Cardiac Kir2.1 and NaV1.5 Channels Traffic Together to the Sarcolemma to Control Excitability.

RATIONALE: In cardiomyocytes, NaV1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. OBJECTIVE: The objective of this study was to test whether NaV1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. METHODS AND RESULTS: In patch-clamp experiments, coexpression of trafficking-deficient mutants Kir2.1Δ314-315 or Kir2.1R44A/R46A with wild-type (WT) NaV1.5WT in heterologous cells reduced inward sodium current compared with NaV1.5WT alone or coexpressed with Kir2.1WT. In cell surface biotinylation experiments, expression of Kir2.1Δ314-315 reduced NaV1.5 channel surface expression. Glycosylation analysis suggested that NaV1.5WT and Kir2.1WT channels associate early in their biosynthetic pathway, and fluorescence recovery after photobleaching experiments demonstrated that coexpression with Kir2.1 increased cytoplasmic mobility of NaV1.5WT, and vice versa, whereas coexpression with Kir2.1Δ314-315 reduced mobility of both channels. Viral gene transfer of Kir2.1Δ314-315 in adult rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current and inward sodium current, maximum diastolic potential and action potential depolarization rate, and increased action potential duration. On immunostaining, the AP1 (adaptor protein complex 1) colocalized with NaV1.5WT and Kir2.1WT within areas corresponding to t-tubules and intercalated discs. Like Kir2.1WT, NaV1.5WT coimmunoprecipitated with AP1. Site-directed mutagenesis revealed that NaV1.5WT channels interact with AP1 through the NaV1.5Y1810 residue, suggesting that, like for Kir2.1WT, AP1 can mark NaV1.5 channels for incorporation into clathrin-coated vesicles at the trans-Golgi. Silencing the AP1 ϒ-adaptin subunit in human induced pluripotent stem cell-derived cardiomyocytes reduced inward rectifier potassium current, inward sodium current, and maximum diastolic potential and impaired rate-dependent action potential duration adaptation. CONCLUSIONS: The NaV1.5-Kir2.1 macromolecular complex pre-assembles early in the forward trafficking pathway. Therefore, disruption of Kir2.1 trafficking in cardiomyocytes affects trafficking of NaV1.5, which may have important implications in the mechanisms of arrhythmias in inheritable cardiac diseases.

Effects of Taping and Balance Exercises on Knee and Lower-Extremity Function in Amateur Soccer Players: A Randomized Controlled Trial.

CONTEXT: Knee injury prevention is a critical aspect in sport rehabilitation sciences, and taping is a widely used technique in this field. Nevertheless, the role and effectiveness of a long-term application of Kinesio Taping (KT) on knee function, disability, and injury prevention remain unclear. OBJECTIVE: To determine the effect of KT, alone or in combination with balance exercises (BE), on dynamic and static knee balance and flexibility. DESIGN: Randomized trial design. SETTING: University of Valencia (Spain). PARTICIPANTS: Forty-eight male amateur soccer players. INTERVENTION: Participants were assigned to 3 groups: Sham KT (sKT) + BE, KT + BE, and KT in isolation. The intervention period lasted 4 weeks. Three evaluations were performed: at baseline (pre), at 2 weeks (mid), and at 4 weeks posttreatment (post). MAIN OUTCOME MEASURES: Y Balance Test, unipedal stance test, the toe touch test, and the Knee Injury and Osteoarthritis Outcome Score. RESULTS: Both sKT + BE and KT + BE groups achieved significant pre-post improvements in SEBT, unipedal stance test, and toe touch test. The KT group only showed significant intragroup differences in the left and right unipedal stance test variable (P < .05, d = 0.76, d = 0.62, respectively). The sham KT group obtained the strongest results in all physical variables. Regarding the Knee Injury and Osteoarthritis Outcome Score, pre-post significant changes were found in the sham group (P < .05, d = 0.28). CONCLUSIONS: Both sham and real KT in combination with BE achieved significant improvements on all physical variables, and these differences were significantly greater compared with those found in the KT in the isolation group, suggesting that benefits in knee function are due to the BE. LEVEL OF EVIDENCE: Therapy level 1b.

Effect of Kinesio Taping and balance exercises on postural control in amateur soccer players: A randomised control trial.

