Laurence Mangin

Conditional glucocorticoid receptor expression in the heart induces atrio-ventricular block

Corticosteroid hormones (aldosterone and glucocorticoids) and their receptors are now recognized as major modulators of cardiovascular pathophysiology, but their specific roles remain elusive. Glucocorticoid hormones (GCs), which are widely used to treat acute and chronic diseases, often have adverse cardiovascular effects such as heart failure, hypertension, atherosclerosis, or metabolic alterations. The direct effects of GC on the heart are difficult to evaluate, as changes in plasma GC concentrations have multiple consequences due to the ubiquitous expression of the glucocorticoid receptor (GR), resulting in secondary effects on cardiac function. We evaluated the effects of GR on the heart in a conditional mouse model in which the GR was overex‐pressed solely in cardiomyocytes. The transgenic mice displayed electrocardiogram (ECG) abnormalities: a long PQ interval, increased QRS and QTc duration as well as chronic atrio‐ventricular block, without cardiac hypertrophy or fibrosis. The ECG alterations were reversible on GR expression shutoff. Isolated ventricular cardiomyo‐cytes showed major ion channel remodeling, with decreases in INa,Ito, and IKslow activity and changes in cell calcium homeostasis (increase in Cal, in Ca2+ transients and in sarcoplasmic reticulum Ca2+ load). This pheno‐type differs from that observed in mice overexpressing the mineralocorticoid receptor in the heart, which displayed ventricular arrhythmia. Our mouse model highlights novel effects of GR activation in the heart indicating that GR has direct and specific cardiac effects in the mouse.—Sainte‐Marie, Y., Cat, A. N. D., Perrier, R., Mangin, L., Soukaseum, C., Peuchmaur, M., Tronche, F., Farman, N., Escoubet, B., Benitah, J‐P., Jaisser, F. Conditional glucocorticoid receptor expression in the heart induces atrio‐ventricular block. FASEB J. 21, 3133–3141 (2007)

Source of human ventilatory chaos: lessons from switching controlled mechanical ventilation to inspiratory pressure support in critically ill patients.

Ventilatory flow measured at the airway opening in humans exhibits a complex dynamics that has the features of chaos. Currently available data point to a neural origin of this feature, but the role of respiratory mechanics has not been specifically assessed. In this aim, we studied 17 critically ill mechanically ventilated patients during a switch form an entirely machine-controlled assistance mode (assist-controlled ventilation ACV) to a patient-driven mode (inspiratory pressure support IPS). Breath-by-breath respiratory variability was assessed with the coefficient of variation of tidal volume, total cycle time, inspiratory time, expiratory time, mean inspiratory flow, duty cycle. The detection of chaos was performed with the noise titration technique. When present, chaos was characterized with numerical indexes (correlation dimension, irregularity; largest Lyapunov exponent, sensitivity to initial conditions). Expectedly, the coefficients of variations of the respiratory variables were higher during IPS than during ACV. During ACV, noise titration failed to detect nonlinearities in 12 patients who did not exhibit signs of spontaneous respiratory activity. This indicates that the mechanical properties of the respiratory system were not sufficient to produce ventilatory chaos in the presence of a nonlinear command (ventilator clock). A positive noise limit was found in the remaining 5 cases, but these patients exhibited signs of active expiratory control (highly variable expiratory time, respiratory frequency higher than the set frequency). A positive noise limit was also observed in 16/17 patients during IPS (p<0.001). These observations suggest that ventilatory chaos predominantly has a neural origin (intrinsic to the respiratory central pattern generators, resulting from their perturbation by respiratory afferents, or both), with little contribution of respiratory mechanics, if any.

Neural Mechanisms Underlying Breathing Complexity

Breathing is maintained and controlled by a network of automatic neurons in the brainstem that generate respiratory rhythm and receive regulatory inputs. Breathing complexity therefore arises from respiratory central pattern generators modulated by peripheral and supra-spinal inputs. Very little is known on the brainstem neural substrates underlying breathing complexity in humans. We used both experimental and theoretical approaches to decipher these mechanisms in healthy humans and patients with chronic obstructive pulmonary disease (COPD). COPD is the most frequent chronic lung disease in the general population mainly due to tobacco smoke. In patients, airflow obstruction associated with hyperinflation and respiratory muscles weakness are key factors contributing to load-capacity imbalance and hence increased respiratory drive. Unexpectedly, we found that the patients breathed with a higher level of complexity during inspiration and expiration than controls. Using functional magnetic resonance imaging (fMRI), we scanned the brain of the participants to analyze the activity of two small regions involved in respiratory rhythmogenesis, the rostral ventro-lateral (VL) medulla (pre-Bötzinger complex) and the caudal VL pons (parafacial group). fMRI revealed in controls higher activity of the VL medulla suggesting active inspiration, while in patients higher activity of the VL pons suggesting active expiration. COPD patients reactivate the parafacial to sustain ventilation. These findings may be involved in the onset of respiratory failure when the neural network becomes overwhelmed by respiratory overload We show that central neural activity correlates with airflow complexity in healthy subjects and COPD patients, at rest and during inspiratory loading. We finally used a theoretical approach of respiratory rhythmogenesis that reproduces the kernel activity of neurons involved in the automatic breathing. The model reveals how a chaotic activity in neurons can contribute to chaos in airflow and reproduces key experimental fMRI findings.

