Association between periodontal pathogens from the red complex and inflammation in patients with acute coronary syndromes

Abstract Funding Acknowledgements Type of funding sources: None. Background Periodontal disease (PD) is an inflammatory condition that increases cardiovascular risk and favours development of acute coronary events; however, the association of periodontal pathogens and inflammatory markers in patients with acute coronary syndromes (ACS) has not been elucidated so far. Purpose the aim of this study was to evaluate the association between periodontal pathogens of the red and orange complex and inflammatory biomarkers in patients with ACS. Methods Sixteen patients with ACS and concomitant PD were enrolled in the present study. All patients underwent a complex dental examination, including DNA sampling collection from the periodontal pocket. The study population was divided into two groups according to the presence of germs from red, respectively orange complex: group 1 – 9 patients with germs from red complex (RC group) and group 2 – 7 patients with germs from red-orange complex (ROC group). Inflammatory status was assessed on the basis of interleukine 6 (IL6), endothelial/ intravascular adhesion molecules (VCAM/ICAM), P-selectin, metalloproteinase (MMP9), Albumin (Ab), Apolipoprotein B (ApoB), C reactive protein (CRP), alkaline phosphatase (AF) and sST2 and lymphocytes to monocytes ratio. Results Germs from red complex (Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola) were more frequent and more expressed compared with those from orange complex (p=0.0008). There was no significant correlation between RC and RCO group and inflammatory markers; however, P-selectin level (185,4 ± 66,73 vs 89,62 ± 40,94 ng/ml, p=0.005) was higher in RC group, while AF level at baseline (47,83 ±12,53 vs 75,72 ±24,42 UI/l, p=0.006) and in day 7 (52,83 ± 6,122 vs 70,95 ± 9,71 UI/l, p =0.01) was more expreesd in ROC group. A significantly higher lymphocytes to monocytes ratio was identified in patients with ROC compared with those with RC only (3,2 ± 1,44 vs 10,94 ± 12,75, p=0.01). Conclusions in patients with ACS and PD, the presence of germs from red complex in the gingival pocket is associated with increased blood vulnerability. The severity of the PD, expressed by the presence of germs of the red complex, is associated with a higher risk of developing acute coronary events. </jats:sec

Long-term If current blockade increases right atrial mRNA expression of HCN4, encoding proteins for If

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS - UEFISCDI, within PNCDI III Background Numerous long-term pharmacologic manipulations of cardiac ion channels have shown potential to modify the expression of genes encoding proteins for those channels. Purpose We aimed to investigate whether long-term pharmacologic inhibition of the hyperpolarization-activated inward current (If) using ivabradine affects the right atrial expression of genes encoding for hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, responsible for If. Methods The right atrial mRNA expression of HCN1, HCN2, and HCN4, and of the neuron-specific HCN3 isoform was quantified in 6 control (Control) and 12 ivabradine-treated (IVA; 10 mg/kg, 4 weeks) adult male Wistar rats. The expression levels of the target genes were normalized with GAPDH housekeeping gene levels and compared between the two groups. Results Right atrial HCN1 and HCN2 expression levels were both similar (both p &amp;gt;0.05) between the IVA and the Control rats. There was also no significant difference in the right atrial expression of the neuron-specific HCN3 isoform between the two groups (p = 0.22). However, the right atrial expression of HCN4, the most highly expressed HCN isoform in the sinus node, was significantly higher in the ivabradine-treated compared to the non-treated rats (p = 0.02). Conclusions Our study shows that chronic If blockade using ivabradine significantly up-regulates right atrial HCN4 expression. Although the examined samples contained both nodal and non-nodal tissue, since HCN4 is highly expressed in the nodal pacemaker cells and only sparsely in the remaining atrial myocardium, it is likely that the HCN4 changes observed in our study reflect sinus node alterations. HCN4 and a consequent If up-regulation could render the sinus node less sensitive to acute vagal inputs and protect against excessive vagal-induced bradycardia. Further studies will have to evaluate this hypothesis. </jats:sec

Long-term effects of hyperpolarization-activated inward current blockade on cardiac parasympathetic activity