The objective of this study was to determine the effect of Kinesio Taping (KT), alone or together with balance exercises (BE), on parameters related to postural control, such as dynamic balance, static balance and flexibility. Forty-four male amateur soccer players (mean age 24.45 (4.79) years) were randomly allocated to 3 groups: KT+BE that received KT and BE (n = 16); KTp+BE, in which the KT was used as a placebo (n = 15) and KT alone (n = 13). The intervention period lasted 4 weeks. Star Excursion Balance Test (SEBT), Unipedal Stance Test (UST) and the Toe Touch Test (TTT) were assessed at baseline (pre), two weeks after beginning the treatment (mid) and after the intervention (post). We observed a significant improvement on the SEBT (mid and post-treatment) and the UST (post-treatment), but not on the TTT in either KT+BE or KTp+BE groups post treatment. No differences were found either in KT group at any time point or between groups in any variable studied. In conclusion, KT functional correction technique does not improve static and dynamic balance when applied alone, whereas BE alone or combined with KT significantly improves these variables. None of these techniques has any effect on flexibility. Abbreviation: KT: Kinesiotaping; BE: Balance exercises; KTp: Placebo Kinesiotaping; UST: Unipedal Stance Test; SEBT: Star Excursion Balance Test; TTT: Toe Touch Test.

Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology.

PURPOSE: Mechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch. METHODS: Atrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n = 28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3 µM). RESULTS: On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3 µM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3 µM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138 ± 26 ms vs 95 ± 9 ms; p < 0.01), ventricular refractoriness (155 ± 18 ms vs 124 ± 16 ms; p < 0.01) and increments in spectral concentration (23 ± 5% vs 17 ± 2%; p < 0.01), the fifth percentile of ventricular activation intervals (46 ± 8 ms vs 31 ± 3 ms; p < 0.05), and wavelength of ventricular fibrillation (2.5 ±0.5 cm vs 1.7 ± 0.3 cm; p < 0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control = 38%, 0.03 µM = 33%, 0.1 µM = 33%, 0.3 µM = 14%; p < 0.01) and the stretch-induced increments in arrhythmia complexity index (control = 62%, 0.03µM = 41%, 0.1 µM = 32%, 0.3 µM = 16%; p < 0.05) progressively decreased on increasing the GS967 concentration. CONCLUSIONS: GS967 attenuates stretch-induced changes in cardiac electrophysiology.

Constitutive Intracellular Na+ Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: In catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac Purkinje cells (PCs) appear more susceptible to Ca(2+) dysfunction than ventricular myocytes (VMs). The underlying mechanisms remain unknown. Using a CPVT mouse (RyR2(R4496C+/Cx40eGFP)), we tested whether PC intracellular Ca(2+) ([Ca(2+)]i) dysregulation results from a constitutive [Na(+)]i surplus relative to VMs. METHODS AND RESULTS: Simultaneous optical mapping of voltage and [Ca(2+)]i in CPVT hearts showed that spontaneous Ca(2+) release preceded pacing-induced triggered activity at subendocardial PCs. On simultaneous current-clamp and Ca(2+) imaging, early and delayed afterdepolarizations trailed spontaneous Ca(2+) release and were more frequent in CPVT PCs than CPVT VMs. As a result of increased activity of mutant ryanodine receptor type 2 channels, sarcoplasmic reticulum Ca(2+) load, measured by caffeine-induced Ca(2+) transients, was lower in CPVT VMs and PCs than respective controls, and sarcoplasmic reticulum fractional release was greater in both CPVT PCs and VMs than respective controls. [Na(+)]i was higher in both control and CPVT PCs than VMs, whereas the density of the Na(+)/Ca(2+) exchanger current was not different between PCs and VMs. Computer simulations using a PC model predicted that the elevated [Na(+)]i of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca(2+) release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na(+)]i monotonically increased delayed afterdepolarization frequency. Confocal imaging experiments showed that postpacing Ca(2+) spark frequency was highest in intact CPVT PCs, but such differences were reversed on saponin-induced membrane permeabilization, indicating that differences in [Na(+)]i played a central role. CONCLUSIONS: In CPVT mice, the constitutive [Na(+)]i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.

Allometric scaling of electrical excitation and propagation in the mammalian heart.

