# Inflammation and Reduced Parasympathetic Cardiac Modulation in Aortic-Valve Sclerosis
## 4 Discussion  
Our main finding is the existence of significant HRV differences in subjects having aortic-valve sclerosis, mainly identified by a reduction of the parasympathetic-driven variability (or increased adrenergic-like response) to the cardiac autonomic modulation. This exploration seems to be the first study documenting that functional subclinical lesions of the aortic valve are accompanied by HRV changes. Subjects with aortic-valve sclerosis also showed significant differences in the left ventricular mass index and relative wall thickness in comparison with normal aortic valve subjects but none of the participants reached a ventricular mass index large enough to fulfill the accepted criteria for hypertrophy [17]. In studies involving severe clinical conditions, such as aortic-valve stenosis and hypertensive heart disease, cardiac hypertrophy has been associated with diminished indices of HRV [23]. Our AVS group, who had by contrast a normal ventricular structure, also showed cardiac autonomic HRV changes (i.e., increased LF, LF/HF, and \(\alpha_{\text{1 sign}}\) and reduced HF at the supine position). The active standing maneuver in AVS subjects introduced a diminished adjustment (i.e., \(\Delta\)), or constricted autonomic response, in most of these HRV indices as well. This maneuver essentially involves a vagal withdrawal and a sympathetic activation in response to the redistribution of blood from central- to lower-body vascular beds [24]. Overall, these standing adjustments and supine differences suggest a reduction of the parasympathetic-driven variability in aortic-valve sclerosis, which is revealed by the increased LF spectral power, reduced spectral HF power, smother variability (\(\alpha_{1}\)) and less anti-correlated (\(\alpha_{\text{1 sign}}\)) HRV behavior [25]. Importantly, this reduction was concomitant with no differences in the mean NN parameter in the supine position (Table 1)--thereby such a reduction cannot be simply attributed to baseline differences in the heart rate [26]. Several studies have associated a diminished HRV with increased mortality of cardiovascular diseases [27]. Particularly, a decreased vagal function was related to both modifiable and non-modifiable cardiovascular risk factors and it was also associated with coronary artery occlusion and plaque rupture [27]. Aortic-valve sclerosis is related to coronary artery disease and inflammation [1] and it is recognized as a marker of cardiovascular risk [6; 8]. Aortic-valve sclerosis thus appears to have a pathogenic link with coronary atherosclerosis, but it also involves other mechanisms resulting in an active inflammatory response that increases the susceptibility of patients [6; 18]. Here, we provide further evidence showing that early sclerotic aortic-valve lesions are accompanied by HRV changes that are probably related to such inflammatory response. Most subjects of both groups studied had similar but abnormal higher plasma levels of C-reactive protein and overweight body mass index (Table 1). However, the aortic-valve sclerosis group showed significantly higher plasma levels of IL-6 and TNF\(\alpha\) that are in line with an active inflammatory response. These cytokines cause both paracrine and endocrine effects that mediate local and systemic responses [28; 29]). According to a recent review [30], the expression of pro-inflammatory cytokines, such as TGF-\(\beta\), TNF\(\alpha\), IL-1\(\beta\), and IL-6, is consistently identified in aortic-valve sclerosis. These cytokines seem to be produced by leaflets' activated fibroblasts, whose differentiation, proliferation, and matrix remodeling participate in the endothelial damage of aortic valve leading to the valve thickening [30]. IL-6 is also known to be involved in the endothelial dysfunction of other cardiovascular diseases by interfering with endothelial nitric oxide synthase expression [31] and, in conjunction with C-reactive protein, is regarded as an indicator of chronic or systemic low-grade inflammation [18].