Contribution of Autonomic Reflexes to the Hyperadrenergic State in Heart Failure

Heart failure (HF) is a complex syndrome representing the clinical endpoint of many cardiovascular diseases of different etiology. Given its prevalence, incidence and social impact, a better understanding of HF pathophysiology is paramount to implement more effective anti-HF therapies. Based on left ventricle (LV) performance, HF is currently classified as follows: (1) with reduced ejection fraction (HFrEF); (2) with mid-range EF (HFmrEF); and (3) with preserved EF (HFpEF). A central tenet of HFrEF pathophysiology is adrenergic hyperactivity, featuring increased sympathetic nerve discharge and a progressive loss of rhythmical sympathetic oscillations. The role of reflex mechanisms in sustaining adrenergic abnormalities during HFrEF is increasingly well appreciated and delineated. However, the same cannot be said for patients affected by HFpEF or HFmrEF, whom also present with autonomic dysfunction. Neural mechanisms of cardiovascular regulation act as "controller units," detecting and adjusting for changes in arterial blood pressure, blood volume, and arterial concentrations of oxygen, carbon dioxide and pH, as well as for humoral factors eventually released after myocardial (or other tissue) ischemia. They do so on a beat-to-beat basis. The central dynamic integration of all these afferent signals ensures homeostasis, at rest and during states of physiological or pathophysiological stress. Thus, the net result of information gathered by each controller unit is transmitted by the autonomic branch using two different codes: intensity and rhythm of sympathetic discharges. The main scope of the present article is to (i) review the key neural mechanisms involved in cardiovascular regulation; (ii) discuss how their dysfunction accounts for the hyperadrenergic state present in certain forms of HF; and (iii) summarize how sympathetic efferent traffic reveal central integration among autonomic mechanisms under physiological and pathological conditions, with a special emphasis on pathophysiological characteristics of HF

Exaggerated Exercise Blood Pressure as a Marker of Baroreflex Dysfunction in Normotensive Metabolic Syndrome Patients

IntroductionExaggerated blood pressure response to exercise (EEBP = SBP ≥ 190 mmHg for women and ≥210 mmHg for men) during cardiopulmonary exercise test (CPET) is a predictor of cardiovascular risk. Sympathetic hyperactivation and decreased baroreflex sensitivity (BRS) seem to be involved in the progression of metabolic syndrome (MetS) to cardiovascular disease.ObjectiveTo test the hypotheses: (1) MetS patients within normal clinical blood pressure (BP) may present EEBP response to maximal exercise and (2) increased muscle sympathetic nerve activity (MSNA) and reduced BRS are associated with this impairment.MethodsWe selected MetS (ATP III) patients with normal BP (MetS_NT, n = 27, 59.3% males, 46.1 ± 7.2 years) and a control group without MetS (C, n = 19, 48.4 ± 7.4 years). We evaluated BRS for increases (BRS+) and decreases (BRS−) in spontaneous BP and HR fluctuations, MSNA (microneurography), BP from ambulatory blood pressure monitoring (ABPM), and auscultatory BP during CPET.ResultsNormotensive MetS (MetS_NT) had higher body mass index and impairment in all MetS risk factors when compared to the C group. MetS_NT had higher peak systolic BP (SBP) (195 ± 17 vs. 177 ± 24 mmHg, P = 0.007) and diastolic BP (91 ± 11 vs. 79 ± 10 mmHg, P = 0.001) during CPET than C. Additionally, we found that MetS patients with normal BP had lower spontaneous BRS− (9.6 ± 3.3 vs. 12.2 ± 4.9 ms/mmHg, P = 0.044) and higher levels of MSNA (29 ± 6 vs. 18 ± 4 bursts/min, P < 0.001) compared to C. Interestingly, 10 out of 27 MetS_NT (37%) showed EEBP (MetS_NT+), whereas 2 out of 19 C (10.5%) presented (P = 0.044). The subgroup of MetS_NT with EEBP (MetS_NT+, n = 10) had similar MSNA (P = 0.437), but lower BRS+ (P = 0.039) and BRS− (P = 0.039) compared with the subgroup without EEBP (MetS_NT−, n = 17). Either office BP or BP from ABPM was similar between subgroups MetS_NT+ and MetS_NT−, regardless of EEBP response. In the MetS_NT+ subgroup, there was an association of peak SBP with BRS− (R = −0.70; P = 0.02), triglycerides with peak SBP during CPET (R = 0.66; P = 0.039), and of triglycerides with BRS− (R = 0.71; P = 0.022).ConclusionNormotensive MetS patients already presented higher peak systolic and diastolic BP during maximal exercise, in addition to sympathetic hyperactivation and decreased baroreflex sensitivity. The EEBP in MetS_NT with apparent well-controlled BP may indicate a potential depressed neural baroreflex function, predisposing these patients to increased cardiovascular risk

