CHA2DS2-VASc was similar in sinus rhythm and non-valvular atrial fibrillation patients for thromboembolic events, cardiovascular hospitalization and all-cause death. This finding is in line with those reported by other authors who demonstrated the prognostic role for adverse cardiovascular events and death in different cohorts of patients. These results might have relevant medical implications in light of the evidence that most embolic events recognized in clinical practice occur in patients in sinus rhythm. Although a low use of cardioprotective drug therapies among patients with a combination of coronary artery disease and diabetes,14 several large clinical trials have recently demonstrated improved cardiovascular outcomes with glucose-lowering medications in this population, all likely mediated via the pleiotropic, non-glycaemic effects of these agents. However, limited data are available to understand the proportion of patients potentially eligible for these trials, in real-world practice. Using clinical registries, it is here shown that the use of the studied medication class, in potentially eligible patients, was as low as within 6%, and when used, these agents were being targeted toward lower-risk populations that are less likely to benefit (in terms of absolute risk reduction).15 Again, this report should be at best considered hypothesis-generating and more robust confirmation is needed. Several investigations have confirmed the hypothesis that physical activity during leisure time is associated with a lower incidence of CAD and all-cause mortality. However, many of these studies assessed the level of physical activity only once.16 Here is presented a study which, based on a random sample of healthy participants examined at least twice between 1976 and 2003, showed an inverse dose–response relationship between persistent leisure time physical activity and both CAD and all-cause mortality. A substantial increase in physical activity was associated with a significant gain in longevity, whereas a decrease in physical activity was associated with even greater loss of longevity. The accompanied editorial17 observes that this is a confirmation that physical activity performed throughout life is associated with profound health benefits but also that high intensity physical activity that increases heart rate is probably superior to low intensity physical activity for overall health effects. However, the major public health challenge is getting people to increase physical activity in the first place, especially during leisure time, throughout life, which is a cost-effective strategy that must be promoted throughout the healthcare industry.18 Clinical registries play an important role in measuring healthcare delivery and supporting quality improvement for individuals with heart disease.19,20 A systematic review to identify cardiac rehabilitation registries internationally and characterize the nature of the data collected and their operation/organization is presented.21 It included cardiac rehabilitation registries in seven countries: Austria, Canada, Denmark, Germany, Mexico, the USA and the United Kingdom (excluding Scotland). In total, these registries included 265,608 participants. This review demonstrates that systematic evaluation of these programmes by registries is extremely limited. Apart from Mexico, all countries included in the review were high income, which aligns with previous literature on cardiac rehabilitation programmes being predominantly available in high-income countries even though 80% of cardiovascular deaths now occur in low- and middle-income countries. Among athletes, the incidences of exercise-related sudden cardiac arrest (SCA) vary within a wide range in different studies: a generally accepted incidence figure is 1–3:100,000 athletes per year. Athletes seem to have a higher risk of SCA than the general population, if they have an underlying cardiovascular abnormality.22 With increasing age (>35 years of age), exercise-related SCA is primarily caused by CAD.23 In a retrospective register based study, the 30-day survival rates were significantly higher in exercise-related versus non-exercise-related SCA, which may be explained by favourable circumstances but may also reflect that these persons experience a SCA at a lower degree of CAD, due to their younger age and to exercise being a trigger.24 The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. The author(s) received no financial support for the research, authorship and/or publication of this article.