Diastolic Interval Research Articles

The LIM Protein fhlA is Essential for Heart Chamber Development in Zebrafish Embryos

Four-and-a-half LIM proteins FHL1-3 play important roles in cardiovascular pathophysiology. However, their roles in heart development remain unclear. Here, we report that fhlA, the zebrafish homolog of human FHL1, was found to be expressed around the 22-somite stage. After 24 hpf, expression was restricted to the heart. fhlA knockdown caused an enlarged cardiac chamber phenotype with up-regulated expression of the cardiac markers, but fhlA overexpression reduced the sizes of the cardiac chambers and down-regulated expression of the markers. The morphology associated with the cmlc2, amhc, and vmhc expression patterns at the 22 somite and 24 hpf stages included a broadened domain in embryos lacking fhlA and a smaller domain in embryos overexpressing fhlA. The changes in the sizes of the chambers were attributed to the changes in the number of ventricular and atrial cells. Loss of fhlA caused a longer heart period and pause between heartbeats in M-modes than in controls, but fhlA overexpression caused shorter systolic and diastolic intervals. Abnormal cardiac chambers and physiological function were found to be largely rescued. We also showed the expression of fhlA in the heart to be increased by retinoic acid (RA) and decreased by the RA synthase inhibitor DEAB. Both fhlA and RA signaling caused a phenotype characterized by the morphological alterations in the chamber sizes, suggesting that the role of fhlA in heart development is probably regulated by RA signaling. Taken together, these results showed that fhlA regulates the size of the heart chamber by reducing the number of cardiac cells.

Optimal temporal windows and dose-reducing strategy for coronary artery bypass graft imaging with 256-slice CT

ObjectiveTo determine the optimal image reconstruction windows in the assessment of coronary artery bypass grafts (CABGs) with 256-slice computed tomography (CT), and to assess their associated optimal pulsing windows for electrocardiogram-triggered tube current modulation (ETCM). MethodsWe recruited 18 patients (three female; mean age 68.9 years) having mean heart rate (HR) of 66.3beats per minute (bpm) and a heart rate variability of 1.3bpm for this study. A total of 36 CABGs with 168 segments were evaluated, including 12 internal mammary artery (33.3%) and 24 saphenous vein grafts (66.7%). We reconstructed 20 data sets in 5%-step through 0–95% of the R–R interval. The image quality of CABGs was assessed by a 5-point scale (1=excellent to 5=non-diagnostic) for each segment (proximal anastomosis, proximal, middle, distal course of graft body, and distal anastomosis). Two reviewers discriminated optimal reconstruction intervals for each CABG segment in each temporal window. Optimal windows for ETCM were also evaluated. ResultsThe determined optimal systolic and diastolic reconstruction intervals could be divided into 2 groups with threshold HR=68. The determined best reconstruction intervals for low heart rate (HR<68) and high heart rate (HR>68) were 76.0±2.5% and 45.0±0% respectively. Average image quality scores were 1.7±0.6 with good inter-observer agreement (Kappa=0.79). Image quality was significantly better for saphenous vein grafts versus arterial grafts (P<0.001). The recommended windows of ETCM for low HR, high HR and all HR groups were 40–50%, 71–81% and 40–96% of R-R interval, respectively. The corresponding dose savings were about 60.8%, 58.7% and 22.7% in that order. ConclusionsWe determined optimal reconstruction intervals and ETCM windows representing a good compromise between radiation and image quality for following bypass surgery using a 256-slice CT.

Electrical Restitution Dynamics during Manipulation of Slow Delayed Rectifier Potassium Current in Pig Ventricles

Blockers and activators of the slow delayed rectifier potassium current (IKs) potentially can impact stability of conduction. However, effects of changes in IKs on restitution and memory in action potential duration (APD), critical factors in electrical stability, are unknown in the pig, which is a widely used model to study arrhythmia. To determine these effects, we recorded transmembrane potentials in right ventricular tissues from 7 farm pigs during reduction and increase of IKs with Chromanol (20 μM) and Mefenamic acid (100 μM), respecitively. Memory in restitution was quantified by using two protocols with sinusoidal changes in diastolic intervals (DI), which ranged between 100 – 700 ms and 10 – 290 ms. Hysteresis in restitution of APD was observed in both protocols; among 5 measures of the hysteresis loop (loop thickness, area, overall tilt, max/min delay), loop thickness and area significantly increased (decreased) after Chromanol 293B (Mefenamic acid), which suggests an increase and decrease of memory, respectively. Standard and dynamic restitution curves obtained from same tissues showed an increase (decrease) in average slope with application of Chromanol 293B (Mefenamic acid). As increase in slope and memory are hypothesized to have opposite effects on electrical stability, these results suggest that reduction and enhancement of IKs likely have offsetting components that effect stability.