Variations in body mass impose constraints on the structure and function of mammalian species, including those of the cardiovascular system. Numerous biological processes, including cardiovascular parameters, have been shown to scale with body mass (BM) according to the law of allometric scaling: Y=Y =a∙BMb (Y, biological process; a, normalization constant; b, scaling exponent, which in many instances is a multiple of »). These parameters include heart and breathing rates, intervals and subintervals of the electrocardiogram (ECG), action potential duration (APD), metabolic rate, and temporal properties of ventricular fibrillation. For instance, the hierarchical branching networks of the vascular system, and of the specialized conduction system in the heart have been proposed to be important determinants of allometric scaling. A global and unifying molecular mechanism of allometric scaling has not been put forth, but changes in gene expression have been proposed to play an important role. Even though it is accepted that differences in body size have cardiovascular effects, the use of scaling in the clinical setting is limited. An increase in the clinical utilization of scaling is thought to lead to improved cardiovascular disease diagnosis and management in patients.

Effects of JTV-519 on stretch-induced manifestations of mechanoelectric feedback.

JTV-519 is a 1,4-benzothiazepine derivative with multichannel effects that inhibits Ca2+ release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca2+ overload. Mechanical stretch increases cellular Na+ inflow, activates the reverse mode of the Na+ /Ca2+ exchanger, and modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. This study aims to determine whether JTV-519 modifies the stretch-induced manifestations of mechanoelectric feedback. The ventricular fibrillation (VF) modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=9) or during JTV-519 perfusion: 0.1 µmol/L (n=9) and 1 µmol/L (n=9). Spectral and mapping techniques were used to establish the baseline, stretch and post-stretch VF characteristics. JTV-519 slowed baseline VF and decreased activation complexity. These effects were dose-dependent (baseline VF dominant frequency: control=13.9±2.2 Hz; JTV 0.1 µmol/L=11.1±1.1 Hz, P<.01; JTV 1 µmol/L=6.6±1.1 Hz, P<.0001). The stretch-induced acceleration of VF (control=38.8%) was significantly reduced by JTV-519 0.1 µmol/L (19.8%) and abolished by JTV 1 µmol/L (-1.5%). During stretch, the VF activation complexity index was reduced in both JTV-519 series (control=1.60±0.15; JTV 0.1 µmol/L=1.13±0.3, P<.0001; JTV 1 µmol/L=0.57±0.21, P<.0001), and was independently related to VF dominant frequency (R=.82; P<.0001). The fifth percentile of the VF activation intervals, conduction velocity and wavelength entered the multiple linear regression model using dominant frequency as the dependent variable (R=-.84; P<.0001). In conclusion, JTV-519 slowed and simplified the baseline VF activation patterns and abolished the stretch-induced manifestations of mechanoelectric feedback.

Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation.

BACKGROUND: Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. METHODS AND RESULTS: Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5, and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up. CONCLUSIONS: In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.

Ranolazine Attenuates the Electrophysiological Effects of Myocardial Stretch in Langendorff-Perfused Rabbit Hearts.

PURPOSE: Mechanical stretch is an arrhythmogenic factor found in situations of cardiac overload or dyssynchronic contraction. Ranolazine is an antianginal agent that inhibits the late Na (+) current and has been shown to exert a protective effect against arrhythmias. The present study aims to determine whether ranolazine modifies the electrophysiological responses induced by acute mechanical stretch. METHODS: The ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n = 9) or during perfusion of the late Na(+) current blocker ranolazine 5 µM (n = 9). Spectral and mapping techniques were used to establish the ventricular fibrillation dominant frequency, the spectral concentration and the complexity of myocardial activation in three situations: baseline, stretch and post-stretch. RESULTS: Ranolazine attenuated the increase in ventricular fibrillation dominant frequency produced by stretch (23.0 vs 40.4 %) (control: baseline =13.6 ± 2.6 Hz, stretch = 19.1 ± 3.1 Hz, p < 0.0001; ranolazine: baseline = 1.4 ± 1.8 Hz, stretch =14.0 ± 2.4 Hz, p < 0.05 vs baseline, p < 0.001 vs control). During stretch, ventricular fibrillation was less complex in the ranolazine than in the control series, as evaluated by the lesser percentage of complex maps and the greater spectral concentration of ventricular fibrillation. These changes were associated to an increase in the fifth percentile of VV intervals during ventricular fibrillation (50 ± 8 vs 38 ± 5 ms, p < .01) and in the wavelength of the activation (2.4 ± 0.3 vs 1.9 ± 0.2 cm, p < 0.001) under ranolazine. CONCLUSIONS: The late inward Na(+) current inhibitor ranolazine attenuates the electrophysiological effects responsible for the acceleration and increase in complexity of ventricular fibrillation produced by myocardial stretch.