Cardiac autonomic control in Rett syndrome: Insights from heart rate variability analysis

Rett syndrome (RTT) is a rare and severe neurological disorder mainly affecting females, usually linked to methyl-CpG-binding protein 2 (MECP2) gene mutations. Manifestations of RTT typically include loss of purposeful hand skills, gait and motor abnormalities, loss of spoken language, stereotypic hand movements, epilepsy, and autonomic dysfunction. Patients with RTT have a higher incidence of sudden death than the general population. Literature data indicate an uncoupling between measures of breathing and heart rate control that could offer insight into the mechanisms that lead to greater vulnerability to sudden death. Understanding the neural mechanisms of autonomic dysfunction and its correlation with sudden death is essential for patient care. Experimental evidence for increased sympathetic or reduced vagal modulation to the heart has spurred efforts to develop quantitative markers of cardiac autonomic profile. Heart rate variability (HRV) has emerged as a valuable non-invasive test to estimate the modulation of sympathetic and parasympathetic branches of the autonomic nervous system (ANS) to the heart. This review aims to provide an overview of the current knowledge on autonomic dysfunction and, in particular, to assess whether HRV parameters can help unravel patterns of cardiac autonomic dysregulation in patients with RTT. Literature data show reduced global HRV (total spectral power and R-R mean) and a shifted sympatho-vagal balance toward sympathetic predominance and vagal withdrawal in patients with RTT compared to controls. In addition, correlations between HRV and genotype and phenotype features or neurochemical changes were investigated. The data reported in this review suggest an important impairment in sympatho-vagal balance, supporting possible future research scenarios, targeting ANS

Resting spontaneous baroreflex sensitivity and cardiac autonomic control in anabolic androgenic steroid users

OBJECTIVES: Misuse of anabolic androgenic steroids in athletes is a strategy used to enhance strength and skeletal muscle hypertrophy. However, its abuse leads to an imbalance in muscle sympathetic nerve activity, increased vascular resistance, and increased blood pressure. However, the mechanisms underlying these alterations are still unknown. Therefore, we tested whether anabolic androgenic steroids could impair resting baroreflex sensitivity and cardiac sympathovagal control. In addition, we evaluate pulse wave velocity to ascertain the arterial stiffness of large vessels. METHODS: Fourteen male anabolic androgenic steroid users and 12 nonusers were studied. Heart rate, blood pressure, and respiratory rate were recorded. Baroreflex sensitivity was estimated by the sequence method, and cardiac autonomic control by analysis of the R-R interval. Pulse wave velocity was measured using a noninvasive automatic device. RESULTS: Mean spontaneous baroreflex sensitivity, baroreflex sensitivity to activation of the baroreceptors, and baroreflex sensitivity to deactivation of the baroreceptors were significantly lower in users than in nonusers. In the spectral analysis of heart rate variability, high frequency activity was lower, while low frequency activity was higher in users than in nonusers. Moreover, the sympathovagal balance was higher in users. Users showed higher pulse wave velocity than nonusers showing arterial stiffness of large vessels. Single linear regression analysis showed significant correlations between mean blood pressure and baroreflex sensitivity and pulse wave velocity. CONCLUSIONS: Our results provide evidence for lower baroreflex sensitivity and sympathovagal imbalance in anabolic androgenic steroid users. Moreover, anabolic androgenic steroid users showed arterial stiffness. Together, these alterations might be the mechanisms triggering the increased blood pressure in this population