The Effects of Sympathetic Nerve Stimulation on Ventricular Electrophysiology in Long QT Syndrome‐1

Congenital long QT syndrome 1 (LQTS1) results from reduced slow activating delayed rectifier potassium channel (IKs) activity. Ventricular arrhythmias occur with increases in sympathetic tone which can cause sudden cardiac death (SCD). Underlying mechanisms are not understood but may include changes in electrical restitution (RT) – the relationship between action potential duration and diastolic interval. We aimed to examine the effects of sympathetic nerve stimulation (SNS) on effective refractory period (ERP), RT slope and inducibility of ventricular fibrillation (VF) in a pharmacological model of LQTS1. The innervated heart preparation from adult male guinea pigs (n=6, 450–550g) were used. ERP and LV apical and basal RT were measured using an extrastimulus protocol. Inducibility of VF was assessed with ventricular fibrillation threshold (VFT). Parameters were measured during baseline (BL) and SNS (3Hz, 1V) in control (Ctrl) and in the presence of the IKs blocker HMR1556 to mimic LQTS1 (HMR). Data are mean±SEM, analysed using Student's T‐Test (*vs BL, **vs Ctrl). During control, SNS significantly reduced ERP and VFT and increased RT slope but only at LV base, (Table). In the presence of HMR1556, the effects of SNS on ERP and VFT were augmented whilst the effect on RT was abolished. In conclusion, SNS increases susceptibility to VF which appears to be augmented in this pharmacological LQTS1 model and related to changes in ERP but not RT.Research support from the University of Leicester

Effects of autonomic ganglion blockade on fractal and spectral components of blood pressure and heart rate variability in free-moving rats

Fractal analysis is a promising tool for assessing autonomic influences on heart rate (HR) and blood pressure (BP) variability. The temporal spectrum of scale coefficients, α(t), was recently proposed to describe the cardiovascular fractal dynamics. Aim of our work is to evaluate sympathetic influences on cardiovascular variability analyzing α(t) and spectral powers of HR and BP after ganglionic blockade. BP was recorded in 11 rats before and after autonomic blockade by hexamethonium infusion (HEX). Systolic and diastolic BP, pulse pressure and pulse interval were derived beat-by-beat. Segments longer than 5 min were selected at baseline and HEX to estimate power spectra and α(t). Comparisons were made by paired t-test. HEX reduced all spectral components of systolic and diastolic BP, the reduction being particularly significant around the frequency of Mayer waves; it induced a reduction on α(t) coefficients at t<2s and an increase on coefficients at t>8s. HEX reduced only slower components of pulse interval power spectrum, but decreased significantly faster scale coefficients (t<8s). HEX only marginally affected pulse pressure variability. Results indicate that the sympathetic outflow contributes to BP fractal dynamics with fractional Gaussian noise (α<1) at longer scales and fractional Brownian motion (α>1) at shorter scales. Ganglionic blockade also removes a fractional Brownian motion component at shorter scales from HR dynamics. Results may be explained by the characteristic time constants between sympathetic efferent activity and cardiovascular effectors. Therefore fractal analysis may complete spectral analysis with information on the correlation structure of the data.

