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We aimed to systematically review the literature on the effects of probiotic consumption on the risk of preeclampsia (PE) development. Eight databases, clinical trial registries, and grey literature were searched until February 2022. Studies were included if they (1) were randomized clinical trials (RCTs), (2) included pregnant women aged ≥ 18 years old, (3) used probiotics products, and (4) were written in the Latin alphabet. A random-effects meta-analysis was performed using the risk ratio as the effect measure with 95% confidence intervals (CI) for PE. The search strategy identified 359 records, from which six RCTs were included. The six RCTs evaluated pregnant women with comorbidities and enrolled 593 women that received probiotics and 625 receiving placebo. None of the included RCTs analyzed healthy women. Probiotics increased by 12% the PE risk (RR 1.12, 95% CI, CI = 0.83-1.53, p  = 0.46, χ 2  = 3.31, df = 5 ( p  = 0.65), I 2  = 0%). The certainty of the evidence, evaluated through the Grading of Recommendations Assessment, Development and Evaluation approach, was rated as very low. In conclusion, probiotics supplementation may slightly increase PE rates in pregnant women with comorbidities. The risk may be higher in obese women and for periods of ingestion longer than eight weeks. However, the evidence certainty is very low. PROSPERO registration No.CRD42021278611., Competing Interests: The authors declare no competing interests.

Despite advances in the treatment of heart failure, prognosis is poor, mortality high and there remains no cure. Heart failure is associated with reduced cardiac pump function, autonomic dysregulation, systemic inflammation and sleep-disordered breathing; these morbidities are exacerbated by peripheral chemoreceptor dysfunction. We reveal that in heart failure the carotid body generates spontaneous, episodic burst discharges coincident with the onset of disordered breathing in male rats. Purinergic (P2X3) receptors were upregulated two-fold in peripheral chemosensory afferents in heart failure, and when antagonized abolished these episodic discharges, normalized both peripheral chemoreceptor sensitivity and the breathing pattern, reinstated autonomic balance, improved cardiac function, and reduced both inflammation and biomarkers of cardiac failure. Aberrant ATP transmission in the carotid body triggers episodic discharges that via P2X3 receptors play a crucial role in the progression of heart failure and as such offer a distinct therapeutic angle to reverse multiple components of its pathogenesis., (© 2023. The Author(s).)

Bioelectronic medicine is a novel field in modern medicine based on the specific neuronal stimulation to control organ function, cardiovascular, and immune homeostasis. However, most studies addressing neuromodulation of the immune system have been conducted on anesthetized animals, which can affect the nervous system and neuromodulation. Here, we review recent studies involving conscious experimental rodents (rats and mice) to better understand the functional organization of neural control of immune homeostasis. We highlight typical experimental models of cardiovascular regulation, such as electrical activation of the aortic depressor nerve or the carotid sinus nerve, bilateral carotid occlusion, the Bezold-Jarisch reflex, and intravenous administration of the bacterial endotoxin lipopolysaccharide. These models have been used to investigate the relationship between neuromodulation of the cardiovascular and immune systems in conscious rodents (rats and mice). These studies provide critical information about the neuromodulation of the immune system, particularly the role of the autonomic nervous system, i.e., the sympathetic and parasympathetic branches acting both centrally (hypothalamus, nucleus ambiguus, nucleus tractus solitarius, caudal ventrolateral medulla, and rostral ventrolateral medulla), and peripherally (particularly spleen and adrenal medulla). Overall, the studies in conscious experimental models have certainly highlighted to the reader how the methodological approaches used to investigate cardiovascular reflexes in conscious rodents (rats and mice) can also be valuable for investigating the neural mechanisms involved in inflammatory responses. The reviewed studies have clinical implications for future therapeutic approaches of bioelectronic modulation of the nervous system to control organ function and physiological homeostasis in conscious physiology., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Key Points: Respiratory sinus arrhythmia is physiological pacing of the heart that disappears in cardiovascular disease and is associated with poor cardiac prognosis. In heart failure, cardiac pacing has little, if any, variation in rate at rest. We proposed that reinstatement of respiratory sinus arrhythmia would improve cardiac function in rats with heart failure. Heart failure rats were paced daily for 2 weeks with either respiratory sinus arrhythmia or paced monotonically at a matched heart rate; cardiac function was measured using non-invasive echocardiography. Cardiac output and stroke volume were increased in rats paced with respiratory sinus arrhythmia compared to monotonic pacing, via improvement in systolic function that persisted beyond the pacing treatment period. We propose that respiratory sinus arrhythmia pacing reverse-remodels the heart in heart failure and is worth considering as a new form of cardiac pacemaking., Abstract: Natural pacing of the heart results in heart rate variability, an indicator of good health and cardiac function. A contributor to heart rate variability is respiratory sinus arrhythmia or RSA - an intrinsic respiratory modulated pacing of heart rate. The loss of RSA is associated with poor cardiac prognosis and sudden cardiac death. We tested if reinstatement of respiratory-modulated heart rate (RMH) would improve cardiac performance in heart failure. Heart failure was induced in Wistar rats by ligation of the left anterior descending coronary artery. Rats were unpaced, monotonically paced and RMH paced; the latter had the same average heart rate as the monotonically paced animals. Cardiac function was assessed non-invasively using echocardiography before and after 2 weeks of daily pacing at a time when pacing was turned off. RMH increased cardiac output by 20 ± 8% compared to monotonic pacing (-3 ± 5%; P < 0.05). This improvement in cardiac output was associated with an increase in stroke volume compared to monotonic pacing (P = 0.03) and improvement in circumferential strain (P = 0.02). Improvements in ejection fraction (P = 0.08) and surrogate measures of left ventricle compliance did not reach significance. Increases in contractility (P < 0.05) and coronary blood flow (P < 0.05) were seen in vitro during variable pacing to mimic RMH. Thus, in rats with left ventricular dysfunction, chronic RMH pacing improved cardiac function through improvements in systolic function. As these improvements were made with pacing switched off, we propose the novel idea that RMH pacing causes reverse-remodelling., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