Exercise training reduces sympathetic nerve activity and improves executive performance in individuals with obstructive sleep apnea

OBJECTIVE: To investigate the effects of exercise training (ET) on muscle sympathetic nerve activity (MSNA) and executive performance during Stroop Color Word Test (SCWT) also referred to as mental stress test. METHODS: Forty-four individuals with obstructive sleep apnea (OSA) and no significant co-morbidities were randomized into 2 groups; 15 individuals completed the control period, and 18 individuals completed the ET. Mini-mental state of examination and intelligence quotient were also assessed. MSNA assessed by microneurography, heart rate by electrocardiography, blood pressure (automated oscillometric device) were measured at baseline and during 3 min of the SCWT. Peak oxygen uptake (VO2 peak) was evaluated using cardiopulmonary exercise testing. Executive performance was assessed by the total correct responses during 3 min of the SCWT. ET consisted of 3 weekly sessions of aerobic exercise, resistance exercises, and flexibility (72 sessions, achieved in 40±3.9 weeks). RESULTS: Baseline parameters were similar between groups. Heart rate, blood pressure, and MSNA responses during SCWT were similar between groups (p>0.05). The comparisons between groups showed that the changes in VO2 (4.7±0.8 vs -1.2±0.4) and apnea-hypopnea index (-7.4±3.1 vs 5.5±3.3) in the exercise-trained group were significantly greater than those observed in the control group respectively (p<0.05) after intervention. ET reduced MSNA responses (p<0.05) and significantly increased the number of correct answers (12.4%) during SCWT. The number of correct answers was unchanged in the control group (p>0.05). CONCLUSIONS: ET improves sympathetic response and executive performance during SCWT, suggesting a prominent positive impact of ET on prefrontal functioning in individuals with OSA. ClinicalTrials.gov: NCT002289625

Exercise training prevents the deterioration in the arterial baroreflex control of sympathetic nerve activity in chronic heart failure patients

Arterial baroreflex control of muscle sympathetic nerve activity (ABRMSNA) is impaired in chronic systolic heart failure (CHF). the purpose of the study was to test the hypothesis that exercise training would improve the gain and reduce the time delay of ABRMSNA in CHF patients. Twenty-six CHF patients, New York Heart Association Functional Class II-III, EF <= 40%, peak (V) over dot O-2 <= 20 ml.kg(-1).min(-1) were divided into two groups: untrained (UT, n = 13, 57 +/- 3 years) and exercise trained (ET, n = 13, 49 +/- 3 years). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique. Arterial pressure was measured on a beat-to-beat basis. Time series of MSNA and systolic arterial pressure were analyzed by autoregressive spectral analysis. the gain and time delay of ABRMSNA was obtained by bivariate autoregressive analysis. Exercise training was performed on a cycle ergometer at moderate intensity, three 60-min sessions per week for 16 wk. Baseline MSNA, gain and time delay of ABRMSNA, and low frequency of MSNA (LFMSNA) to high-frequency ratio (HFMSNA) (LFMSNA/HFMSNA) were similar between groups. ET significantly decreased MSNA. MSNA was unchanged in the UT patients. the gain and time delay of ABRMSNA were unchanged in the ET patients. in contrast, the gain of ABRMSNA was significantly reduced [3.5 +/- 0.7 vs. 1.8 +/- 0.2, arbitrary units (au)/mmHg, P = 0.04] and the time delay of ABRMSNA was significantly increased (4.6 +/- 0.8 vs. 7.9 +/- 1.0 s, P = 0.05) in the UT patients. LFMSNA-to-HFMSNA ratio tended to be lower in the ET patients (P < 0.08). Exercise training prevents the deterioration of ABRMSNA in CHF patients.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundacao ZerbiniCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Heart, Lung, and Blood InstituteUniv São Paulo, Sch Med, Heart Inst InCor, São Paulo, BrazilUniv São Paulo, Sch Phys Educ & Sport, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, Div Cardiol, São Paulo, BrazilUniv Calif Los Angeles, David Geffen Sch Med, Dept Med Cardiol & Physiol, Los Angeles, CA 90095 USAUniversidade Federal de São Paulo, Dept Med, Div Cardiol, São Paulo, BrazilFAPESP: 2010/50048-1FAPESP: 140643/2009-5FAPESP: 2013/07651-7CNPq: 142366/2009-9CNPq: 301867/2010-0CNPq: 308068/2011-4FAPESP: 2013/15651-7National Heart, Lung, and Blood Institute: RO1-HL084525Web of Scienc