Reduced Na⁺ current density underlies impaired propagation in the diabetic rabbit ventricle.

Diabetes is associated with an increased risk of sudden cardiac death, but the underlying mechanisms remain unclear. Our goal was to investigate changes occurring in the action potential duration (APD) and conduction velocity (CV) in the diabetic rabbit ventricle, and delineate the principal ionic determinants. A rabbit model of alloxan-induced diabetes was utilized. Optical imaging was used to record electrical activity in isolated Langendorff-perfused hearts in normo-, hypo- and hyper-kalemia ([K(+)]o=4, 2, 12 mM respectively). Patch clamp experiments were conducted to record Na(+) current (I(Na)) in isolated ventricular myocytes. The mRNA/protein expression levels for Nav1.5 (the α-subunit of I(Na)) and connexin-43 (Cx43), as well as fibrosis levels were examined. Computer simulations were performed to interpret experimental data. We found that the APD was not different, but the CV was significantly reduced in diabetic hearts in normo-, hypo-, and, hyper-kalemic conditions (13%, 17% and 33% reduction in diabetic vs. control, respectively). The cell capacitance (Cm) was increased (by ~14%), and the density of INa was reduced by ~32% in diabetic compared to control hearts, but the other biophysical properties of I(Na) were unaltered. The mRNA/protein expression levels for Cx43 were unaltered. For Nav1.5, the mRNA expression was not changed, and though the protein level tended to be less in diabetic hearts, this reduction was not statistically significant. Staining showed no difference in fibrosis levels between the control and diabetic ventricles. Computer simulations showed that the reduced magnitude of I(Na) was a key determinant of impaired propagation in the diabetic ventricle, which may have important implications for arrhythmogenesis.

Differences in Long-Term Heart Rate Variability between Subjects with and without Metabolic Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Our aim was to determine the impact that metabolic syndrome (MS) produces in long-term heart rate variability (HRV), quantitatively synthesizing the results of published studies to characterize the cardiac autonomic dysfunction in MS. METHODS: We searched electronic databases for original research works with long-term HRV recordings (24 h) that compared people with MS (MS+) versus healthy people as a control group (MS-). This systematic review and meta-analysis (MA) was performed according to PRISMA guidelines and registered at PROSPERO (CRD42022358975). RESULTS: A total of 13 articles were included in the qualitative synthesis, and 7 of them met the required criteria to be included in the MA. SDNN (-0.33 [-0.57, 0.09], p = 0.008), LF (-0.32 [-0.41, -0.23], p < 0.00001), VLF (-0.21 [-0.31, -0.10], p = 0.0001) and TP (-0.20 [-0.33, -0.07], p = 0.002) decreased in patients with MS. The rMSSD (p = 0.41), HF (p = 0.06) and LF/HF ratio (p = 0.64) were not modified. CONCLUSIONS: In long-term recordings (24 h), SDNN, LF, VLF and TP were consistently decreased in patients with MS. Other parameters that could be included in the quantitative analysis were not modified in MS+ patients (rMSSD, HF, ratio LF/HF). Regarding non-linear analyses, the results are not conclusive due to the low number of datasets found, which prevented us from conducting an MA.