There is a body of evidence that supports the notion that gut dysbiosis plays a role in the pathogenesis of cardiovascular diseases. Decreased cardiac function can reduce intestinal perfusion, resulting in morphological alterations, which may contribute to changes in the gut microbiota composition in patients with heart failure (HF). In this regard, a germane question is whether changes in gut microbiota composition are a cause or consequence of the cardiovascular disturbance. We tested the hypothesis that the development of HF, after myocardial infarction, would cause gut dysbiosis. Fecal samples were collected before and 6 wk after myocardial infarction or sham surgery. Gut microbiota were characterized by sequencing the bacterial 16S ribosomal DNA. The composition of bacterial communities in the fecal samples was evaluated by calculating three major ecological parameters: 1 ) the Chao 1 richness, 2 ) the Pielou evenness, and 3 ) the Shannon index. None of these indices was changed in either sham or HF rats. The Firmicutes/Bacteroidetes ratio was not altered in HF rats. The number of species in each phylum was also not different between sham and HF rats. β-Diversity analysis showed that the composition of gut microbiota was not changed with the development of HF. Bacterial genera were grouped according to their major metabolic end-products (acetate, butyrate, and lactate), but no differences were observed in HF rats. Therefore, we conclude that HF induced by myocardial infarction does not affect gut microbiota composition, at least in rats, indicating that the dysbiosis observed in patients with HF may precede cardiovascular disturbance. NEW & NOTEWORTHY Our study demonstrated that, following myocardial infarction in rats, heart failure (HF) development did not affect the intestinal microbiota despite distinct differences reported in the gut microbiota of humans with HF. Our finding is consistent with the notion that dysbiosis observed in patients with HF may precede cardiovascular dysfunction and therefore offers potential for early diagnosis and treatment.

Heart rate variability (HRV) has been extensively explored by traditional linear approaches (e.g., spectral analysis); however, several studies have pointed to the presence of nonlinear features in HRV, suggesting that linear tools might fail to account for the complexity of the HRV dynamics. Even though the prevalent notion is that HRV is nonlinear, the actual presence of nonlinear features is rarely verified. In this study, the presence of nonlinear dynamics was checked as a function of time scales in three experimental models of rats with different impairment of the cardiac control: namely, rats with heart failure (HF), spontaneously hypertensive rats (SHRs), and sinoaortic denervated (SAD) rats. Multiscale entropy (MSE) and refined MSE (RMSE) were chosen as the discriminating statistic for the surrogate test utilized to detect nonlinearity. Nonlinear dynamics is less present in HF animals at both short and long time scales compared with controls. A similar finding was found in SHR only at short time scales. SAD increased the presence of nonlinear dynamics exclusively at short time scales. Those findings suggest that a working baroreflex contributes to linearize HRV and to reduce the likelihood to observe nonlinear components of the cardiac control at short time scales. In addition, an increased sympathetic modulation seems to be a source of nonlinear dynamics at long time scales. Testing nonlinear dynamics as a function of the time scales can provide a characterization of the cardiac control complementary to more traditional markers in time, frequency, and information domains. NEW & NOTEWORTHY Although heart rate variability (HRV) dynamics is widely assumed to be nonlinear, nonlinearity tests are rarely used to check this hypothesis. By adopting multiscale entropy (MSE) and refined MSE (RMSE) as the discriminating statistic for the nonlinearity test, we show that nonlinear dynamics varies with time scale and the type of cardiac dysfunction. Moreover, as complexity metrics and nonlinearities provide complementary information, we strongly recommend using the test for nonlinearity as an additional index to characterize HRV., (Copyright © 2017 the American Physiological Society.)

