Our main finding that elevated P-NT-proBNP levels were associated with presence and severity of WMH has to our best knowledge not been described before. The association was independent of all tested CV risk factors and particular age and systolic blood pressure, which are considered the main predictors of WMH. Noteworthy, the association between P-NT-proBNP and WMH was strengthened and not attenuated by the addition of CV risk factors and in particular CIMT, and this may suggest that the cause is not related to an age systemic atherosclerosis but indeed organ heart and brain specific, therefore linking the heart with the brain. In humans the left ventricle is the main source of P-NT-proBNP with increased myocyte stretch or myocardial ischemia. It therefore seemed unlikely, based on physiology that elevated P-NT-proBNP from the heart
per se directly promoted WMH or cerebrovascular disease in the present study. In contrast, heart disease such as heart failure or presence of atrial fibrillation that are known determinants of higher P-NT-proBNP levels and associated with increased risk of strokes, could be a common driver of both elevated P-NT-proBNP and WMH [
7]. Our patients, however, were without acute illness and had normal ejection fraction without atrial fibrillation or valvular disease, and patients also had lower levels of P-NT-proBNP than seen in congestive heart failure [
11]. Furthermore, we performed concomitant analyses with measures of subclinical heart disease, and the association between P-NT-proBNP and WMH remained significant after adjustment for LVEF, CCS and asymptomatic CAD. Along that line when patients with CAD were excluded, the association between P-NT-proBNP and WMH actually persisted. This is particular important, since the differences in P-NT-proBNP levels between patients with and without CAD were large and this could drive a false association between P-NT-proBNP and WMH. Of note, we only included patients with or without previously screen detected asymptomatic CAD in order to include patients with a wide risk profile. Accordingly, our present study suggests that the cause of the association between P-NT-proBNP and WMH is not explained by a common typical CV or heart disease driver, therefore possibly directly linking P-NT-proBNP and WMH. Along that line, recent studies have documented that plasma brain natiurectic peptide (BNP) itself increases the risk of stroke [
16]. WMH are commonly found on MRI of elderly individuals with frequencies ranging from 11-21% at age 60 to 94% at age 82 [
4]. Although often referred to as 'incidental', WMH have been associated with decline in cognitive function in independently living elderly populations and with a two-fold increased risk of dementia or stroke [
4]. Furthermore, WMH are regarded as expressions of chronic hypoperfusion and small vessel cerebral disease. Small vessel cerebral disease is the most prevalent asymptomatic neurological disease, its incidence reported to be 6- to 10-fold that of symptomatic stroke [
9,
10]. Presence of WMH has been reported to predict a three-fold increased risk of stroke and two-fold increased risk of mortality in the general population [
4]. In the recent Framingham Offspring Stroke Study, the presence of WMH predicted CV mortality and this was independent of risk factors and strokes or dementia [
17]. Following the discussion of the mechanism underlying the relationship between P-NT-proBNP and WMH, the reverse could also be true; WMH induced elevated P-NT-proBNP levels through abnormal neuroendocrine signals to the cardiac ventricles and thereby functional asymptomatic heart failure [
7]. Accordingly, the chronic cerebral hypoperfusion seen in patients with WMH could indirectly promote NT-proBNP realise from the heart. Our measurement of cardiac autonomic neuropathy (heart rate variability), however, did not change the association between P-NT-proBNP and WMH in the present study. Increased P-NT-proBNP levels could, however, also reflect other counter actions to the damages associated with WMH and accordingly mediated through other pathways. Along that line, other studies have suggested that BNP include several actions in addition to vasodilation and promotion of natriuresis and diuresis such as inhibition of the sympathetic nervous system and inhibition of several hormone systems, including the renin-angiotensin-aldosterone-system (RAAS), endothelins, cytokines, and vasopressin [
18,
19].
Finally, the correlation between P-NT-proBNP and WMH could also be brain to brain instead of heart to brain. Along that line, damage or hypoperfusion of the brain (WMH) might directly induce realise of NT-proBNP from the brain [
20]. Brain natriuretic peptide (BNP) was actually first described in the porcine brain and accordingly later localized in the hypothalamus, thalamus, cerebellum, pons and cortex of the human brain [
20]. Few studies have investigated BNP and NT-proBNP from the brain in disease. Specifically, in rats status epilepticus induced increase in plasma ANP (8), and occlusion of the middle cerebral artery stimulates BNP mRNA expression in rat brain tissues [
21]. In humans, the BNP gene promoter region contains a hypoxia-inducible factor-1 binding site, which activates BNP expression [
22], and in patients with subarachnoid hemorrhage plasma BNP concentrations were higher than controls. Some studies have also shown that P-NT-proBNP is increased in patients with acute ischemic stroke [
6,
7,
23‐
25] but these studies may not have convincingly demonstrated that this association is independent from heart disease. In contrast, Tomati et al. examined all included patients with acute stroke with echocardiography in order to exclude the presence of heart disease and hereby investigate if BNP levels were elevated in patients with acute stroke, independently of heart disease. The study demonstrated that plasma BNP levels were indeed associated with the severity of cerebrovascular disease and particular volume of brain infarct size. One human CT study also recently suggested that the ischemic brain tissue
per se release NT-proBNP into the circulation [
26]. Importantly, all our patients were without acute illnesses; since acute disease such as stroke might be a condition that
per se with sympathetic and catecholamines activity, cause stress of the heart and therefore BNP secretion. In contrast, our patients with CAD had higher WMH and lower BPF, however no longer after adjustment for age and sex (Table
1). Our study also demonstrated that WMH is higher and BPF lower in our patients compared to age-matched controls, where 69% had no signs of WMH.