Endothelial NOS (NOS3) impairs myocardial function in developing sepsis

Endothelial nitric oxide synthase (NOS)3-derived nitric oxide (NO) modulates inotropic response and diastolic interval for optimal cardiac performance under non-inflammatory conditions. In sepsis, excessive NO production plays a key role in severe hypotension and myocardial dysfunction. We aimed to determine the role of NOS3 on myocardial performance, NO production, and time course of sepsis development. NOS3−/− and C57BL/6 wildtype mice were rendered septic by cecum ligation and puncture (CLP). Cardiac function was analyzed by serial echocardiography, in vivo pressure and isolated heart measurements. Cardiac output (CO) increased to 160 % of baseline at 10 h after sepsis induction followed by a decline to 63 % of baseline after 18 h in wildtype mice. CO was unaltered in septic NOS3−/− mice. Despite the hyperdynamic state, cardiac function and mean arterial pressure were impaired in septic wildtype as early as 6 h post CLP. At 12 h, cardiac function in septic wildtype was refractory to catecholamines in vivo and respective isolated hearts showed impaired pressure development and limited coronary flow reserve. Hemodynamics remained stable in NOS3−/− mice leading to significant survival benefit. Unselective NOS inhibition in septic NOS3−/− mice diminished this survival benefit. Plasma NOx- and local myocardial NOx- and NO levels (via NO spin trapping) demonstrated enhanced NOx- and bioactive NO levels in septic wildtype as compared to NOS3−/− mice. Significant contribution by inducible NOS (NOS2) during this early phase of sepsis was excluded. Our data suggest that NOS3 relevantly contributes to bioactive NO pool in developing sepsis resulting in impaired cardiac contractility.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-013-0330-8) contains supplementary material, which is available to authorized users.

Semiautomatic and rapid quantification of heartbeat parameters inDrosophilausing optical coherence tomography imaging

We report a semiautomatic algorithm that is specialized for rapid analysis of beat-to-beat contraction-relaxation parameters of the heart in Drosophila. The presented algorithm adapts the general graph theoretical image segmentation algorithm and a histogram-based thresholding algorithm, which can measure many cardiac parameters, including heart rate, heart period, diastolic and systolic intervals, and end-diastolic and end-systolic areas. Additionally, dynamic cardiac functions, such as arrhythmia index and percent fractional shortening, can be automatically calculated for all the recorded heartbeats over significant periods of time.

Viewpoint: Is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone?

it is well known that athletes have a low resting heart rate, i.e., a resting bradycardia and heart rates below 30 beats/min have been reported ([7][1]). For example, Wikipedia states that the Tour de France cyclist, Miguel Indurain, had a resting heart rate of 28 beats/min when race fit. The

Evaluation of tissue Doppler imaging for regional quantification of radial left ventricular wall motion in healthy horses

To compare the feasibility and repeatability of tissue Doppler imaging (TDI) for quantification of radial left ventricular (LV) velocity and deformation from different imaging planes and to correlate cardiac event timing data obtained by TDI to M-mode and pulsed-wave Doppler-derived time intervals in horses. 10 healthy adult horses. Repeated echocardiography was performed by 2 observers from right and left parasternal short-axis views at papillary muscle and chordal levels. The TDI measurements of systolic and diastolic velocity, strain rate, strain peak values, and timing were performed in 8 LV wall segments (LV free wall and interventricular septum from right parasternal views; left and right region of LV wall from left parasternal views). The inter- and intraobserver within- and between-day variability and measurement variability were assessed. The correlation between TDI-based measurements and M-mode and pulsed-wave Doppler-based time measurements was calculated. TDI measurements of velocity, strain rate, and strain were feasible in each horse, although deformation could often not be measured in the LV free wall. Systolic and diastolic time intervals could be determined with low to moderate variability, whereas peak amplitude variability ranged from low to high. The TDI-based time measurements were significantly correlated to M-mode and pulsed-wave Doppler measurements. TDI measurements of radial LV velocity and deformation were feasible with low to moderate variability in 8 LV segments. These measurements can be used for evaluating LV function in further clinical studies.

Multiscale multivariate fuzzy entropy analysis

Multiscale multivariate sample entropy can test the multivariate complexity, which is accepted as a kind of reflection of nonlinear dynamical interactions in multichannel data. It is however relatively unstable due to the rigid ranking scheme used in comparison among different patterns. It is not applicable to the nonlinear and non-stationary data because the multiscale framework used is in fact handled by moving average succeeded by down-sampling, which actually has a premise of stationary data. We substitute a fuzzy membership function for the original rigid one and compare the performances of different kinds of fuzzy membership functions. In addition, we employ the multivariate empirical mode decomposition (MEMD) to capture different scales. Results show that the substitution of fuzzy membership function brings in significant stability. It is much more obvious by using the introduced physical fuzzy membership function (PFMF). Also MEMD could capture scales more robustly. In conclusion, the introduced PFMF- and MEMD-based MMFE perform best. Final analysis on the interactions between heart rate variability (HRV) and heart diastolic time interval variability (DIV) validates it. In addition, the results show that the multivariate complexity between HRV and DIV decreases in aging or heart failure group but in a distinctly different decreasing manner–it deceased at low scales with aging, indicating a loss of short-range correlation but both at low and high scales with heart failure, which shows the losses of both short- and long-range correlations. Studies in noninvasive detection of cardiovascular diseases should benefit from the above conclusions.

