Editor’s presentation: Do we really need biomarkers for cardiovascular risk prediction?

Traditional risk assessment tools, such as the Systematic COronary Risk Evaluation (SCORE) and the Framingham risk score (FRS), have been proposed in clinical practice to calculate an individual’s risk of cardiovascular mortality and/or morbidity based on clinical characteristics and laboratory tests. However, the limited discriminative ability of these approaches1 has promoted studies evaluating several additional non-circulating and circulating biomarkers as means of refining risk stratification.2,3 Here, in a population-based cohort study of apparently healthy men and women, it was observed that higher baseline values of three indicators (i.e. high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and soluble urokinase plasminogen activator receptor (suPAR)) were each associated with an increased long-term risk of cardiovascular death. However, only NT-proBNP significantly improved discriminative ability when added to traditional cardiovascular risk factors, while all three biomarkers improved reclassification. In conclusion, perhaps NT-proBNP is the most important risk marker and could be incorporated in future risk algorithms. However, other risk markers such as, for example, a positive family history of cardiovascular disease was not tested in multivariate analysis. In general, exercise intensity prescription for cardiovascular rehabilitation is mainly based on a percentage range of heart rate, such as between 40% and 70% heart rate reserve (HRR). This recommendation is based on the assumption that this value may reflect a submaximal level of exercise (i.e. near the ventilatory anaerobic threshold (VAT)) at which exercise may safely be performed also for patients with cardiovascular diseases. However, the presence of significant inter-clinician variance in prescribing exercise for patients with cardiovascular diseases exists, highlighting the challenges posed by this recommendation.4 Here a study aimed to compare this recommendation with a more objective measure of exercise prescription, namely the VAT derived from respiratory gas exchange during a maximal cardiopulmonary exercise testing (CPET). The findings indicate that current exercise prescription guidelines appear susceptible to substantial inaccuracy with more than half of the study cohort achieving a VAT outside the recommended target range of 40–70% HRR. In particular, 45% of patients had VAT identified at less than 40% HRR, and in 9% of patients VAT was identified at greater than 70% HRR, suggesting that the recommended exercise intensity spectrum can be under-dosed or over-dosed in approximately one in two patients. Thus a ‘one size fits all’ approach is ineffective, and a shift from predictive equations and submaximal exercise tests to gold standard CPET on entry to cardiovascular rehabilitation would be required to improve exercise prescription. Despite the development of effective therapeutic options, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, many patients fail to achieve adequate lowering of low-density lipoprotein (LDL) cholesterol.5 The limitations of available therapies in terms of effectiveness as well as tolerability, adherence and access highlight the unmet need for additional therapeutic options for lipid lowering.6 Bempedoic acid is a once-daily, oral, first-in-class adenosine triphosphate-citrate lyase (ACL) inhibitor. By inhibiting ACL, bempedoic acid suppresses cholesterol synthesis. Here, in a small trial lasting only 12 weeks, bempedoic acid with a fixed-dose combination with ezetimibe significantly lowered LDL-cholesterol versus placebo or other oral monotherapies, and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. Thus we can at least conclude that in patients requiring intensive LDL-cholesterol lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together. An ongoing outcome trial will provide more information on the long-term safety and effectiveness of this novel approach. Several well-known cardiovascular risk factors, including obesity, diabetes mellitus, sedentary habits7 and hypertension, increase the risk of both predicted cardiovascular disease and cancer. The endothelium is a prime site for the effects of cardiovascular risk factors. Thus, in reflecting the summative contribution of these risk factors that are associated with inflammation and oxidative stress, endothelial function can be viewed as an integrated index and sensitive marker of cardiovascular disease risk. A small study involving 488 patients showed that the presence of microvascular endothelial dysfunction (defined as a reactive hyperaemia peripheral arterial tonometry index equal to or below 2.0) was associated with a greater than two-fold increased risk of solid tumour cancer. Microvascular endothelial dysfunction may be a useful marker to predict the future risk of solid tumour cancer, in addition to its known ability to predict cardiovascular disease. Previously, the GAUDI-CRT study showed that only patients with greater scar mass, wider scar heterogeneity and more border zone channels assessed by cardiac magnetic resonance (CMR) experienced life-threatening ventricular arrhythmias and sudden cardiac death which benefit from cardiac resynchronisation (CRT) with implantable cardioverter defibrillator (ICD) device implantation.8 Based on these important results, the same group here investigated the economic side of this strategy: a cost-effectiveness analysis performed on 181 patients of the GAUDI-CRT study showed that CMR-based CRT candidate screening can be more cost-effective than the simple clinical evaluation. The authors calculated that almost €7487 could have been saved over the lifetime of each overprotected patient not needing ICD implantation. On the other hand, only 8% of patients classified as high risk with CMR had undergone CRT-P implantation, being theoretically under-protected. However, these patients mainly died due to non-sudden cardiac death or non-cardiac causes. Many clinical scores for risk stratification in patients with atrial fibrillation have been proposed. In a systematic review and network meta-regression, all the clinical scores considered (i.e. ATRIA bleeding, CHADS2, CHA2DS2-VASc and HAS-BLED) were associated with an increased risk of all-cause death. Also, all the scores had only modest predictive performance, without any significant difference between each other. Only the CHA2DS2-VASc score had consistently high negative predictive value during follow-up, and the highest probability of being the best performing clinical score in predicting all-cause death. The beneficial impact of regular physical activity on cardiovascular health is well established.9,10 Nevertheless, there is increasing evidence that the cumulative effects of high endurance training loads may induce a broad spectrum of right ventricular (RV) adaptive patterns, with a small subset of athletes showing extreme RV remodelling, mimicking initial stages of arrhythmogenic cardiomyopathy with a potential increased incidence of ventricular arrhythmias.11,12 Here, in a comparison between 93 highly trained endurance athletes (53% men) with 72 healthy controls (58% men), who were younger and performed less than 3 hours moderate exercise per week, athletes showed as expected significantly greater cardiac chamber volumes, left ventricular (LV) mass and stroke volume while both LV and RV ejection fractions were slightly lower. A novel finding in this study was that the indexed pulmonary artery area was significantly greater in the athletes and seven of 93 (9.3%) asymptomatic endurance athletes had markedly elevated pulmonary vascular resistance suggestive of pulmonary hypertension. Thus, athletes may present an increased risk of pulmonary hypertension as compared with the general population, and involvement of the pulmonary circulation should be considered as another feature of the physiological heart adaptation to long-term endurance training. 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.