Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure

Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice

Cardiomyocyte hypertrophy occurs in response to a variety of physiological and pathological stimuli. While pathological hypertrophy in heart failure is usually coupled with depressed contractile function, physiological hypertrophy associates with increased contractility. In the present study, we explored whether 8 weeks of moderate intensity exercise training would lead to a cardiac anti-remodelling effect in an experimental model of heart failure associated with a deactivation of a pathological (calcineurin/NFAT, CaMKII/HDAC) or activation of a physiological (Akt-mTOR) hypertrophy signalling pathway. The cardiac dysfunction, exercise intolerance, left ventricle dilatation, increased heart weight and cardiomyocyte hypertrophy from mice lacking alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO mice) were associated with sympathetic hyperactivity induced heart failure. The relative contribution of Ca(2+)-calmodulin high-affinity (calcineurin/NFAT) and low-affinity (CaMKII/HDAC) targets to pathological hypertrophy of alpha(2A)/alpha(2C)ARKO mice was verified. While nuclear calcineurin B, NFATc3 and GATA-4 translocation were significantly increased in alpha(2A)/alpha(2C)ARKO mice, no changes were observed in CaMKII/HDAC activation. As expected, cyclosporine treatment decreased nuclear translocation of calcineurin/NFAT in alpha(2A)/alpha(2C)ARKO mice, which was associated with improved ventricular function and a pronounced anti-remodelling effect. The Akt/mTOR signalling pathway was not activated in alpha(2A)/alpha(2C)ARKO mice. Exercise training improved cardiac function and exercise capacity in alpha(2A)/alpha(2C)ARKO mice and decreased heart weight and cardiomyocyte width paralleled by diminished nuclear NFATc3 and GATA-4 translocation as well as GATA-4 expression levels. When combined, these findings support the notion that deactivation of calcineurin/NFAT pathway-induced pathological hypertrophy is a preferential mechanism by which exercise training leads to the cardiac anti-remodelling effect in heart failure.

Exercise training reduces cardiac angiotensin II levels and prevents cardiac dysfunction in a genetic model of sympathetic hyperactivity-induced heart failure in mice

The role of exercise training (ET) on cardiac renin-angiotensin system (RAS) was investigated in 3-5 month-old mice lacking alpha(2A-) and alpha(2C-)adrenoceptors (alpha(2A)/alpha(2C)ARKO) that present heart failure (HF) and wild type control (WT). ET consisted of 8-week running sessions of 60 min, 5 days/week. In addition, exercise tolerance, cardiac structural and function analysis were made. At 3 months, fractional shortening and exercise tolerance were similar between groups. At 5 months, alpha(2A)/alpha(2C)ARKO mice displayed ventricular dysfunction and fibrosis associated with increased cardiac angiotensin (Ang) II levels (2.9-fold) and increased local angiotensin-converting enzyme activity (ACE 18%). ET decreased alpha(2A)/alpha(2C)ARKO cardiac Ang II levels and ACE activity to age-matched untrained WT mice levels while increased ACE2 expression and prevented exercise intolerance and ventricular dysfunction with little impact on cardiac remodeling. Altogether, these data provide evidence that reduced cardiac RAS explains, at least in part, the beneficial effects of ET on cardiac function in a genetic model of HF.

Intracellular mechanisms of specific beta-adrenoceptor antagonists involved in improved cardiac function and survival in a genetic model of heart failure

beta-blockers, as class, improve cardiac function and survival in heart failure (HF). However, the molecular mechanisms underlying these beneficial effects remain elusive. In the present study, metoprolol and carvedilol were used in doses that display comparable heart rate reduction to assess their beneficial effects in a genetic model of sympathetic hyperactivity-induced HF (alpha(2A)/alpha(2C)-ARKO mice). Five month-old HF mice were randomly assigned to receive either saline, metoprolol or carvedilol for 8 weeks and age-matched wild-type mice (WT) were used as controls. HF mice displayed baseline tachycardia, systolic dysfunction evaluated by echocardiography, 50% mortality rate, increased cardiac myocyte width (50%) and ventricular fibrosis (3-fold) compared with WT. All these responses were significantly improved by both treatments. Cardiomyocytes from HF mice showed reduced peak [Ca(2+)](i) transient (13%) using confocal microscopy imaging. Interestingly, while metoprolol improved [Ca(2+)](i) transient, carvedilol had no effect on peak [Ca(2+)](i) transient but also increased [Ca(2+)] transient decay dynamics. We then examined the influence of carvedilol in cardiac oxidative stress as an alternative target to explain its beneficial effects. Indeed, HF mice showed 10-fold decrease in cardiac reduced/oxidized glutathione ratio compared with WT, which was significantly improved only by carvedilol treatment. Taken together, we provide direct evidence that the beneficial effects of metoprolol were mainly associated with improved cardiac Ca(2+) transients and the net balance of cardiac Ca(2+) handling proteins while carvedilol preferentially improved cardiac redox state. (C) 2008 Elsevier Inc. All rights reserved.

