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Analysis of heart rate variability (HRV) by nonlinear approaches has been gaining interest due to their ability to extract additional information from heart rate (HR) dynamics that are not detectable by traditional approaches. Nevertheless, the physiological interpretation of nonlinear approaches remains unclear. Therefore, we propose long-term (60 min) protocols involving selective blockade of cardiac autonomic receptors to investigate the contribution of sympathetic and parasympathetic function upon nonlinear dynamics of HRV. Conscious male Wistar rats had their electrocardiogram (ECG) recorded under three distinct conditions: basal, selective (atenolol or atropine), or combined (atenolol plus atropine) pharmacological blockade of autonomic muscarinic or β 1 -adrenergic receptors. Time series of RR interval were assessed by multiscale entropy (MSE) and detrended fluctuation analysis (DFA). Entropy over short (1 to 5, MSE 1-5 ) and long (6 to 30, MSE 6-30 ) time scales was computed, as well as DFA scaling exponents at short (α short , 5 ≤ n ≤ 15), mid (α mid , 30 ≤ n ≤ 200), and long (α long , 200 ≤ n ≤ 1,700) window sizes. The results show that MSE 1-5 is reduced under atropine blockade and MSE 6-30 is reduced under atropine, atenolol, or combined blockade. In addition, while atropine expressed its maximal effect at scale six, the effect of atenolol on MSE increased with scale. For DFA, α short decreased during atenolol blockade, while the α mid increased under atropine blockade. Double blockade decreased α short and increased α long Results with surrogate data show that the dynamics during combined blockade is not random. In summary, sympathetic and vagal control differently affect entropy (MSE) and fractal properties (DFA) of HRV. These findings are important to guide future studies. NEW & NOTEWORTHY Although multiscale entropy (MSE) and detrended fluctuation analysis (DFA) are recognizably useful prognostic/diagnostic methods, their physiological interpretation remains unclear. The present study clarifies the effect of the cardiac autonomic control on MSE and DFA, assessed during long periods (1 h). These findings are important to help the interpretation of future studies., (Copyright © 2017 the American Physiological Society.)

The analysis of heart rate variability (HRV) by nonlinear methods has been gaining increasing interest due to their ability to quantify the complexity of cardiovascular regulation. In this study, multiscale entropy (MSE) and refined MSE (RMSE) were applied to track the complexity of HRV as a function of time scale in three pathological conscious animal models: rats with heart failure (HF), spontaneously hypertensive rats (SHR), and rats with sinoaortic denervation (SAD). Results showed that HF did not change HRV complexity, although there was a tendency to decrease the entropy in HF animals. On the other hand, SHR group was characterized by reduced complexity at long time scales, whereas SAD animals exhibited a smaller short- and long-term irregularity. We propose that short time scales (1 to 4), accounting for fast oscillations, are more related to vagal and respiratory control, whereas long time scales (5 to 20), accounting for slow oscillations, are more related to sympathetic control. The increased sympathetic modulation is probably the main reason for the lower entropy observed at high scales for both SHR and SAD groups, acting as a negative factor for the cardiovascular complexity. This study highlights the contribution of the multiscale complexity analysis of HRV for understanding the physiological mechanisms involved in cardiovascular regulation., (Copyright © 2016 the American Physiological Society.)

Heart failure induced by myocardial infarct (MI) attenuates the heart rate variability (HRV) and baroreflex sensitivity, which are important risk factors for life-threatening cardiovascular events. Therapies with mesenchymal stem cells (MSCs) have shown promising results after MI. However, the effects of MSCs on hemodynamic (heart rate and arterial pressure) variability and baroreflex sensitivity in chronic heart failure (CHF) following MI have not been evaluated thus far. Male Wistar rats received MSCs or saline solution intravenously 1 week after ligation of the left coronary artery. Control (noninfarcted) rats were also evaluated. MI size was assessed using single-photon emission computed tomography (SPECT). The left ventricular ejection fraction (LVEF) was evaluated using radionuclide ventriculography. Four weeks after MSC injection, the animals were anesthetized and instrumented for chronic ECG recording and catheters were implanted in the femoral artery to record arterial pressure. Arterial pressure and HRVs were determined in time and frequency domain (spectral analysis) while HRV was also examined using nonlinear methods: DFA (detrended fluctuation analysis) and sample entropy. The initial MI size was the same among all infarcted rats but was reduced by MSCs. CHF rats exhibited increased myocardial interstitial collagen and sample entropy combined with the attenuation of the following cardiocirculatory parameters: DFA indices, LVEF, baroreflex sensitivity, and HRV. Nevertheless, MSCs hampered all these alterations, except the LVEF reduction. Therefore, 4 weeks after MSC therapy was applied to CHF rats, MI size and myocardial interstitial fibrosis decreased, while baroreflex sensitivity and HRV improved.