The Impact of Obstructive Sleep Apnea on Metabolic and Inflammatory Markers in Consecutive Patients with Metabolic Syndrome

Background: Obstructive Sleep Apnea (OSA) is tightly linked to some components of Metabolic Syndrome (MetS). However, most of the evidence evaluated individual components of the MetS or patients with a diagnosis of OSA that were referred for sleep studies due to sleep complaints. Therefore, it is not clear whether OSA exacerbates the metabolic abnormalities in a representative sample of patients with MetS. Methodology/Principal Findings: We studied 152 consecutive patients (age 48 +/- 9 years, body mass index 32.3 +/- 3.4 Kg/m(2)) newly diagnosed with MetS (Adult Treatment Panel III). All participants underwent standard polysomnography irrespective of sleep complaints, and laboratory measurements (glucose, lipid profile, uric acid and C-reactive protein). The prevalence of OSA (apnea-hypopnea index >= 15 events per hour of sleep) was 60.5%. Patients with OSA exhibited significantly higher levels of blood pressure, glucose, triglycerides, cholesterol, LDL, cholesterol/HDL ratio, triglycerides/HDL ratio, uric acid and C-reactive protein than patients without OSA. OSA was independently associated with 2 MetS criteria: triglycerides: OR: 3.26 (1.47-7.21) and glucose: OR: 2.31 (1.12-4.80). OSA was also independently associated with increased cholesterol/HDL ratio: OR: 2.38 (1.08-5.24), uric acid: OR: 4.19 (1.70-10.35) and C-reactive protein: OR: 6.10 (2.64-14.11). Indices of sleep apnea severity, apnea-hypopnea index and minimum oxygen saturation, were independently associated with increased levels of triglycerides, glucose as well as cholesterol/HDL ratio, uric acid and C-reactive protein. Excessive daytime sleepiness had no effect on the metabolic and inflammatory parameters. Conclusions/Significance: Unrecognized OSA is common in consecutive patients with MetS. OSA may contribute to metabolic dysregulation and systemic inflammation in patients with MetS, regardless of symptoms of daytime sleepiness.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)[200032/2009-7]Fundacao Zerbini, BrazilNational Sleep Foundation/American Lung Association Pickwick[SF-78568 N]National Institutes of Health (NIH)[HL07534]National Institutes of Health (NIH)[R01 HL80105]National Institutes of Health (NIH)[5P50HL084945]American Heart Association[0765293U](BSF) United States Israel Binational Science Foundation[2005265

Influência da hereditariedade para hipertensão arterial na hipotensão pós-exercício

