345 Blood pressure and autonomic function in essential hypertension: comparative evaluation of 24-hour heart rate variability and blood pressure

Aims Arterial hypertension (AHT) represents the leading cause of cardiovascular disease (CVD) and premature death worldwide. Essential AHT accounts for 95% of all cases of hypertension; although the aetiology of essential AHT is still largely unknown, a pivotal role of autonomic nervous system has been proposed and demonstrated. Both excessive sympathetic tone and vagal withdrawal, that define autonomic dysfunction, has been associated with essential AHT. The aim of our study was to investigate the relationship between blood pressure and autonomic function in essential hypertension; this was done comparing 24 h heart rate variability and 24 h blood pressure data, simultaneously collected, in a population of essential AHT subjects. Methods A prospective registry of 179 consecutive not selected essential AHT patients were considered in the present study. All patients underwent cardiac evaluation at the Primary and Secondary Cardiovascular Prevention Unit of the Don Gnocchi Foundation of Parma. All subjects underwent 24 h ECG monitoring, and 24 h Ambulatory Blood Pressure Monitoring, during the same day. Twenty-four hours Heart Rate variability analysis included: Time-domain, frequency-domain and non-linear domain. Results Mean age was 60 0a11.7 years, male gender was prevalent (68.4%). Among the population 26 (14.7%) subjects had diabetes; the prevalence of family history of CVD was 61.7% and 66.5% had dyslipidaemia; body mass index mean values were 27.6 7.4.3. In the whole population, the prevalence of uncontrolled AHT was 80.5%, divided into: 53.1% systo-diastolic, 17.9% isolated systolic, and 9.5% isolated diastolic. The prevalence of untreated AHT (recent diagnosis) was 40.2%, while treated AHT was 59.8% and only 19.6% had controlled blood pressure values (AHT at target). 12.3% of patients were treated with Beta Blockers. A significant correlations between diastolic blood pressure (DBP) values (24 h and day-time), LF/HF ratio (24 h) (r = 0.200; P = 007) and DFA alfa1 (24 h) (r = 0.325; P = 0.000), two know markers of sympathetic tone, were found. A higher sympathetic tone, expressed as high LF/HF, was found in isolated diastolic AHT compared to other types of AHT and the lowest sympathetic tone was found in isolated systolic AHT. Considering non-linear (complexity) analysis, DFA alfa1 (24 h) showed a significant correlation with DBP values that remained independent even after multiple adjustment for BMI, age, gender and Beta Blockers (β = 0.218; P = 0.011). Moreover, the lack of DBP control was associated with high sympathetic tone (LF/HF 3.8 112.3 vs 5.5 .33.3; P < 0.0001). On the other hand, no significant correlations between all DBP data and vagal markers, such as SDNN index, RMSSD and HF, were found. Again, no significant correlations between 24 h, daytime, night-time SBP and time or frequency HRV data as well as with non-linear (complexity) analysis were found. Finally, considering ‘autonomic dipping’, expressed as changes in HRV data between day and night, a strong inverse correlation between vagal markers and Heart Rate Dipping (r = −0.297; P < 0.0001) was found; correlation that remain independent even adjusted for age, gender, BMI, and BB. On the other hand, no association between blood pressure dipping and autonomic dipping was found. Conclusion Diastolic blood pressure and uncontrolled diastolic AHT, rather than systolic AHT, are associated with a hyper-sympathetic tone rather than with blunted vagal tone. The lack of heart rate dipping during night-time in AHT is associated with blunted vagal activation rather than a persistent night-time hyper-adrenergic tone.