Exercise training delays cardiac dysfunction and prevents calcium handling abnormalities in sympathetic hyperactivity-induced heart failure mice

Exercise training (ET) is a coadjuvant therapy in preventive cardiology. It delays cardiac dysfunction and exercise intolerance in heart failure (HF); however, the molecular mechanisms underlying its cardioprotection are poorly understood. We tested the hypothesis that ET would prevent Ca2+ handling abnormalities and ventricular dysfunction in sympathetic hyperactivity-induced HF mice. A cohort of male wildtype (WT) and congenic (alpha 2A/alpha 2C)-adrenoceptor knockout ((alpha 2A/alpha 2C)ARKO) mice with C57BL6/J genetic background (3-5 mo of age) were randomly assigned into untrained and exercise-trained groups. ET consisted of 8-wk swimming session, 60 min, 5 days/wk. Fractional shortening (FS) was assessed by two-dimensional guided M-mode echocardiography. The protein expression of ryanodine receptor (RyR), phospho-Ser(2809)-RyR, sarcoplasmic reticulum Ca2+ ATPase (SERCA2), Na+/Ca2+ exchanger (NCX), phospholamban (PLN), phospho-Ser(16)-PLN, and phospho-Thr(17)-PLN were analyzed by Western blotting. At 3 mo of age, no significant difference in FS and exercise tolerance was observed between WT and (alpha 2A/alpha 2C)ARKO mice. At 5 mo, when cardiac dysfunction is associated with lung edema and increased plasma norepinephrine levels, (alpha 2A/alpha 2C)ARKO mice presented reduced FS paralleled by decreased SERCA2 (26%) and NCX (34%). Conversely, (alpha 2A/alpha 2C)ARKO mice displayed increased phospho-Ser(16)-PLN (76%) and phospho-Ser(2809)-RyR (49%). ET in (alpha 2A/alpha 2C)ARKO mice prevented exercise intolerance, ventricular dysfunction, and decreased plasma norepinephrine. ET significantly increased the expression of SERCA2 (58%) and phospho-Ser(16)-PLN (30%) while it restored the expression of phospho-Ser(2809)-RyR to WT levels. Collectively, we provide evidence that improved net balance of Ca2+ handling proteins paralleled by a decreased sympathetic activity on ET are, at least in part, compensatory mechanisms against deteriorating ventricular function in HF.

Baroreflex Sensitivity Impairment Is Associated With Cardiac Diastolic Dysfunction in Rats

Background: Studies have shown that the autonomic dysfunction accompanied by impaired baroreflex sensitivity was associated with higher mortality. However, the influence of decreased baroreflex sensitivity on cardiac function, especially in diastolic function, is not well understood. This study evaluated the morpho-functional changes associated with baroreflex impairment induced by chronic sinoaortic denervation (SAD). Methods and Results: Animals were divided into sinoaortic denervation (SAD) and control (C) groups. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses, induced by vasoactive drugs. Cardiac function was studied by echocardiography and by left ventricle (LV) catheterization. LV collagen content and the expression of regulatory proteins involved in intracellular Ca(2+) homeostasis were quantified. Results showed higher LV mass in SAD versus C animals. Furthermore, an increase in deceleration time of E-wave in the SAD versus the C group (2.14 +/- 0.07 ms vs 1.78 +/- 0.03 ms) was observed. LV end-diastolic pressure was increased and the minimum dP/dt was decreased in the SAD versus the C group (12 +/- 1.5 mm Hg vs 5.3 +/- 0.2 mm Hg and 7,422 +/- 201 vs 4,999 +/- 345 mm Hg/s, respectively). SERCA/NCX ratio was lower in SAD than in control rats. The same was verified in SERCA/PLB ratio. Conclusions: The results suggest that baroreflex dysfunction is associated with cardiac diastolic dysfunction independently of the presence of other risk factors. (J Cardiac Fail 2011;17:519-525)

Is acute static stretching able to reduce the time to exhaustion at power output corresponding to maximal oxygen uptake?