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS - UEFISCDI Background The autonomic control of the pacemaker current, If, and the molecular mechanisms underlying parasympathetic If modulation are well understood. Conversely, the effects of chronic If blockade on the parasympathetic nervous system and on the heart rate (HR) response to acute parasympathetic changes are still largely unknown. Such interactions could significantly influence the course of patients undergoing chronic therapy with the If blocker ivabradine. Purpose We aimed to assess the effects of long-term If blockade using ivabradine on cardiac autonomic modulation and on the cardiovascular response to acute in vivo and in vitro parasympathetic stimulation. Methods Radiotelemetry ECG transmitters were implanted in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day); sympathetic and parasympathetic heart rate variability parameters were assessed. At the end of the study, the right atrium was removed and right atrial HCN(1-4) RNA expression levels were analyzed. The HR and systolic blood pressure (SBP) responses to in vivo electrical stimulation of the right vagus nerve (2–20 Hz) and the spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10-9–10-6 mol/L) were assessed in 6 additional Control and 10 IVA rats. Results At the end of the study, mean 24-h HR was significantly lower in the IVA compared with the Control rats (301.3 ± 7.5 bpm vs. 341.5 ± 8.3 bpm; p&amp;lt; 0.01). Ivabradine administration led to a significant increase in vagal tone and shifted the sympatho-vagal balance towards vagal dominance (awake, asleep, and over 24-h; all p&amp;lt; 0.05). In the Control rats, in vivo vagus nerve stimulation induced a progressive decrease in both the SBP (p = 0.0001) and the HR (p&amp;lt; 0.0001). Meanwhile, in the IVA rats, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p&amp;lt; 0.05). Ivabradine-treated rats also presented a significantly lower SNDR drop in response to carbamylcholine (p&amp;lt; 0.01) and significantly higher HCN4 expression (p = 0.02). Conclusion Long-term If blockade using ivabradine caused a significant increase in vagal tone and shifted the autonomic balance towards vagal dominance in rats. Given the highly proarrhythmic effects of vagal activation at the atrial level, these findings could provide an explanation for the increased risk of atrial fibrillation associated with ivabradine use in clinical trials. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in vivo vagal stimulation, and led to significant sinus node HCN4 up-regulation. These data suggest that ivabradine-induced HCN4 and the consequent If up-regulation could render the sinus node less sensitive to acute vagal inputs and could thus protect against excessive bradycardia induced by acute vagal activation. </jats:sec

Proarrhythmic atrial structural and molecular remodeling with advancing age. Implications for post-coronary artery bypass grafting atrial fibrillation occurrence

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS-UEFISCDI Background Advancing age has been identified as a strong predictor of post-coronary artery bypass grafting (CABG) atrial fibrillation (AF). However, the exact substrate underlying this increased aging-related propensity to post-CABG AF remains insufficiently understood. Purpose We aimed to assess whether a preexisting electrical, structural, autonomic, and/or molecular remodeling could explain the increased risk of elderly individuals for post-CABG AF occurrence. Methods Thirty-one consecutive patients free of AF history scheduled for an elective CABG procedure were prospectively evaluated. All patients underwent continuous ECG monitoring prior to and following the CABG procedure, up to the day of discharge. The occurrence of post-CABG AF was recorded. The right atrial appendage, normally considered "surgical waste", was collected and divided into 3 samples that were used for single cell action potential recordings using the microelectrode technique, for histological, and mRNA analysis. Electrical remodeling preexistent to CABG was assessed by P-wave analysis (i.e., amplitude, duration, fragmentation) using 12-lead surface ECG and Lewis leads recordings and atrial action potential analysis (i.e., amplitude, duration). Atrial structural remodeling was evaluated using echocardiographic (i.e., left atrial [LA] area and antero-posterior diameter) and histological (i.e., fibrosis and fat tissue infiltration) parameters. Autonomic remodeling was evaluated using heart rate variability analysis based on the pre-CABG Holter ECG recordings. Molecular remodeling was assessed by mRNA analysis of several genes previously incriminated in AF occurrence (i.e., CACNA1C, GJA5, KCNE2, KCNJ2, KCNQ1, and SCN5A). Results Post-CABG AF occurred in 11 (35.4%) patients. Patients with post-CABG AF were significantly older than their non-arrhythmic counterparts (65.2 ± 5.8 years vs. 58.0 ± 10.4 years; p = 0.04). Age above 59 years predicted post-CABG AF with 81.8% sensitivity and 57.9% specificity. All analyzed electrical and autonomic parameters were similar between patients above and below the age of 59 years (all p &amp;gt;0.05). However, patients &amp;gt;59 years had significantly higher LA area and diameter (both p&amp;lt; 0.01), more important atrial fatty infiltration (p = 0.02), and significantly lower mRNA expression of SCN5A (p = 0.01). Conclusion In the present cohort, post-CABG AF occurrence was 3.4-fold more common in patients &amp;gt;59 years than in their younger peers. Although there was no evidence of aging-related cellular electrical or autonomic remodeling, elderly individuals presented significantly more important LA dilation and atrial fatty infiltration, and significantly lower expression of SCN5A, encoding for Na+ channels. These changes could contribute to the increased aging-related propensity to post-CABG AF by altering intra-atrial conduction and promoting reentry. </jats:sec