346 Baroreflex sensitivity and autonomic function in Takotsubo syndrome long after the acute phase

Aims Takotsubo Syndrome (TS) occurs as an acute coronary syndrome (ACS) characterized by severe left ventricular (LV) dysfunction that typically recovers spontaneously within days or weeks and in the absence of obstructive coronary artery disease. Although during the acute phase it is well documented that an exaggerated sympathetic tone plays a central role in the development of TS, whether an impaired sympatho-vagal balance may persist long after the acute phase, despite the recovery of left ventricular function, is still an open issue. Interestingly, recent evidences suggest that an impairment in central autonomic network not only persist long after the acute event but also may be pre-existent before the acute onset of TS. The Aim of the study was to investigate whether an impairment of the autonomic function is still present long after a TS event. Methods and results We evaluated 67 patients (91% female, mean age 66 ± 8 years) divided into three groups: 24 with a history of TS (1 year after acute event), 21 subjects with a previous history of acute coronary syndrome (ACS) and complete LV ejection fraction recovery (1 year after acute event) and 22 age- and gender-matched healthy subjects. All patients underwent a non-invasive beat-to-beat arterial blood pressure and heart rate recording (short term: 5 min), after at least 3 days of β-blockers wash-out, to obtain heart rate variability (HRV) and spontaneous baroreflex sensitivity (sBRS) data. An overall autonomic dysfunction was found in both TS and ACS groups compared to controls. In particular, a lower heart rate variability, expressed as lower SDNN, has been found in TS and ACS groups compared to controls (31 ± 12 vs. 25 ± 11 vs. 41 ± 22; P = 0.006—Figure A) as a consequence of blunted vagal tone, expressed as lower RMSSD (20 ± 12 vs. 19 ± 11 vs. 40 ± 37; P = 0.007—Figure B) and higher sympathetic tone, expressed as higher LF/HF ratio (P = 0.007 Figure C) which was found to be higher in TS even when compared to ACS (TS: 3.5 ± 2.5 vs. ACS: 2.1 ± 1.7; P = 0.011). Moreover, fractal analysis of HRV showed higher complexity of heart rate regulation, expressed as higher fractal dimension (DFA 1.48 ± 0.06 vs. 1.53 ± 0.05 vs. 1.40 ± 0.10; P < 0.0001—Figure D), in both TS and ACS compared to controls. Interestingly, spontaneous BRS showed the lowest values in the TS group (sSBP: 5.6 ± 2.6 vs. 7.5 ± 3.0 vs. 12.1 ± 11.9; P = 0.027—Figure E), associated with highest levels of sympathetic peripheral control of systolic blood pressure (SBP), expressed as LF-BRS (13.7 ± 9.6 vs. 8.3 ± 5.2 ± 6.8 ± 5.8; P = 0.008—Figure F). Conclusions An autonomic dysfunction, characterized by a hyper-sympathetic tone, reduced baroreflex sensitivity and increased peripheral adrenergic control of blood pressure, persists in TS patients long after the acute phase.

Maternal Angiotensin II–Induced Hypertension Sensitizes Postweaning High‐Fat Diet–Elicited Hypertensive Response Through Increased Brain Reactivity in Rat Offspring

Background Prenatal and postnatal insults can induce a physiological state that leaves offspring later in life vulnerable to subsequent challenges (stressors) eliciting cardiometabolic diseases including hypertension. In this study, we investigated whether maternal angiotensin II–induced hypertension in rats sensitizes postweaning high‐fat diet (HFD)‐elicited hypertensive response and whether this is associated with autonomic dysfunction and altered central mechanisms controlling sympathetic tone in offspring. Methods and Results When eating a low‐lard‐fat diet, basal mean arterial pressure of male offspring of normotensive or hypertensive dams were comparable. However, HFD feeding significantly increased mean arterial pressure in offspring of normotensive and hypertensive dams, but the elevated mean arterial pressure induced by HFD was greater in offspring of hypertensive dams, which was accompanied by greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin II or leptin. HFD feeding also produced comparable elevations in cardiac sympathetic activity and plasma levels of angiotensin II, interleukin‐6, and leptin in offspring of normotensive and hypertensive dams. Reverse transcriptase polymerase chain reaction analyses in key forebrain regions implicated in the control of sympathetic tone and blood pressure indicated that HFD feeding led to greater increases in mRNA expression of leptin, several components of the renin‐angiotensin system and proinflammatory cytokines in offspring of hypertensive dams when compared with offspring of normotensive dams. Conclusions The results indicate that maternal hypertension sensitized male adult offspring to HFD‐induced hypertension. Increased expression of renin‐angiotensin system components and proinflammatory cytokines, elevated brain reactivity to pressor stimuli, and augmented sympathetic drive to the cardiovascular system likely contributed.