Samogin Lopes, FA, Menegon, EM, Franchini, E, Tricoli, V, and de M. Bertuzzi, RC. Is acute static stretching able to reduce the time to exhaustion at power output corresponding to maximal oxygen uptake? J Strength Cond Res 24(6): 1650-1656, 2010-This study analyzed the effect of an acute static stretching bout on the time to exhaustion (T(lim)) at power output corresponding to (V) over dotO(2)max. Eleven physically active male subjects (age 22.3 +/- 2.8 years, (V) over dotO(2)max 2.7 +/- 0.5 L . min(-1)) completed an incremental cycle ergometer test, 2 muscle strength tests, and 2 maximal tests to exhaustion at power output corresponding to (V) over dotO(2)max with and without a previous static stretching bout. The T(lim) was not significantly affected by the static stretching (164 +/- 28 vs. 150 +/- 26 seconds with and without stretching, respectively, p = 0.09), but the time to reach (V) over dotO(2)max (118 +/- 22 vs. 102 +/- 25 seconds), blood-lactate accumulation immediately after exercise (10.7 +/- 2.9 vs. 8.0 +/- 1.7 mmol . L(-1)), and oxygen deficit (2.4 +/- 0.9 vs. 2.1 +/- 0.7 L) were significantly reduced (p <= 0.02). Thus, an acute static stretching bout did not reduce T(lim) at power output corresponding to (V) over dotO(2)max possibly by accelerating aerobic metabolism activation at the beginning of exercise. These results suggest that coaches and practitioners involved with aerobic dependent activities may use static stretching as part of their warm-up routines without fear of diminishing high-intensity aerobic exercise performance.

Influence of angiotensinogen and angiotensin-converting enzyme polymorphisms on cardiac hypertrophy and improvement on maximal aerobic capacity caused by exercise training

Background The allele threonine (T) of the angiotensinogen has been associated with ventricular hypertrophy in hypertensive patients and soccer players. However, the long-term effect of physical exercise in healthy athletes carrying the T allele remains unknown. We investigated the influence of methionine M or T allele of the angiotensinogen and D or I allele of the angiotensin-converting enzyme on left-ventricular mass index (LVMI) and maximal aerobic capacity in young healthy individuals after long-term physical exercise training. Design Prospective clinical trial. Methods Eighty-three policemen aged between 20 and 35 years (mean +/- SD 26 +/- 4.5 years) were genotyped for the M235T gene angiotensinogen polymorphism (TT, n=25; MM/MT, n=58) and angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism (11, n=18; DD/DI, n=65). Left-ventricular morphology was evaluated by echocardiography and maximal aerobic capacity (VO(2peak)) by cardiopulmonary exercise test before and after 17 weeks of exercise training (50-80% VO(2peak)). Results Baseline VO(2peak) and LVMI were similar between TT and MM/MT groups, and II and DD/DI groups. Exercise training increased significantly and similarly VO(2peak) in homozygous TT and MM/MT individuals, and homozygous II and DD/DI individuals. In addition, exercise training increased significantly LVMI in TT and MM/MT individuals (76.5 +/- 3 vs. 86.7 +/- 4, P=0.00001 and 76.2 +/- 2 vs. 81.4 +/- 2, P=0.00001, respectively), and II and DD/DI individuals (777 +/- 4 vs. 81.5 +/- 4, P=0.0001 and 76 +/- 2 vs. 83.5 +/- 2, P=0.0001, respectively). However, LVMI I in TT individuals was significantly greater than in MM/MT individuals (P=0.04). LVMI was not different between 11 and DD/DI individuals. Conclusion Left-ventricular hypertrophy caused by exercise training is exacerbated in homozygous TT individuals with angiotensinogen polymorphism. Eur J Cardiovasc Prev Rehabil 16:487-492 (C) 2009 The European Society of Cardiology

Robust model predictive controller with output feedback and target tracking

A model predictive controller (MPC) is proposed, which is robustly stable for some classes of model uncertainty and to unknown disturbances. It is considered as the case of open-loop stable systems, where only the inputs and controlled outputs are measured. It is assumed that the controller will work in a scenario where target tracking is also required. Here, it is extended to the nominal infinite horizon MPC with output feedback. The method considers an extended cost function that can be made globally convergent for any finite input horizon considered for the uncertain system. The method is based on the explicit inclusion of cost contracting constraints in the control problem. The controller considers the output feedback case through a non-minimal state-space model that is built using past output measurements and past input increments. The application of the robust output feedback MPC is illustrated through the simulation of a low-order multivariable system.