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

Cardiac ATP-sensitive potassium (K(ATP)) channels are key sensors and effectors of the metabolic status of cardiomyocytes. Alteration in their expression impacts their effectiveness in maintaining cellular energy homeostasis and resistance to injury. We sought to determine how activation of calcium/calmodulin-dependent protein kinase II (CaMKII), a central regulator of calcium signaling, translates into reduced membrane expression and current capacity of cardiac K(ATP) channels. We used real-time monitoring of K(ATP) channel current density, immunohistochemistry, and biotinylation studies in isolated hearts and cardiomyocytes from wild-type and transgenic mice as well as HEK cells expressing wild-type and mutant K(ATP) channel subunits to track the dynamics of K(ATP) channel surface expression. Results showed that activation of CaMKII triggered dynamin-dependent internalization of K(ATP) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)YSKF(333) endocytosis motif of the K(ATP) channel Kir6.2 pore-forming subunit. A molecular model of the μ2 subunit of the endocytosis adaptor protein, AP2, complexed with Kir6.2 predicted that μ2 docks by interaction with (330)YSKF(333) and Thr-180 on one and Thr-224 on the adjacent Kir6.2 subunit. Phosphorylation of Thr-180 and Thr-224 would favor interactions with the corresponding arginine- and lysine-rich loops on μ2. We concluded that calcium-dependent activation of CaMKII results in phosphorylation of Kir6.2, which promotes endocytosis of cardiac K(ATP) channel subunits. This mechanism couples the surface expression of cardiac K(ATP) channels with calcium signaling and reveals new targets to improve cardiac energy efficiency and stress resistance.

A model for simulating restitution phenomenon in a single cardiac cell

Up to now, a large number of electrophysiological models have been introduced for simulating the cells. These models are very complicated and they use much time to run. One of most important goals for researchers is to offer a model which has less computational complexity, in the other word, has the minimum number of state variables. In this paper, is introduced a minimal model for cardiac cell which has a minimum number of state variables and It is enable to simulate different features of Action potential, restitution curve for action potential duration (APD) and least Diastolic interval (DI). For validation this model, it is compared to reliable electrophysiological model. At the result, this minimal model (MM) is very simple to simulate restitution, so it is proper to simulate tissue level.

Influence of Type 2 Diabetes and the Sex on the Occurrence of Sub-Clinic Left-Ventricular Diastolic Dysfunction of the Heart

Aims: To test the hypothesis that: the potential of type 2 diabetes, in precipitation of the sub clinical left ventricular diastolic dysfunction at the female sex, in absence of high blood pressure disease, coronary disease and other known heart disease, is different in comparison to the male sex. Material and Methods: Prospectively, 180 people with type 2 diabetes were tested, at the ages between 45 and 55, divided into 2 groups: 1) Control group- was comprised of 60 patients (30 male and 30 female), without diabetes, with similar epidemiological-demographic characteristics; 2) Diabetes group - was comprised of 120 patients (60 women and 60 men) with type 2 diabetes. The estimation of the diastolic function of the left ventricular was made by Doppler echocardiograph analysis of the diastolic time intervals, as well as analysis of the model of ventricular filling, shown with a transmitral flow-velocity profile, acquired with a conventional pulsed-wave Doppler. Results: Significant changes between the groups in clinical variables were observed regarding body mass index, low density cholesterol and triglycerides, the variables gotten with the pulsed-wave Doppler of the transmitral flow, and the duration of the isovolumetric relaxation time. Conclusions: In this study, we do not prove the hypothesis that the type 2 diabetes potential in the precipitation of the sub clinical left ventricular diastolic dysfunction at the female sex, in absence of coronary disease, blood pressure disease and other well known heart diseases, is different in comparison to the male sex.