Short-Term Heart Rate Variability in Metabolic Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Our aim was to determine the differences in short-term heart rate variability (HRV) between patients with metabolic syndrome (MS) and healthy controls. METHODS: We searched electronic databases for primary works with short-term HRV recordings (≤30 min) that made comparisons between individuals with MS versus healthy controls. This systematic review and meta-analysis (MA) was performed according to PRISMA guidelines and registered at PROSPERO (CRD42022358975). RESULTS: Twenty-eight articles were included in the qualitative synthesis and nineteen met the criteria for the MA. Patients with MS showed decreased SDNN (-0.36 [-0.44, -0.28], p < 0.001), rMSSD (-7.59 [-9.98, -5.19], p < 0.001), HF (-0.36 [-0.51, -0.20], p < 0.00001) and LF (-0.24 [-0.38, -0.1], p = 0.001). In subsequent subanalyses, we found a decrease in SDNN (-0.99 (-1.45, -0.52], p < 0.001), rMSSD (-10.18 [-16.85, -3.52], p < 0.01) and HF (-1.04 [-1.97, -0.1] p < 0.05) in women. In men, only LF showed a significant lower value (-0.26 [-0.5, -0.02], p < 0.05). We could not perform MA for non-linear variables. CONCLUSIONS: Patients with MS showed changes in time-domain analyses, with lower values in SDNN and rMSSD. Regarding frequency-domain analyses, MS patients showed a decrease in HF and LF When sex was used as a grouping variable, the MA was only possible in one of both sexes (men or women) in rMSSD and LF/HF. Lastly, when data for both men and women were available, subanalyses showed a different behavior compared to mixed analyses for SDNN, HF and LF, which might point towards a different impact of MS in men and women.

PPARγ as an indicator of vascular function in an experimental model of metabolic syndrome in rabbits.

BACKGROUND AND AIMS: Underlying mechanisms associated with vascular dysfunction in metabolic syndrome (MetS) remain unclear and can even vary from one vascular bed to another. METHODS: In this study, MetS was induced by a high-fat, high-sucrose diet, and after 28 weeks, aorta and renal arteries were removed and used for isometric recording of tension in organ baths, protein expression by Western blot, and histological analysis to assess the presence of atherosclerosis. RESULTS: MetS induced a mild hypertension, pre-diabetes, central obesity and dyslipidaemia. Our results indicated that MetS did not change the contractile response in either the aorta or renal artery. Conversely, vasodilation was affected in both arteries in a different way. The aorta from MetS showed vascular dysfunction, including lower response to acetylcholine and sodium nitroprusside, while the renal artery from MetS presented a preserved relaxation to acetylcholine and an increased sensitivity to sodium nitroprusside. We did not find vascular oxidative stress in the aorta from MetS, but we found a significant decrease in PPARγ, phospho-Akt (p-Akt) and phospho-eNOS (p-eNOS) protein expression. On the other hand, we found oxidative stress in the renal artery from MetS, and PPARγ, Akt and p-Akt were overexpressed. No evidence of atherosclerosis was found in arteries from MetS. CONCLUSIONS: MetS affects vascular function differently depending on the vessel. In the aorta, it decreases both the vasodilation and the expression of the PPARγ/Akt/eNOS pathway, while in the renal artery, it increases the expression of PPARγ/Akt signalling pathway without decreasing the vasodilation.

Efficacy of a proprioceptive exercise program in patients with nonspecific neck pain: a randomized controlled trial.

BACKGROUND: Nonspecific neck pain is associated with chronic pain, disability, reduced cervical mobility, postural control disorders and impaired proprioceptive control. AIM: The aim of this study was to compare the effectiveness of two therapeutic exercise programs (i.e. cervical proprioception and cervical mobility) in reducing pain and disability in individuals with nonspecific neck pain. We further aimed to compare the effectiveness of the two treatments in improving pressure pain threshold, cervical range of motion and head repositioning accuracy. DESIGN: This study was designed as a randomized controlled trial. SETTING: This study took place in a private rehabilitation clinic. POPULATION: Forty-two participants diagnosed with nonspecific neck pain, aged 18-65 years, were randomized to a cervical mobility group (N.=22) or a proprioception group (N.=20). METHODS: The cervical mobility group combined a passive treatment and active mobility exercises, whereas the Proprioception group combined a passive treatment and proprioceptive exercises. Pain intensity, disability, pressure pain threshold, range of motion, and head repositioning accuracy were assessed at baseline and after 10 sessions. RESULTS: Pain intensity and disability significantly improved for both interventions (p<0.01), but such improvement was greater for pain intensity in the proprioception group than in the cervical mobility group (P<0.01). Pressure pain threshold, range of motion and head repositioning accuracy improved only in the proprioception group (P<0.01). CONCLUSIONS: A program based on cervical proprioception exercises demonstrated to improve pain, disability, pressure pain threshold, range of motion and head repositioning accuracy in patients with nonspecific neck pain. However, a program based on cervical mobility exercises only showed to improve pain intensity and disability, while such improvement was not clinically relevant. CLINICAL REHABILITATION IMPACT: The proprioceptive exercise program may be considered as the treatment of choice in patients with nonspecific neck pain.

