Impact of pro-atrial natriuretic peptide in atrial fibrillation and stroke

Natriuretic peptides are increased in response to mechanical stretching of cardiomyocytes, atrial natriuretic peptide (ANP) is more highly expressed in atria and atrial fibrillation (AF) is a major risk factor for ischaemic stroke. Stroke is a leading cause of death and disability worldwide.1 Natriuretic peptides, such as ANP and brain natriuretic peptide (BNP) are released from cardiomyocytes in response to atrial or ventricular wall stretch. Natriuretic peptides are associated with different cardiovascular outcomes, such as incidence of AF, stroke, heart failure (HF), chronic infections and subclinical atherosclerosis, and they predict poor outcomes in cardiovascular disease.2–6 Mid-regional pro-ANP (MR-proANP) is a stable fragment of the prohormone of ANP. MR-proANP is useful as a marker of prognosis in the acute phase of stroke, independently predicting post-stroke mortality and functional outcome. MR-proANP is also used to improve the discriminatory values of the National Institutes of Health Stroke Scale.7 In this issue of the journal, Berntsson and colleagues explored the relationship between MR-proANP levels and risk for AF and stroke, as well as whether measurement improves the predictions of these outcomes.8 MR-proANP was measured in 5130 subjects (69% men) without a history of AF or stroke from the general population. Incidence of AF and stroke was monitored over a median follow-up of 5.6 years. MR-proANP was significantly associated with incidence of AF and stroke in all causes. The hazard ratio for stroke events related to patients with AF was 1.79 per 1 SD. MR-proANP significantly improved the prediction of AF when added to a risk score of conventional risk factors, mainly by down-classifying subjects who did not develop AF. A smaller improvement in predictive ability was observed for stroke. One of the limitations of this study was not conducting the electrocardiograms and other cardiographic diagnostic tools at baseline in order to assess AF and heart diseases.8 Ravielli and colleagues reported that atrial dilation and strain are associated with increased risk of AF.9,10 Elevated levels of MR-proANP in subjects without AF may reflect a cumulative exposure of risk factors for myocardial diastolic or systolic subclinical dysfunction, which may result in increased filling pressures and increased risk of AF.11 The relationship between natriuretic peptides and cardioembolic stroke is expected and has been suggested in previous studies.2,3 Rubattu and colleagues suggested that ANP has a more direct role in the pathophysiology of stroke compared to BNP.12 Natriuretic peptides are elevated in subjects with HF, and this has been shown to be a risk factor for AF and stroke.13 Hypertension was associated with higher baseline levels of MR-proANP, and this may contribute to an increased risk of AF and stroke.14 In a recent systematic review, the authors reported that the association of natriuretic peptides in the blood and pleural fluid (PF) are effective diagnostic markers for HF.15 These natriuretic peptides include N-terminal pro-brain natriuretic peptide (NT-proBNP), brain natriuretic peptide (BNP) and MR-proANP. The diagnostic accuracy of PF MR-proANP and blood and PF BNP was not analysed due to the small number of studies. Additional studies are needed in order to evaluate the diagnostic accuracy of PF and blood MR-proANP and BNP for the diagnosis of HF.15 Katan and colleagues assessed risk factors for incident vascular disease in a multi-ethnic cohort (Northern Manhattan Study [NOMAS]).16 A total of 1178 individuals underwent magnetic resonance imaging of the brain and had blood samples collected. After adjusting for risk factors, subjects with procalcitonin or MR-proANP in the top quartile compared with the lowest quartile were more likely to have silent brain infarcts and increased white matter hyper-intensity volumes. The authors showed that a high concentration of procalcitonin – a marker of infection – and MR-proANP – a marker of cardiac dysfunction – are independently associated with subclinical cerebrovascular damage.16 In another study, the authors established confounding factors of MR-proANP assessment in 684 patients. The authors found MR-proANP to be independently associated with body mass index, creatinine, ischaemic aetiology, left ventricular ejection fraction and New York Heart Association (NYHA) class. MR-proANP is subject to the almost identical influencing factors like NT-proBNP.17 Zabarovskaja and colleagues measured and compared NT-proBNP, MR-proANP and mid-regional pro-adrenomedullin (MR-proADM) in 86 patients with HF with preserved ejection fraction (HFpEF), 49 patients with HF with reduced ejection fraction (HFrEF), 13 patients at 1 year post-left ventricular assist device (LVAD) implantation and 22 patients at 1 year post-heart transplantation (HTx).18 In both HFpEF and HFrEF patients, NT-proBNP and MR-proANP predicted survival free from HTx or LVAD, independent of age, gender, NYHA class and estimate of glomerular filtration rate (eGFR). NT-proBNP and MR-proANP independently predicted prognosis in both HFpEF and HFrEF patients. Laboratory values of the cardiomyocyte stress hormones NT-proBNP and MR-proANP suggest that compared to HFrEF patients, HFpEF patients may represent milder disease, and LVAD and HTx may represent progressive resolution of HF severity.18 Lindberg and colleagues included 680 patients with an ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Blood samples were drawn immediately before PCI. During 5 years of follow-up, MR-proANP was associated with an increased risk of all-cause mortality and major adverse cardiac events (MACEs). After adjustment for confounding risk factors (age, gender, hypertension, diabetes, hypercholesterolaemia, smoking, previous myocardial infarction, body mass index, eGFR, C-reactive protein (CRP), peak troponin I (TnI), symptom-to-balloon time, multi-vessel disease, complex lesion, Left Anterior Descending (LAD) lesion and use of a glycoprotein inhibitor), MR-proANP remained an independent predictor of all-cause mortality and MACEs. Plasma MR-proANP independently predicted all-cause mortality and MACEs in patients with STEMI.6 Klug et al. investigated the relationship between increased aortic stiffness and biomarkers of myocardial wall stress at 4 months after STEMI.19 The sample consisted of 48 STEMI patients who were reperfused by primary coronary angioplasty and who underwent cardiovascular magnetic resonance at baseline and at 4 months of follow-up. Patients with aortic pulse wave velocities (PWVs) above the median (>7.0 m/second) had significantly higher NT-proBNP, MR-proADM and MR-proANP concentrations at 4 months of follow-up than patients with a PWV below the median. Aortic stiffness is directly associated with biomarkers of myocardial wall stress 4 months after reperfused STEMI, suggesting a role for aortic stiffness in chronic left ventricular remodelling.19 In another study, the authors examined whether MR-proADM plasma concentrations predicted incident cardiovascular outcomes in the general population. Natriuretic peptides (NT-proBNP, BNP and MR-proANP) were analysed for comparison. In a healthy general population, MR-proADM significantly predicted all-cause death, MACEs and especially HF even better than NT-proBNP.20 Fischer and colleagues analysed the prognostic value of MR-proANP in patients with haemorrhagic stroke (i.e. subarachnoid and intracerebral haemorrhage). Increased levels of MR-proANP were associated with poor functional outcomes and increased mortality after 180 days in patients with haemorrhagic stroke.21 Tzikas et al. evaluated MR-proADM and MR-proANP as prognostic biomarkers in 1386 patients with suspected acute coronary syndrome. MR-proADM and MR-proANP were predictors of future cardiovascular events in patients presenting with acute chest pain, and so they might facilitate the choice of treatment in these patients.22 In conclusion, the article by Berntsson and colleagues8 suggests that high plasma MR-proANP appears to be associated with increased incidence of AF and stroke, and the literature suggests its association with HF. Further research is needed in order to assess whether patients with higher levels of MR-proANP may benefit from preventive measures or therapeutic interventions. 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.