Verificar o comportamento cardiovascular de homens normotensos com histórico familiar positivo para hipertensão arterial proveniente da mãe e de homens normotensos com histórico familiar proveniente do pai após uma sessão de exercício aeróbio. Foram selecionados 35 homens adultos divididos nos grupos: HF+mãe (somente mãe com hipertensão arterial, n=14) e HF+pai (somente pai com hipertensão arterial, n=21). Os participantes foram submetidos ao exercício aeróbio, em cicloergômetro (Kikos®), por 50 minutos, em intensidade de 50 a 70% da frequência cardíaca de reserva (sessão exercício) e a uma sessão controle. As variáveis pressão arterial média (FinometerPro®) e fluxo sanguíneo do antebraço (Pletismografia de Oclusão Venosa-Hokanson®) foram registradas continuamente durante 10 minutos pré e 30 minutos pós cada sessão. A resistência vascular do antebraço foi calculada pela divisão da pressão arterial média pelo fluxo sanguíneo do antebraço. Foi considerado p≤0,05 como diferença significativa. No grupo HF+mãe a pressão arterial média e a resistência vascular do antebraço não modificaram significativamente no momento pós em relação ao momento pré-exercício. Diferentemente, no grupo HF+pai a pressão arterial média e resistência vascular do antebraço reduziram significativamente na recuperação do exercício. Na sessão controle essas variáveis aumentaram significativamente no pós em relação ao pré, em ambos os grupos. O exercício físico não provocou modificações no sistema cardiovascular de homens normotensos, com histórico familiar positivo para hipertensão proveniente da mãe. Enquanto aqueles com histórico familiar positivo para hipertensão proveniente do pai apresentaram hipotensão pós-exercício, comportamento parcialmente justificado pela diminuição da resistência vascular do antebraço.To verify the cardiovascular response of normotensive men with positive family history of arterial hypertension from the mother and of normotensive men with positive family history of arterial hypertension from the father after an aerobic exercise session. Were selected 35 adult men divided into groups: HF+mother (only mother with arterial hypertension, n = 14) and HF+father (only father with arterial hypertension, n = 21). The participants underwent aerobic exercise, on a cycle ergometer (Kikos®), for 50 minutes, at intensity of 50 to 70% of the reserve heart rate (exercise session) and a control session. The variables mean arterial pressure (FinometerPro®) and forearm blood flow (Venous Occlusion Plethysmography-Hokanson®) were continuously recorded for 10 minutes before and 30 minutes after each session. The forearm vascular resistance was calculated by dividing the mean arterial pressure by the forearm blood flow. Was considered significant p≤0.05. In the HF+mother group, mean arterial pressure and forearm vascular resistance did not change significantly in the post-moment compared to the pre-exercise moment. In contrast, in the HF+father group, mean arterial pressure and forearm vascular resistance significantly reduced in recovery from exercise. In the control session, these variables increased significantly in the post compared to the pre, in both groups. Physical exercise did not cause changes in the cardiovascular system of normotensive men, with a positive family history of hypertension from the mother. While those with a positive family history of hypertension from their father presented post-exercise hypotension, behavior partially justified by the decrease in vascular resistance in the forearm

Effect of exercise training and hypocaloric diet on sympathetic autonomic modulation in patients with metabolic syndrome and obstructive sleep apnea