Exercise Training Protocols in Rabbits Applied in Cardiovascular Research.

Rabbit exercise protocols allow for the evaluation of physiological and biomechanical changes and responses to episodes of acute or chronic exercise. The observed physiological changes are normal responses to stress, that is, adaptive responses to maintain or restore homeostasis after acute exercise. Indeed, the rabbit model is advantageous since (a) it has important physiological similarities in terms of the functioning of multiple organ systems, and can quickly induce alterations in pathophysiological conditions that resemble those of humans, and (b) it allows the implementation of a low-cost model in comparison with other large animals. When designing an exercise training protocol for rabbits, it is important to consider variables such as race, gender, age and, especially, training parameters such as volume, intensity, or rest, among others, to determine the outcome of the research. Therefore, the objective of this review is to identify and analyze exercise training protocols in rabbits in different experimental applications and the various physiological adaptations that are presented, with special focus in cardiovascular adaptations.

Development and Long-Term Follow-Up of an Experimental Model of Myocardial Infarction in Rabbits.

A chronic model of acute myocardial infarction was developed to study the mechanisms involved in adverse postinfarction ventricular remodeling. In an acute myocardial infarction (AMI), the left circumflex coronary artery of New Zealand White rabbits (n = 9) was occluded by ligature for 1 h, followed by reperfusion. A specific care protocol was applied before, during, and after the intervention, and the results were compared with those of a sham operated group (n = 7). After 5 weeks, programmed stimulation and high-resolution mapping were performed on isolated and perfused hearts using the Langendorff technique. The infarct size determined by 2,3,5-triphenyltetrazolium chloride inside of the area at risk (thioflavin-S) was then determined. The area at risk was similar in both groups (54.33% (experimental infarct group) vs. 58.59% (sham group), ns). The infarct size was 73.16% as a percentage of the risk area. The experimental infarct group had a higher inducibility of ventricular arrhythmias (100% vs. 43% in the sham group, p = 0.009). A reproducible chronic experimental model of myocardial infarction is presented in which the extent and characteristics of the lesions enable the study of the vulnerability to develop ventricular arrhythmias because of the remodeling process that occurs during cardiac tissue repair.

Diet-Induced Rabbit Models for the Study of Metabolic Syndrome.

Obesity and metabolic syndrome (MetS) have become a growing problem for public health and clinical practice, given their increased prevalence due to the rise of sedentary lifestyles and excessive caloric intake from processed food rich in fat and sugar. There are several definitions of MetS, but most of them describe it as a cluster of cardiovascular and metabolic alterations such as abdominal obesity, reduced high-density lipoprotein (HDL) and elevated low-density lipoprotein (LDL) cholesterol, elevated triglycerides, glucose intolerance, and hypertension. Diagnosis requires three out of these five criteria to be present. Despite the increasing prevalence of MetS, the understanding of its pathophysiology and relationship with disease is still limited. Indeed, the pathological consequences of MetS components have been reported individually, but investigations that have studied the effect of the combination of MeS components on organ pathological remodeling are almost nonexistent. On the other hand, animal models are a powerful tool in understanding the mechanisms that underlie pathological processes such as MetS. In the first part of the review, we will briefly overview the advantages, disadvantages and pathological manifestations of MetS in porcine, canine, rodent, and rabbit diet-induced experimental models. Then, we will focus on the different dietary regimes that have been used in rabbits to induce MetS by means of high-fat, cholesterol, sucrose or fructose-enriched diets and their effects on physiological systems and organ remodeling. Finally, we will discuss the use of dietary regimes in different transgenic strains and special rabbit breeds.

Modifications of short-term intrinsic pacemaker variability in diet-induced metabolic syndrome: a study on isolated rabbit heart.