Key Points: The integrity of the baroreflex control of sympathetic activity in heart failure (HF) remains under debate. We proposed the use of the sequence method to assess the baroreflex control of renal sympathetic nerve activity (RSNA). The sequence method assesses the spontaneous arterial pressure (AP) fluctuations and their related changes in heart rate (or other efferent responses), providing the sensitivity and the effectiveness of the baroreflex. Effectiveness refers to the fraction of spontaneous AP changes that elicits baroreflex-mediated variations in the efferent response. Using three different approaches, we showed that the baroreflex sensitivity between AP and RSNA is not altered in early HF rats. However, the sequence method provided evidence that the effectiveness of baroreflex in changing RSNA in response to AP changes is markedly decreased in HF. The results help us better understand the baroreflex control of the sympathetic nerve activity., Abstract: In heart failure (HF), the reflex control of the heart rate is known to be markedly impaired; however, the baroreceptor control of the sympathetic drive remains under debate. Applying the sequence method to a series of arterial pressure (AP) and renal sympathetic nerve activity (RSNA), we demonstrated a clear dysfunction in the baroreflex control of sympathetic activity in rats with early HF. We analysed the baroreflex control of the sympathetic drive using three different approaches: AP vs. RSNA curve, cross-spectral analysis and sequence method between AP and RSNA. The sequence method also provides the baroreflex effectiveness index (BEI), which represents the percentage of AP ramps that actually produce a reflex response. The methods were applied to control rats and rats with HF induced by myocardial infarction. None of the methods employed to assess the sympathetic baroreflex gain were able to detect any differences between the control and the HF group. However, rats with HF exhibited a lower BEI compared to the controls. Moreover, an optimum delay of 1 beat was observed, i.e. 1 beat is required for the RSNA to respond after AP changing, which corroborates with the findings related to the timing between these two variables. For delay 1, the BEI of the controls was 0.45 ± 0.03, whereas the BEI of rats with HF was 0.29 ± 0.09 (P < 0.05). These data demonstrate that while the gain of the baroreflex is not affected in early HF, its effectiveness is markedly decreased. The analysis of the spontaneous changes in AP and RSNA using the sequence method provides novel insights into arterial baroreceptor reflex function., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

In vitro and ex vivo experiments indicate that elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, is an alternative pathway for angiotensin II (Ang II) generation. However, the role played by ELA-2 in vivo is unclear. We examined ELA-2 knockout (ELA-2KO) mice compared to wild-type (WT) mice and determined whether ELA-2 played a role in hemodynamics [arterial pressure (AP) and heart rate (HR)], cardiocirculatory sympathovagal balance and baroreflex sensitivity. The variability of systolic arterial pressure (SAP) and pulse interval (PI) for evaluating autonomic modulation was examined for time and frequency domains (spectral analysis), whereas a symbolic analysis was also used to evaluate PI variability. In addition, baroreflex sensitivity was examined using the sequence method. Cardiac function was evaluated echocardiographically under anesthesia. The AP was normal whereas the HR was reduced in ELA-2KO mice (425 ± 17 vs. 512 ± 13 bpm from WT). SAP variability and baroreflex sensitivity were similar in both strains. The LF power from the PI spectrum (33.6 ± 5 vs. 51.8 ± 4.8 nu from WT) and the LF/HF ratio (0.60 ± 0.1 vs. 1.45 ± 0.3 from WT) were reduced, whereas the HF power was increased (66.4 ± 5 vs. 48.2 ± 4.8 nu from WT) in ELA-2KO mice, indicating a shift toward parasympathetic modulation of HR. Echocardiographic examination showed normal fractional shortening and an ejection fraction in ELA-2KO mice; however, the cardiac output, stroke volume, and ventricular size were reduced. These findings provide the first evidence that ELA-2 acts on the sympathovagal balance of the heart, as expressed by the reduced sympathetic modulation of HR in ELA-2KO mice.

