Issue 29.11 focus on biomarkers

The present issue is focussing on the role of biomarkers in risk stratification and cardiovascular disease (CVD) prevention, considering both healthy individuals and patients with different pathological conditions. Accurate cardiovascular risk assessment for early identification of individuals that would qualify for intensified lifestyle and medical interventions is endorsed by major guidelines as a cornerstone of primary prevention of CVD.1 To this, the addition of new biomarkers to the risk prediction models has increasingly gained interest. In a study here presented, addition of N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT) to a model including traditional cardiovascular risk factors [e.g. blood pressure (BP), diabetes, lipid, smoking habit] significantly improved model performance for 10-year risk predictions for various CVD [such as coronary artery event, heart failure (HF), stroke].2 To be clinically applicable, the new cardiovascular biomarkers should lead to clinically relevant risk reclassifications. Addition of NT-proBNP provided relevant improvements in risk reclassifications. Also hs-cTnT improved risk reclassifications for coronary artery disease and HF in women and for stroke in men. Instead, the predictive performance of creatine kinase myocardial band (CK-MB) for improving cardiovascular risk predictions was limited. A limitation was the old age of the study population, mainly white, so this finding cannot be generalized. The blood assessment of gamma-glutamyltransferase (GGT) activity is a common, inexpensive, highly sensitive, and accurate laboratory test. Recent epidemiology and pathology investigations reveal its independent role in the pathophysiology and clinical progression of cardiovascular illnesses caused by atherosclerosis despite being regarded an indicator of hepatobiliary dysfunction and alcohol addiction. GGT has been found within atherosclerotic plaque and it has been proposed as a risk factor for plaque destabilization. The amount of coronary artery calcium (CAC) and the epicardial fat volume has been recommended as a risk modifier because their additive value over established cardiovascular risk factors.3 In their paper Aimo et al.4 explored the relationship between a subfraction of GGT (big-GGT), computed tomography findings, and long-term outcomes in the general population. The authors revealed that plasma big-GGT predicts epicardial fat content and exhibits a link with the risk of cardiovascular mortality or acute coronary syndrome, both independently from various cardiovascular risk factors, albeit not from the degree of coronary artery calcifications. Increased blood uric acid (UA) has been linked to an increased risk of acute myocardial infarction, stroke, and congestive HF, according to a vast number of studies.5 However, when significant risk variables were taken into account, several analyses, failed to demonstrate an independent link between UA and unfavourable outcomes. It has been hypothesized that UA needs specific permissive conditions to exert its negative effects on the cardiovascular system. Elevated heart rate (HR) is a clinical variable which may determine a condition favourable to the occurrence of cardiovascular events. This link is believed to be attributable in part to the direct effect of HR on the cardiovascular system and in part to the fact that high HR is a marker of enhanced sympathetic tone. The authors of a here presented study examined whether the level of resting HR affected the risk of cardiovascular mortality linked with higher UA while taking into consideration that high sympathetic tone might regulate the effect of UA: they enrolled 19 128 participants from the multicentre UA Right for heArt Health study. After a median follow-up of 11.2 years the found that both UA and HR, either considered as continuous or categorical variables were independent predictors of cardiovascular mortality. In particular the risk related to hyperuricaemia was higher in people with HR ≥76 bpm than in those with HR <66 bpm.6 Yand et al.,7 in another study, evaluated the role of UA on incidence of HF. Using a bidirectional Mendelian randomization (MR) on 457 690 individuals, reported that genetically determined serum UA level was associated with HF (odds ratio, 1.07). On the contrary, no evidence was found for the causal effect of HF on serum urate levels. Thus UA lowering therapy may be of cardiovascular benefit in the prevention of HF. The treatment and management of atrial fibrillation (AF) place a significant burden on healthcare systems and are linked to an elevated risk of both fatal and nonfatal cardiovascular events. Existing evidence on how to successfully prevent AF is limited. According to observational studies, an increase in systolic BP of 20 mmHg was linked to a greater incidence of AF. However, there is no convincing proof that BP-lowering therapy lowers the risk of AF, according to randomized controlled trials and meta-analyses. Recent developments in genome-wide association studies (GWAS) have uncovered a huge number of genetic variations that play a significant role in the aetiology of AF. Together with the growing availability of genetic data from huge biobanks, these factors present an opportunity to use MR to extend the findings of prior observational epidemiological research and therapeutic trials. In this study, Georgiopoulos et al.8 used MR to investigate the potential causal association of BP levels with the risk of developing AF. They showed that the association between high BP and the risk of AF is likely causative. Notably, the link between BP levels and the risk of AF did not involve only systolic, but also diastolic and pulse BP. In addition, sensitivity analysis revealed that the putative causal link between hypertension and AF is not influenced by other well-established risk factors associated with both illnesses. Calcific aortic stenosis (AS) is the most common form of valvular heart disease and contributes to the most common cause of death from non-rheumatic valvular disease. Patho-physiologically, multiple mechanisms are involved in the development of AS including inflammation activation, lipid deposition, fibrosis, and calcification. AS has been widely observed in patients with end-stage renal disease in prior studies and was attributed to disturbed mineral metabolisms. However, in the setting of patients with preserved renal function, there has been little agreement on the association of serum calcium, phosphate, and vitamin D levels with the risk of developing AS. Here data from the UK Biobank in a population-based prospective cohort, the associations of serum calcium, phosphate, and vitamin D levels were evaluated with the risk of developing AS: a positive association between increased serum phosphate levels and increased risk of incidental AS was observed independently of traditional cardiovascular risk factors and kidney function. Moreover, associations of serum calcium or vitamin D levels with AS were not observed.9 A causative role of hydroxyapatite deposition is hypothesised, which can induce the formation of osteoblast-like interstitial stromal cells and smooth muscle cells. This osteoblast phenotype shift further facilitates hydroxyapatite crystallization in the aortic valves. A putative role insulin resistance in the development of cardiac remodelling and dysfunction has been hypothesized.10 However, the ‘gold standard’ examination for insulin sensitivity, i.e. the hyperinsulinaemic-euglycaemic clamp test, is time-consuming, costly, and invasive, leading to its limitation in clinical practice. The triglyceride-glucose (TyG) index, measured by fasting triglyceride and glucose, is a convenient, reliable, and valid surrogate marker of insulin resistance. Here for the first time, it is showed that insulin resistance assessed by the TyG index was associated with the development of HF and impaired cardiac structure and function. In a large community-based cohort study, it was found that the incidence of HF was higher in participants with a greater baseline and a long-term TyG index during a median follow-up of 22.5 years. Besides, a greater TyG index was significantly related to adverse LV remodelling and impaired LV function.11 The clinical course of obstructive hypertrophic cardiomyopathy (OHCM) patients is characterized by a broad phenotypic spectrum, spanning from asymptomatic individuals with normal lifetime, to sudden cardiac death (SCD), or medically refractory HF symptoms.12 Recent data in Chinese and North American populations indicate that female patients had a higher all-cause mortality rate, whose causes have not yet been determined. In this issue of the journal, Javidgonbadi et al.12 studied risk-factors for disease-related death in both sexes in a geographical cohort of patients with OHCM. They confirmed that female sex was associated with a higher cardiac mortality than males in age-matched groups occurring most frequently in HF and myocardial infarction patients. This has been attributed to women OHCM being diagnosed later in life and receiving less aggressive pharmacological treatment than men at an age when atherosclerosis may be a significant co-morbidity.13