Metabolic syndrome (MetS) describes a condition associated with multiple diseases concomitantly such as diabetes, hypertension, obesity, and dyslipidemia. It has been linked with higher prevalence of cardiovascular disease, atrial fibrillation, and sudden cardiac death. One of the underlying mechanisms could be altered automaticity, which would reflect modifications of sinus node activity. These phenomena can be evaluated analyzing the components of heart rate variability (HRV). Our aim was to examine the modifications of sinus node variability in an isolated heart model of diet-induced obesity and MetS. Male NZW rabbits were randomly assigned to high-fat (HF, n = 8), control (HF-C, n = 7), high-fat, high-sucrose (HFHS, n = 9), and control (HFHS-C, n = 9) groups, fed with their respective diets during 18/28 weeks. After euthanasia, their hearts were isolated in a Langendorff system. We recorded 10-15 min of spontaneous activity. Short RR time series were analyzed, and standard HRV parameters were determined. One-way ANOVA, Kruskal-Wallis test, and bivariate correlation were used for statistical analysis (p < 0.05). We did find an increase in the complexity and irregularity of intrinsic pacemaker activity as shown by modifications of approximate entropy, sample entropy, minimum multiscale entropy, and complexity index in HFHS animals. Even though no differences were found in standard time and frequency-domain analyses, spectral heterogeneity increased in HFHS group. Animal weight and glucose intolerance were highly correlated with the modifications of intrinsic pacemaker variability. Finally, modifications of intrinsic HRV seemed to be reliant on the number of components of MetS present, given that only HFHS group showed significant changes towards an increased complexity and irregularity of intrinsic pacemaker variability.

Diet-Induced Metabolic Syndrome Reduced Heart Rate Variability and Increased Irregularity and Complexity of Short-Term RR Time Series in Rabbits.

Metabolic syndrome (MetS) has been linked to a higher prevalence of sudden cardiac death (SCD), but the mechanisms are not well understood. One possible underlying mechanism may be an abnormal modulation of autonomic activity, which can be quantified by analyzing heart rate variability (HRV). Our aim was to investigate the modifications of short-term HRV in an experimental rabbit model during the time-course of MetS development. NZW rabbits were randomly assigned to a control (n = 10) or a MetS group (n = 13), fed 28 weeks with control or high-fat, high-sucrose diets. After anesthesia, a 15-min ECG recording was acquired before diet administration and at weeks 14 and 28. We analyzed short RR time series using time-domain, frequency-domain and nonlinear analyses. A mixed-model factorial ANOVA was used for statistical analysis. Time-domain analysis showed a 52.4% decrease in the standard deviation of heart rate in animals from the MetS group at week 28, but no changes in the rest of parameters. In the frequency domain, we found a 9.7% decrease in the very low frequency and a 380.0% increase of the low frequency bands in MetS animals at week 28, whereas high frequency remained unchanged. Nonlinear analyses showed increased complexity and irregularity of the RR time series in MetS animals.

Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart.

A study has been made of the effect of chronic exercise on myocardial electrophysiological heterogeneity and stability, as well as of the role of cholinergic neurons in these changes. Determinations in hearts from untrained and trained rabbits on a treadmill were performed. The hearts were isolated and perfused. A pacing electrode and a recording multielectrode were located in the left ventricle. The parameters determined during induced VF, before and after atropine (1µM), were: fibrillatory cycle length (VV), ventricular functional refractory period (FRPVF), normalized energy (NE) of the fibrillatory signal and its coefficient of variation (CV), and electrical ventricular activation complexity, as an approach to myocardial heterogeneity and stability. The VV interval was longer in the trained group than in the control group both prior to atropine (78±10 vs. 68±10 ms) and after atropine (76±8 vs. 67±10 ms). Likewise, FRPVF was longer in the trained group than in the control group both prior to and after atropine (53±8 vs. 42±7 ms and 50±6 vs. 40±6 ms, respectively), and atropine did not modify FRPVF. The CV of FRPVF was lower in the trained group than in the control group prior to atropine (12.5±1.5% vs. 15.1±3.8%) and, decreased after atropine (15.1±3.8% vs. 12.2±2.4%) in the control group. The trained group showed higher NE values before (0.40±0.04 vs. 0.36±0.05) and after atropine (0.37±0.04 vs. 0.34±0.06; p = 0.08). Training decreased the CV of NE both before (23.3±2% vs. 25.2±4%; p = 0.08) and after parasympathetic blockade (22.6±1% vs. 26.1±5%). Cholinergic blockade did not modify these parameters within the control and trained groups. Activation complexity was lower in the trained than in the control animals before atropine (34±8 vs. 41±5), and increased after atropine in the control group (41±5 vs. 48±9, respectively). Thus, training decreases the intrinsic heterogeneity of the myocardium, increases electrophysiological stability, and prevents some modifications due to muscarinic block.