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.)

Chronic heart failure (CHF) is characterized by autonomic dysfunction combined with baroreflex attenuation. The hypotensive and bradycardic responses produced by electrical stimulation of the aortic depressor nerve (ADN) were examined in conscious CHF and control male Wistar rats (12-13 wk old). Furthermore, the role of parasympathetic and sympathetic nervous system in mediating the cardiovascular responses to baroreflex activation was evaluated by selective β1-adrenergic and muscarinic receptor antagonists. CHF was induced by myocardial infarction. After 6 wk, the subjects were implanted with electrodes for ADN stimulation. Twenty-four hours later, electrical stimulation of the ADN was applied for 20 s using five different frequencies (5, 15, 30, 60, and 90 Hz), while the arterial pressure was recorded by a catheter implanted into the femoral artery. Electrical stimulation of the ADN elicited progressive and similar hypotensive and bradycardic responses in control (n = 12) and CHF (n = 11) rats, while the hypotensive response was not affected by methylatropine. Nevertheless, the reflex bradycardia was attenuated by methylatropine in control, but not in CHF rats. Atenolol did not affect the hypotensive or bradycardic response in either group. The ADN function was examined under anesthesia through electroneurographic recordings. The arterial pressure-ADN activity relationship was attenuated in CHF rats. In conclusion, despite the attenuation of baroreceptor function in CHF rats, the electrical stimulation of the ADN elicited a stimulus-dependent hypotension and bradycardia of similar magnitude as observed in control rats. Therefore, electrical activation of the aortic baroreflex overcomes both the attenuation of parasympathetic function and the sympathetic overdrive., (Copyright © 2016 the American Physiological Society.)

In an emerging bioelectronics era, there is a clinical need for physiological devices incorporating biofeedback that permits natural and demand-dependent control in real time. Here, we describe a novel device termed a central pattern generator (CPG) that uses cutting edge analog circuitry producing temporally controlled, electrical stimulus outputs based on the real time integration of physiological feedback. Motivated by the fact that respiratory sinus arrhythmia (RSA), which is the cyclical changes in heart rate every breath, is an essential component of heart rate variability (HRV) (an indicator of cardiac health), we have explored the versatility and efficiency of the CPG for producing respiratory modulation of heart rate in anesthetized, spontaneously breathing rats. Diaphragmatic electromyographic activity was used as the input to the device and its output connected to either the right cervical vagus nerve or the right atrium for pacing heart rate. We found that the CPG could induce respiratory related heart rate modulation that closely mimicked RSA. Whether connected to the vagus nerve or right atrium, the versatility of the device was demonstrated by permitting: (i) heart rate modulation in any phase of the respiratory cycle, (ii) control of the magnitude of heart rate modulation, and (iii) instant adaptation to changes in respiratory frequency. Vagal nerve pacing was only possible following transection of the nerve limiting its effective use chronically. Pacing via the right atrium permitted better flexibility and control of heart rate above its intrinsic level. This investigation now lays the foundation for future studies using this biofeedback technology permitting closer analysis of both the function and dysfunction of RSA.