Abstract MP26: Angiotensin-(1-7) Increases Vascular Beta-2 Adrenergic Receptor Expression In Aging Mice

Aging is associated with increased sympathetic tone, which desensitizes vascular beta-2 adrenergic receptors (B2AR) to impair vasodilation and promote hypertension. We recently demonstrated that chronic treatment with angiotensin (Ang)-(1-7), a protective hormone of the renin-angiotensin system, decreases blood pressure and cardiac sympathetic tone in aging mice. In this study, we hypothesized that sympathoinhibitory effects of Ang-(1-7) would restore vascular B2AR expression to lower blood pressure in aging. To test this, aging (16-month-old) and young (2-month-old) male C57BL/6J mice received Ang-(1-7) [400 ng/kg/min, n=4] or saline (n=4) infusion for 6 weeks via subcutaneous osmotic mini-pump. At end of treatment, alpha- and beta-adrenergic receptor gene expression was measured in mesenteric arteries, thoracic aorta, and cardiac tissue by quantitative real-time PCR and quantified with 2-ΔΔCT methods. In a separate experiment, male C57BL/6J mice received a single subcutaneous injection of Ang-(1-7) (2 mg/mg, n=4), saline (n=3), or the B2AR antagonist ICI 118,551 (1 mg/kg) plus Ang-(1-7) (n=3). Blood pressure was measured via a carotid artery catheter at baseline and post-treatment. We found that aging mice have decreased mesenteric B2AR gene expression, which was restored by Ang-(1-7) (young saline: 1.04±0.35; aged saline: 0.46±0.17; aged Ang-(1-7): 1.04±0.31 A.U., p=0.026). As a control, Ang-(1-7) did not induce significant changes in B2AR mRNA in thoracic aorta or cardiac tissue, or changes in other adrenergic receptor subtypes (alpha1 or beta1) in any of the tissues studied in aging mice (p>0.05). We further found that depressor effects of acute Ang-(1-7) in mice are attenuated by B2AR blockade (saline: Δ -11±4 mmHg; Ang-(1-7): Δ -26±3 mmHg; ICI 118,551+Ang-(1-7): Δ -4±4 mmHg, p=0.009). Overall, these findings suggest that Ang-(1-7) restores B2AR expression in mesenteric resistance vessels in aging mice, and depressor effects of acute Ang-(1-7) are partially mediated by B2AR. These data support the concept that Ang-(1-7) decreases blood pressure in aging by restoring B2AR-mediated vasodilation. More broadly, Ang-(1-7) may provide a novel treatment target for age-related hypertension and cardiovascular disease.

Abstract P194: Voluntary Exercise Eliminates Maternal Gestational Hypertension-induced Hypertensive Response Sensitization (htrs) In Post-weaning High Fat Diet Fed Male Adult Offspring

Exercise has profound effects on cardiovascular function and metabolism in both physiological and pathophysiological states. Our previous studies demonstrated that maternal gestational hypertension (MGHT) induces hypertensive response sensitization (HTRS) elicited by post-weaning high fat diet (HFD) in male offspring. The present study tested whether voluntary exercise would protect against MGHT-induced HTRS in HFD fed male offspring. Male offspring from both normotensive (NT) and MGHT dams were given access to either “blocked” (sedentary offspring) or functional running (exercised offspring) wheels for 10 weeks during normal fat diet (NFD) or HFD feeding. HFD feeding significantly increased resting blood pressure (BP) in sedentary offspring of both NT (112.3±0.7 to 119.9±1.2 mmHg, p<0.05) and MGHT (112.5±0.9 to 129.6±1.0 mmHg, p<0.05) dams, but the elevated BP induced by HFD was greater in sedentary offspring of MGHT dams (129.6±1.0 vs. 119.9±1.2 mmHg, p<0.05). The sedentary offspring of MGHT dams also displayed greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin (ANG) II or leptin. The running distance was comparable in four groups of exercise offspring (9.183±1.183, 9.192±1.677, 7.233±1.080, 8.482±1.455 kilometers/day, p>0.05). Voluntary exercise did not alter BP in NFD fed offspring and HFD fed offspring of NT dams, but it attenuated BP in HFD fed offspring of MGHT dams (129.6±1.0 to 121.1±0.8 mmHg, p<0.05) and body weight and heart rate in all offspring. Moreover, voluntary exercise significantly reduced sympathetic tone (Hexamethonium, ip, MAP Δ-50.6±1.0 to Δ-29.7±2.7 mmHg, p<0.05) and pressor responses to central ANG II and leptin in HFD fed offspring of both NT (ANG II: Δ16.0±0.9 to Δ7.5±1.1 mmHg; leptin: Δ11.8±0.6 to Δ5.4±0.9 mmHg, p<0.05) and MGHT (ANG II: Δ24.3±2.1 to Δ7.6±1.8 mmHg; leptin: Δ16.8±0.9 to Δ5.2±1.0 mmHg, p<0.05) dams and eliminated the differences in these responses between NFD fed offspring and HFD fed offspring. These results indicate that exercise training plays a beneficial role in preventing MGHT-induced HTRS and that this effect is associated with reduced brain reactivity to pressor stimuli and centrally driven sympathetic activity.