We investigated the effects of acute pyridostigmine (PYR) treatment, an acetylcholinesterase inhibitor, on arterial pressure (AP), heart rate (HR), cardiac sympathovagal balance, and the incidence of arrhythmias during the first 4 h after myocardial infarction (MI) in anesthetized rats. Male Wistar rats were implanted with catheters into the femoral artery and vein for AP recordings and drug administration. Rats received the autonomic receptor blockers methyl-atropine (1 mg/kg iv) and propranolol (2 mg/kg iv) at intervals of 15 min, 1 h after saline (n=16) or PYR (0.25 mg/kg iv, n=18), to indirectly assess sympathovagal balance. Acute treatment with PYR increased cardiac vagal (86±7 vs. 44±5 beats/min) and decreased sympathetic tone (-31±8 vs. -69±7 beats/min). Different animals were implanted with ECG electrodes and catheters. A large MI was induced via left coronary artery ligation after basal recordings. Rats received PYR (n=14) or saline (n=14) 10-15 min after MI, and the recordings lasted up to 4 h. In part of the animals, hearts were removed for connexin43 quantification after all procedures. MI elicited a fall in AP (-45±5 mmHg), a progressive rise in HR (26±14 beats/min), and an increase in corrected QT interval (33±13 ms). PYR elicited a prompt bradycardia (-50±14 beats/min) that returned to basal levels over time, and it prevented the lengthening of the corrected QT interval. Treatment with PYR increased by ∼20% the occurrence of rats free of arrhythmias after MI. MI markedly decreased connexin43 in left ventricles, and PYR treatment partially prevented this decrease., (Copyright © 2015 the American Physiological Society.)

We examined the effect of chronic (15 days) administration of antihypertensive agents, from different pharmacologic classes, on arterial pressure (AP) and heart rate variability in two-kidney, one-clip hypertensive (2K1C) rats. The 2K1C rats received by gavage one of the following: water, ramipril, losartan, atenolol, amlodipine, or hydrochlorothiazide. Sham-operated normotensive rats received water. After 15 days of treatment AP was continuously sampled from an indwelling catheter in awake rats during a 2-h period and systolic AP and pulse interval (PI) were submitted to autoregressive spectral analysis with oscillatory components quantified in low (LF: 0.25 to 0.75 Hz) and high (HF: 0.75 to 3.0 Hz) frequency bands. The AP measured by tail-cuff was 170 +/- 2 mm Hg in 2K1C and 131 +/- 3 mm Hg in normotensive rats. Pooled data indicated that all antihypertensive agents reduced the AP of 2K1C rats to 127 +/- 2 mm Hg, whereas 2K1C rats treated with water remained hypertensive (206 +/- 11 mm Hg). Variance of systolic AP was found increased in 2K1C rats treated with water (34 +/- 2 mm Hg2), whereas 2K1C rats treated with ramipril, atenolol, amlodipine, or hydrochlorothiazide presented AP variance similar to normotensive rats (16 +/- 2 mm Hg2). Losartan normalized AP of 2K1C rats but variance of systolic AP remained increased (34 +/- 7 mm Hg2). The 2K1C rats treated with water had increased LF of systolic AP, whereas 2K1C rats treated with losartan showed higher LF of systolic AP and PI. Atenolol presented lower LF and higher HF of PI. In conclusion, losartan normalized AP but did not reduce AP variability, suggesting an autonomic imbalance characterized by higher sympathetic modulation of the cardiovascular system.