Cardiovascular Effects of Aldosterone Insight From Adult Carriers of Mineralocorticoid Receptor Mutations

Background—High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations. Methods and Results—In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P<0.0001), together with increased salt appetite (1.8-fold; P=0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P=0.001; E/e′, P=0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women. Conclusions—Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling. Clinical Trial Registration—http://www.clinicaltrials.gov; unique identifier: NCT00646828.Background— High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations.nnMethods and Results— In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P <0.0001), together with increased salt appetite (1.8-fold; P =0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P =0.001; E/e′, P =0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women.nnConclusions— Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling.nnClinical Trial Registration— ; unique identifier: [NCT00646828][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00646828&atom=%2Fcirccvg%2F6%2F4%2F381.atom

Chaotic dynamics of cardioventilatory coupling in humans: effects of ventilatory modes

Cardioventilatory coupling (CVC), a transient temporal alignment between the heartbeat and inspiratory activity, has been studied in animals and humans mainly during anesthesia. The origin of the coupling remains uncertain, whether or not ventilation is a main determinant in the CVC process and whether the coupling exhibits chaotic behavior. In this frame, we studied sedative-free, mechanically ventilated patients experiencing rapid sequential changes in breathing control during ventilator weaning during a switch from a machine-controlled assistance mode [assist-controlled ventilation (ACV)] to a patient-driven mode [inspiratory pressure support (IPS) and unsupported spontaneous breathing (USB)]. Time series were computed as R to start inspiration (RI) and R to the start of expiration (RE). Chaos was characterized with the noise titration method (noise limit), largest Lyapunov exponent (LLE) and correlation dimension (CD). All the RI and RE time series exhibit chaotic behavior. Specific coupling patterns were displayed in each ventilatory mode, and these patterns exhibited different linear and chaotic dynamics. When switching from ACV to IPS, partial inspiratory loading decreases the noise limit value, the LLE, and the correlation dimension of the RI and RE time series in parallel, whereas decreasing intrathoracic pressure from IPS to USB has the opposite effect. Coupling with expiration exhibits higher complexity than coupling with inspiration during mechanical ventilation either during ACV or IPS, probably due to active expiration. Only 33% of the cardiac time series (RR interval) exhibit complexity either during ACV, IPS, or USB making the contribution of the cardiac signal to the chaotic feature of the coupling minimal. We conclude that 1) CVC in unsedated humans exhibits a complex dynamic that can be chaotic, and 2) ventilatory mode has major effects on the linear and chaotic features of the coupling. Taken together these findings reinforce the role of ventilation in the CVC process.

Respiratory Neural Network: Activity and Connectivity

Chaos in the rhythmic activity is a major issue that has been discussed in many studies of neuroscience and physiology, and especially in the respiratory air flow. Here, we present the results of two studies concerning the activity and the connectivity of the respiratory neural network in healthy humans and patients with obstructive lung disease. Our results show an increase in the dynamic chaos of airway flow in patients, focusing on expiratory flow. We then sought the reasons for this augmentation in analyzing the activity of neural centers involved in respiratory rhythmogenesis, using functional brain imaging of the automatic neural networks, the first group generating inspiration (pre-Botzinger complex) and the second in charge of expiration (the parafacial group). Brain imaging reveals in healthy humans a significant activation of the pre-Botzinger complex linked to a high active inspiration while patients have a higher expiratory parafacial excitability leading to an active expiration. We also propose a theoretical model of respiratory rhythmogenesis which reproduces the synchronized respiratory neural network from two chaotic pacemakers, the first modelling the pre-Botzinger complex and the second modelling the expiration. Our model reveals how the synchronized chaotic activity of this network reproduced the experimental data of the activity of the respiratory nerve centers both in healthy humans and the patients. We are able to reproduce fMRI signal after hemodynamic convolution of the simulated synchronized neural network. Besides, the respiratory neural network comprises the automatic brainstem and voluntary cortical network. The extension of the study to other important aspects as functional connectivity and Granger causality allow to better understand the communication within the network with the aim to develop new therapeutic strategies involving the modulation of brain oscillation (Hess et al., PLoS One 8:e75740, 2013; Yu et al., Hum. Brain Mapp. 37:2736–2754, 2016).

Cardiovascular Effects of AldosteroneClinical Perspective: Insight From Adult Carriers of Mineralocorticoid Receptor Mutations

Background—High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations. Methods and Results—In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P<0.0001), together with increased salt appetite (1.8-fold; P=0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P=0.001; E/e′, P=0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women. Conclusions—Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling. Clinical Trial Registration—http://www.clinicaltrials.gov; unique identifier: NCT00646828.Background— High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations.nnMethods and Results— In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P <0.0001), together with increased salt appetite (1.8-fold; P =0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P =0.001; E/e′, P =0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women.nnConclusions— Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling.nnClinical Trial Registration— ; unique identifier: [NCT00646828][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00646828&atom=%2Fcirccvg%2F6%2F4%2F381.atom

Cardiovascular Effects of AldosteroneClinical Perspective

Background—High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations. Methods and Results—In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P<0.0001), together with increased salt appetite (1.8-fold; P=0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P=0.001; E/e′, P=0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women. Conclusions—Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling. Clinical Trial Registration—http://www.clinicaltrials.gov; unique identifier: NCT00646828.Background— High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations.nnMethods and Results— In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P <0.0001), together with increased salt appetite (1.8-fold; P =0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P =0.001; E/e′, P =0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women.nnConclusions— Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling.nnClinical Trial Registration— ; unique identifier: [NCT00646828][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00646828&atom=%2Fcirccvg%2F6%2F4%2F381.atom