Positive Relationship Between Precompetitive Sympathetic Predominance and Competitive Performance in Elite Extreme Sports Athletes

Elite athletes achieve superior performance under high pressure in competitive situations. Although it is known that such situations affect the precompetitive activity of their autonomic nervous system (ANS), the relationship between precompetitive ANS activity and performance remains controversial. Especially in extreme sports, it has been shown that cardiac sympathetic tone occurs in athletes before competition attempts. However, the relationship between precompetitive sympathetic tone and performance is unclear. To investigate this relationship in extreme sports, we organized a freestyle snowboard jumping competition and examined competitors' physiological states and performance during this event. The electrocardiograms (ECGs) of 20 elite snowboarders were measured 10 min before each jump in different competitive situations: practice, qualifying, and final sessions. The mean heart rate (HR), the low-frequency to high-frequency component ratio (LF/HF ratio), the logarithm of the HF (lnHF) component of the frequency-domain of the heart rate variability (HRV), the ratio of the standard deviation of all R–R intervals to the root mean square of successive differences of R–R intervals (SDNN/rMSSD ratio), and the rMSSD of the time-domain of the HRV were calculated from the ECG data. The results showed a significant increase in the mean HR as well as significant decreases in the lnHF component and rMSSD of the HRV as the sessions progressed. Interestingly, the mean HR, LF/HF ratio and SDNN/rMSSD ratio of the HRV showed significant positive correlations with competitive scores, and the lnHF component and rMSSD of the HRV showed significant negative correlations with the scores. Our results indicate that precompetitive ANS activity becomes predominantly sympathetic in elite extreme athletes, such as freestyle snowboarders, when the competition intensifies, and that this sympathetic predominance is positively related to competitive performance.

Spinal Cord Injury Changes the Structure and Functional Potential of Gut Bacterial and Viral Communities

ABSTRACT Emerging data indicate that gut dysbiosis contributes to many human diseases, including several comorbidities that develop after traumatic spinal cord injury (SCI). To date, all analyses of SCI-induced gut dysbiosis have used 16S rRNA amplicon sequencing. This technique has several limitations, including being susceptible to taxonomic “blind spots,” primer bias, and an inability to profile microbiota functions or identify viruses. Here, SCI-induced gut dysbiosis was assessed by applying genome- and gene-resolved metagenomic analysis of murine stool samples collected 21 days after an experimental SCI at the 4th thoracic spine (T4) or 10th thoracic spine (T10) spinal level. These distinct injuries partially (T10) or completely (T4) abolish sympathetic tone in the gut. Among bacteria, 105 medium- to high-quality metagenome-assembled genomes (MAGs) were recovered, with most (n = 96) representing new bacterial species. Read mapping revealed that after SCI, the relative abundance of beneficial commensals (Lactobacillus johnsonii and CAG-1031 spp.) decreased, while potentially pathogenic bacteria (Weissella cibaria, Lactococcus lactis_A, Bacteroides thetaiotaomicron) increased. Functionally, microbial genes encoding proteins for tryptophan, vitamin B6, and folate biosynthesis, essential pathways for central nervous system function, were reduced after SCI. Among viruses, 1,028 mostly novel viral populations were recovered, expanding known murine gut viral species sequence space ∼3-fold compared to that of public databases. Phages of beneficial commensal hosts (CAG-1031, Lactobacillus, and Turicibacter) decreased, while phages of pathogenic hosts (Weissella, Lactococcus, and class Clostridia) increased after SCI. Although the microbiomes and viromes were changed in all SCI mice, some of these changes varied as a function of spinal injury level, implicating loss of sympathetic tone as a mechanism underlying gut dysbiosis. IMPORTANCE To our knowledge, this is the first article to apply metagenomics to characterize changes in gut microbial population dynamics caused by a clinically relevant model of central nervous system (CNS) trauma. It also utilizes the most current approaches in genome-resolved metagenomics and viromics to maximize the biological inferences that can be made from these data. Overall, this article highlights the importance of autonomic nervous system regulation of a distal organ (gut) and its microbiome inhabitants after traumatic spinal cord injury (SCI). By providing information on taxonomy, function, and viruses, metagenomic data may better predict how SCI-induced gut dysbiosis influences systemic and neurological outcomes after SCI.