Cardiac rhythm management devices provide therapies for both arrhythmias and resynchronisation but not heart failure, which affects millions of patients worldwide. This paper reviews recent advances in biophysics and mathematical engineering that provide a novel technological platform for addressing heart disease and enabling beat-to-beat adaptation of cardiac pacing in response to physiological feedback. The technology consists of silicon hardware central pattern generators (hCPGs) that may be trained to emulate accurately the dynamical response of biological central pattern generators (bCPGs). We discuss the limitations of present CPGs and appraise the advantages of analog over digital circuits for application in bioelectronic medicine. To test the system, we have focused on the cardio-respiratory oscillators in the medulla oblongata that modulate heart rate in phase with respiration to induce respiratory sinus arrhythmia (RSA). We describe here a novel, scalable hCPG comprising physiologically realistic (Hodgkin-Huxley type) neurones and synapses. Our hCPG comprises two neurones that antagonise each other to provide rhythmic motor drive to the vagus nerve to slow the heart. We show how recent advances in modelling allow the motor output to adapt to physiological feedback such as respiration. In rats, we report on the restoration of RSA using an hCPG that receives diaphragmatic electromyography input and use it to stimulate the vagus nerve at specific time points of the respiratory cycle to slow the heart rate. We have validated the adaptation of stimulation to alterations in respiratory rate. We demonstrate that the hCPG is tuneable in terms of the depth and timing of the RSA relative to respiratory phase. These pioneering studies will now permit an analysis of the physiological role of RSA as well as its any potential therapeutic use in cardiac disease., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Heart failure (HF) is characterized by elevated sympathetic activity and reduced parasympathetic control of the heart. Experimental evidence suggests that the increase in parasympathetic function can be a therapeutic alternative to slow HF evolution. The parasympathetic neurotransmission can be improved by acetylcholinesterase inhibition. We investigated the long-term (4 wk) effects of the acetylcholinesterase inhibitor pyridostigmine on sympathovagal balance, cardiac remodeling, and cardiac function in the onset of HF following myocardial infarction. Myocardial infarction was elicited in adult male Wistar rats. After 4 wk of pyridostigmine administration, per os, methylatropine and propranolol were used to evaluate the cardiac sympathovagal balance. The tachycardic response caused by methylatropine was considered to be the vagal tone, whereas the bradycardic response caused by propranolol was considered to be the sympathetic tone. In conscious HF rats, pyridostigmine reduced the basal heart rate, increased vagal, and reduced sympathetic control of heart rate. Pyridostigmine reduced the myocyte diameter and collagen density of the surviving left ventricle. Pyridostigmine also increased vascular endothelial growth factor protein in the left ventricle, suggesting myocardial angiogenesis. Cardiac function was assessed by means of the pressure-volume conductance catheter system. HF rats treated with pyridostigmine exhibited a higher stroke volume, ejection fraction, cardiac output, and contractility of the left ventricle. It was demonstrated that the long-term administration of pyridostigmine started right after coronary artery ligation augmented cardiac vagal and reduced sympathetic tone, attenuating cardiac remodeling and left ventricular dysfunction during the progression of HF in rats.

Background: Imaging techniques enable in vivo sequential assessment of the morphology and function of animal organs in experimental models. We developed a device for high-resolution single photon emission computed tomography (SPECT) imaging based on an adapted pinhole collimator., Objective: To determine the accuracy of this system for quantification of myocardial infarct area in rats., Methods: Thirteen male Wistar rats (250 g) underwent experimental myocardial infarction by occlusion of the left coronary artery. After 4 weeks, SPECT images were acquired 1.5 hours after intravenous injection of 555 MBq o f 99mTc-Sestamibi. The tomographic reconstruction was performed by using specially developed software based on the Maximum Likelihood algorithm. The analysis of the data included the correlation between the area of perfusion defects detected by scintigraphy and extent of myocardial fibrosis assessed by histology., Results: The images showed a high target organ/background ratio with adequate visualization of the left ventricular walls and cavity. All animals presenting infarction areas were correctly identified by the perfusion images. There was no difference of the infarct area as measured by SPECT (21.1 ± 21.2%) and by histology (21.7 ± 22.0%; p=0.45). There was a strong correlation between individual values of the area of infarction measured by these two methods., Conclusion: The developed system presented adequate spatial resolution and high accuracy for the detection and quantification of myocardial infarction areas, consisting in a low cost and versatile option for high-resolution SPECT imaging of small rodents.

This study aimed to characterize the role played by baroreceptors and chemoreceptors in the hypertensive response to bilateral carotid occlusion (BCO) in conscious C57BL mice. On the day before the experiments the animals were implanted with pneumatic cuffs around their common carotid arteries and a femoral catheter for measurement of arterial pressure. Under the same surgical approach, groups of mice were submitted to aortic or carotid sinus denervation or sham surgery. BCO was performed for 30 or 60 s, promoting prompt and sustained increase in mean arterial pressure and fall in heart rate. Compared with intact mice, the hypertensive response to 30 s of BCO was enhanced in aortic-denervated mice (52 ± 4 vs. 41 ± 4 mmHg; P < 0.05) but attenuated in carotid sinus-denervated mice (15 ± 3 vs. 41 ± 4 mmHg; P < 0.05). Suppression of peripheral chemoreceptor activity by hyperoxia [arterial partial pressure of oxygen (Pa(O(2))) > 500 mmHg] attenuated the hypertensive response to BCO in intact mice (30 ± 6 vs. 51 ± 5 mmHg in normoxia; P < 0.05) and abolished the bradycardia. It did not affect the hypertensive response in carotid sinus-denervated mice (20 ± 4 vs. 18 ± 3 mmHg in normoxia; P < 0.05). The attenuation of the hypertensive response to BCO by carotid sinus denervation or hyperoxia indicates that the hypertensive response in conscious mice is mediated by both baro- and chemoreceptors. In addition, aortic denervation potentiates the hypertensive response elicited by BCO in conscious mice.