Enlarging the domain of attraction of stable MPC controllers, maintaining the output performance

This work presents an alternative way to formulate the stable Model Predictive Control (MPC) optimization problem that allows the enlargement of the domain of attraction, while preserving the controller performance. Based on the dual MPC that uses the null local controller, it proposed the inclusion of an appropriate set of slacked terminal constraints into the control problem. As a result, the domain of attraction is unlimited for the stable modes of the system, and the largest possible for the non-stable modes. Although this controller does not achieve local optimality, simulations show that the input and output performances may be comparable to the ones obtained with the dual MPC that uses the LQR as a local controller. (C) 2009 Elsevier Ltd. All rights reserved.

Galerkin Method and Weighting Functions Applied to Nonlinear H(infinity) Control with Output Feedback

This paper considers two aspects of the nonlinear H(infinity) control problem: the use of weighting functions for performance and robustness improvement, as in the linear case, and the development of a successive Galerkin approximation method for the solution of the Hamilton-Jacobi-Isaacs equation that arises in the output-feedback case. Design of nonlinear H(infinity) controllers obtained by the well-established Taylor approximation and by the proposed Galerkin approximation method applied to a magnetic levitation system are presented for comparison purposes.

On the convergence of successive Galerkin approximation for nonlinear output feedback H(infinity) control

Although the formulation of the nonlinear theory of H(infinity) control has been well developed, solving the Hamilton-Jacobi-Isaacs equation remains a challenge and is the major bottleneck for practical application of the theory. Several numerical methods have been proposed for its solution. In this paper, results on convergence and stability for a successive Galerkin approximation approach for nonlinear H(infinity) control via output feedback are presented. An example is presented illustrating the application of the algorithm.

Particle-Image Velocimetry Study of a Pediatric Ventricular Assist Device

Particle-image velocimetry (PIV) was used to visualize the flow within an optically transparent pediatric ventricular assist device (PVAD) under development in our laboratory The device studied is a diaphragm type pulsatile pump with an ejection volume of 30 ml per beating cycle intended for temporary cardiac assistance as a bridge to transplantation or recovery in children. Of particular interest was the identification of flow patterns, including regions of stagnation and/or strong turbulence that often promote thrombus formation and hemolysis, which can degrade the usefulness of such devices. For this purpose, phase-locked PIV measurements were performed in planes parallel to the diaphram that drives the flow in the device. The test fluid was seeded with 10 Am polystyrene spheres, and the motion of these particles was used to determine the instantaneous flow velocity distribution in the illumination plane. These measurements revealed that flow velocities up to 1.0 m/s can occur within the PVAD. Phase-averaged velocity fields revealed the fixed vortices that drive the bulk flow within the device, though significant cycle-to-cycle variability was also quite apparent in the instantaneous velocity distributions, most notably during the filling phase. This cycle-to-cycle variability can generate strong turbulence that may contribute to greater hemolysis. Stagnation regions have also been observed between the input and output branches of the prototype, which can increase the likelihood of thrombus formation. [DOI: 10.1115/1.4001252]

Predation and reproductive output of the ladybird beetle Stethorus tridens preying on tomato red spider mite Tetranychus evansi

Predatory behaviour and reproductive output of the ladybird beetle Stethorus tridens Gordon as function of the tomato red spider mite (TRSM), Tetranychus evansi Baker & Pritchard, densities was investigated in the laboratory. Adult female of S. tridens were isolated in cylindrical plastic arenas, containing a leaf disc of Solanum americanum Mill. with 5, 20, 40, 60, 80 or 100 T. evansi nymphs. The number of prey consumed and eggs laid were evaluated daily for ten consecutive days, starting at the oviposition. Oviposition of S. tridens was positively correlated with prey consumption and lower threshold prey consumption for S. tridens laying eggs was 16.3 mites per day. The instantaneous rate of attack (ca. discovery area) and the handling time were 0.0062 h(-1) and 0.83 h, and 0.00254 h(-1) and 0.78 h, respectively, for predators at the 1st- and 10th-oviposition day. The predator exhibited a type II functional response at 1st- and 10th-oviposition day with a maximum consumption per predator of 33 T. evansi nymphs per day at the highest prey density. The ladybird beetle S. tridens is often collected associated with red spider mite colonies on solanaceous wild plants and the results suggest the potential of this ladybird beetle to control T. evansi in tomatoes crops.

The Heart and Patterns of Cardiac Outflow in Crocodilia

The anatomy of the crocodilian heart and major arteries has fascinated people for a very long time. The first scientific paper seems to be that by the Italian anatomist Bartolomeo Panizza in 1833 who wrote about the structure of the heart and the circulation of the blood in /Crocodilys lucius/, an early name for the American Alligator. Since 1833 there have been many papers and the crocodilian heart has attracted the attention of generation after generation of anatomists and physiologists with ever-increasingly sophisticated investigatory techniques be­ing applied to questions about the functional significance of the puzzlingly complex anatomy.