A Novel Surface Electrocardiogram–Based Marker of Ventricular Arrhythmia Risk in Patients With Ischemic Cardiomyopathy

BackgroundBetter sudden cardiac death risk markers are needed in ischemic cardiomyopathy (ICM). Increased heterogeneity of electrical restitution is an important mechanism underlying the risk of ventricular arrhythmia (VA). Our aim was to develop and test a novel quantitative surface electrocardiogram–based measure of VA risk in patients with ICM: the Regional Restitution Instability Index (R2I2).Methods and ResultsR2I2, the mean of the standard deviation of residuals from the mean gradient for each ECG lead at a range of diastolic intervals, was measured retrospectively from high-resolution 12-lead ECGs recorded during an electrophysiology study. Patient groups were as follows: Study group, 26 patients with ICM being assessed for implantable defibrillator; Control group, 29 patients with supraventricular tachycardia undergoing electrophysiology study; and Replication group, 40 further patients with ICM. R2I2 was significantly higher in the Study patients than in Controls (mean ± standard error of the mean: 1.09±0.06 versus 0.63±0.04, P<0.001). Over a median follow-up period of 23 months, 6 of 26 Study group patients had VA or death. R2I2 predicted VA or death independently of demographic factors, electrophysiology study result, left ventricular ejection fraction, or QRS duration (Cox model, P=0.029). R2I2 correlated with peri-infarct zone as assessed by cardiac magnetic resonance imaging (r=0.51, P=0.024). The findings were replicated in the Replication group: R2I2 was significantly higher in 11 of 40 Replication patients experiencing VA (1.18±0.10 versus 0.92±0.05, P=0.019). In combined analysis of ICM cohorts, R2I2 ≥1.03 identified subjects with significantly higher risk of VA or death (43%) compared with R2I2 <1.03 (11%) (P=0.004).ConclusionsIn this pilot study, we have developed a novel VA risk marker, R2I2, and have shown that it correlated with a structural measure of arrhythmic risk and predicted risk of VA or death in patients with ICM. R2I2 may improve risk stratification and merits further evaluation. (J Am Heart Assoc. 2012;1:e001552 doi: 10.1161/JAHA.112.001552.)

055 Successful application of a novel restitution gradient based marker of ventricular arrhythmia to patients with non-ischaemic conditions

BackgroundThere are major limitations with Sudden Cardiac Death (SCD) risk assessment, especially in patients without ischaemic heart disease (IHD). Electrical restitution, that is,. the relationship between action potential duration (APD)...

Bioequivalence study of two Losartan tablet formulations with special emphasis on cardiac safety

To study the bioequivalence of Losartan Potassium Tablets 50 mg manufactured by Micro Labs Ltd. India to Cozaar® Tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in normal healthy adult subjects under fasting condition along with the comparative safety evaluation of both treatments. The in vitro dissolution studies were carried out on 12 units each of test and reference products using the paddle method and dissolution media like water, 0.1 N hydrochloric acid with pH 1.2, pH 4.5 acetate buffer and pH 6.8 phosphate buffer. An open label, randomized, two-treatment, two-period, two-sequence, crossover bioequivalence study with a washout period of 7 days was conducted in 60 healthy Indian male subjects. Serial blood samples were collected after drug administration in each study period. Plasma concentrations of losartan and losartan acid were determined using a validated LC-MS-MS method. The pharmacokinetic parameters of losartan and losartan acid were determined using a non compartmental model. Occurrence of adverse events, change in systolic blood pressure, diastolic blood pressure, heart rate and QT interval from the baseline to 3.50 h post dose were studied and compared between the two treatments as safety parameters. The in vitro study proved the essential similarity of both the formulations as evident from the similarity factor of > 50% in all the dissolution media. The ratios for geometric least square means and 90% confidence intervals were within the acceptance criteria of 80% to 125% for log transformed C(max), AUC(0-t) and AUC(0-∞) for losartan. No statistically significant difference between the two treatments was observed for either of the safety parameters. The test product Losartan Potassium tablets 50 mg manufactured by Micro Labs Limited, India was bioequivalent to Cozaar® tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in terms of rate and extent of absorption. Both treatments were well tolerated and had similar non significant effect on the safety parameters.