INTRODUÇÃO: Pacientes com síndrome metabólica (SMet) apresentam aumento na atividade nervosa simpática muscular (ANSM) e diminuição no ganho do controle barorreflexo arterial (CBR). E, a apnéia obstrutiva do sono (AOS), uma comorbidade frequentemente encontrada em pacientes com SMet, exacerba essas disfunções autonômicas. Sabe-se que a incidência dos disparos e o padrão oscilatório da ANSM dependem do ganho (sensibilidade) e do tempo de retardo (latência) do CBR da ANSM (CBRANSM). Contudo, o padrão oscilatório da ANSM e o tempo de retardo do CBRANSM em pacientes com SMet associada ou não à AOS são desconhecidos. Além disso, estudos prévios demonstram que o treinamento físico associado à dieta hipocalórica (TF+D) diminui a incidência dos disparos da ANSM e aumenta o ganho do CBR em pacientes com SMet. No entanto, os efeitos de TF+D no padrão oscilatório da ANSM e no ganho e tempo de retardo do CBRANSM em pacientes com SMet associado ou não a AOS permanecem desconhecidos. MÉTODOS: Foram estudados quarenta e quatro pacientes com SMet (critérios do ATP III), sem uso de medicamentos, que foram divididos em dois grupos de acordo com a presença da AOS (SMet-AOS, n=23 e SMet+AOS, n=21). Um grupo controle saudável (n=12) foi, também, incluído no estudo. Para avaliar o efeito da intervenção, os pacientes foram divididos consecutivamente em quatro grupos: 1- Sedentário sem AOS (SMet-AOS Sed, n=10); 2- Sedentário com AOS (SMet+AOS Sed, n=10); 3- TF+D sem AOS (SMet-AOS TF+D, n=13) e; 4- TF+D com AOS (SMet+AOS TF+D, n=11). Os grupos TF+D foram submetidos ao treinamento físico aeróbio (40 min, 3 vezes por semana) associado à dieta hipocalórica (-500 kcal/dia) durante quatro meses e os grupos sedentários não realizaram a intervenção (TF+D) e somente receberam orientações clínicas. A AOS foi determinada através do índice de apneia e hipopneia (IAH) >15 eventos/hora (polissonografia). A ANSM (microneurografia), pressão arterial (batimento a batimento, método oscilométrico), padrão oscilatório da ANSM (relação dos componentes de baixa frequência-BF, e alta frequência-AF da ANSM, BFANSM/AFANSM, análise espectral autorregressivo monovariada) e o CBRANSM espontâneo (ganho e tempo de retardo, análise espectral autorregressivo bivariada) foram avaliados durante o repouso na posição deitada por 10 minutos. RESULTADOS: No período pré-intervenção, os pacientes com SMet-AOS e SMet+AOS apresentaram redução no BFANSM/AFANSM (P=0,01 e P15 events/hour (polysomnography). The MSNA (microneurography), blood pressure (beat-to-beat basis, oscillometry method), oscillatory pattern of MSNA (relationship of the components of low frequency - LF, and high frequency - HF of MSNA, LFMSNA/HFMSNA, monovariate autoregressive spectral analysis) and spontaneous BRCMSNA (gain and time delay, bivariate autoregressive spectral analysis) were evaluated during rest at lying position for 10 min. RESULTS: In the pre-intervention period, patients with MetS-OSA and MetS+OSA showed reduced LFMSNA/HFMSNA (P=0.01 and P<0.001, respectively) and gain of BRCMSNA (P=0.01 and P<0.001, respectively) compared to Control group. And, the patients with MetS+OSA had lower LFMSNA/HFMSNA (P=0.02) and gain of BRCMSNA (P<0.001) compared to MetS- OSA. The time delay of BRCMSNA was higher in MetS+OSA group compared to MetS-OSA and Control groups (P=0.01 and P<0.001, respectively). After ET+D, both groups MetS-OSA and MetS+OSA decreased body weight, waist circumference and systolic blood pressure and increased peak oxygen uptake during exercise. In patients with MetS-OSA, the ET+D increased LFMSNA/HFMSNA (P<0.05) and the gain of BRCMSNA (P<0.01). In patients with MetS+OSA, ET+D increased minimum oxygen saturation level (P=0.02) during polysomnography, the LFMSNA/HFMSNA (P=0.001) and the gain of BRCMSNA (P<0.01) and decresed AHI (P<0.01) during polysomnography and the time delay of BRCMSNA (P=0.01). No alterations were observed in both sedentary groups. CONCLUSION: ET+D increase the oscillatory pattern of MSNA and the gain of BRCMSNA in patients with MetS, regardless of the presence of OSA. However, this effect is more pronounced in patients with MetS+OSA, since after intervention the time delay of BRCMSNA was also diminished in these patient