Effects of ventricular pacing protocol on electrical restitution assessments in guinea‐pig heart

The steep slope of the rate adaptation of ventricular action potential duration (APD) is thought to indicate profibrillatory tendency. In cardiac patients, APD restitution is commonly assessed by extrasystolic (S(1)-S(2)) stimulations rather than dynamic pacing, because the latter may provoke myocardial ischaemia. In this study, ventricular APD and effective refractory period (ERP) were measured in perfused guinea-pig hearts to determine whether S(1)-S(2) stimulations and dynamic pacing may have similar value in APD restitution assessments aimed to predict arrhythmic risk. The maximal restitution slope was greater upon S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), 1.2 ± 0.08; dynamic, 0.72 ± 0.06; P = 0.0004) and endocardium (S(1)-S(2), 1.45 ± 0.08; dynamic, 0.95 ± 0.06; P = 0.0003). This difference was partly accounted for by an effect of the previous pacing history, as evidenced by flattening of APD restitution upon reductions in the regular beating interval prior to S(2) application. Furthermore, shorter ERP than APD relationships enabled ventricular capture at shorter diastolic intervals during S(1)-S(2) stimulation than dynamic pacing at the epicardium (S(1)-S(2), -1 ± 3 ms; dynamic, 35 ± 3 ms; P < 0.0001) and endocardium (S(1)-S(2), -1 ± 7 ms; dynamic, 38 ± 3 ms; P < 0.0001), thereby contributing to greater maximal restitution slope values. Flecainide, a Na(+) channel blocker, increased the ERP-to-APD ratio and eliminated early premature beats (diastolic interval of ∼0 ms), thereby flattening the S(1)-S(2) restitution curve, but had no effect on dynamic restitution. In hypokalaemia-induced arrhythmogenicity, a reduction in ventricular fibrillation threshold was paralleled by increased steepness of dynamic APD restitution, while no change in the maximal restitution slope was revealed by S(1)-S(2) stimulations. In summary, changes in electrical restitution obtained from extrasystolic stimulations may dissociate from those revealed by dynamic pacing. These findings therefore challenge the value of electrical restitution assessments based on extrasystolic stimulation alone, as commonly performed in the clinical setting.

Role of KATP channel in electrical depression and asystole during long-duration ventricular fibrillation in ex vivo canine heart.

Long-duration ventricular fibrillation (LDVF) in the globally ischemic heart is characterized by transmurally heterogeneous decline in ventricular fibrillation rate (VFR), emergence of inexcitable regions, and eventual global asystole. Rapid loss of both local and global excitability is detrimental to successful defibrillation and resuscitation during cardiac arrest. We sought to assess the role of the ATP-sensitive potassium current (I(KATP)) in the timing and spatial pattern of electrical depression during LDVF in a structurally normal canine heart. We analyzed endo-, mid-, and epicardial unipolar electrograms and epicardial optical recordings in the left ventricle of isolated canine hearts during 10 min of LDVF in the absence (control) and presence of an I(KATP) blocker glybenclamide (60 μM). In all myocardial layers, average VFR was the same or higher in glybenclamide-treated than in control hearts. The difference increased with time of LDVF and was overall significant in all layers (P < 0.05). However, glybenclamide did not significantly affect the transmural VFR gradient. In epicardial optical recordings, glybenclamide shortened diastolic intervals, prolonged action potential duration, and decreased the percentage of inexcitable area (all differences P < 0.001). During 10 min of LDVF, asystole occurred in 55.6% of control and none of glybenclamide-treated hearts (P < 0.05). In three hearts paced after the onset of asystole, there was no response to LV epicardial or atrial pacing. In structurally normal canine hearts, I(KATP) opening during LDVF is a major factor in the onset of local and global inexcitability, whereas it has a limited role in overall deceleration of VFR and the transmural VFR gradient.

Relationship of Cardiovascular Complications with Level of Consciousness in Patients with Acute Carbamazepine Intoxication

Carbamazepine is an iminostilbene derivative structurally related to cyclic antidepressants which implies its potential cardiotxic properties, especially in acute poisoning. This study aimed to determine the frequency and severity of cardiovascular complications in carbamazepine intoxication and its relationship with level of consciousness. Patients with carbamazepine intoxication referred to our department recruited using convenience sampling method. Analysis included following parameters: systolic (SBP) and diastolic (DBP) blood pressure, ECG parameters: heart rate (HR), QRS width, PR interval and corrected QT interval (QTc). Relations between features on admission, 12 and 24 hours later and level of consciousness evaluated. 77 patients (28 males, 49 females; median age 25.1) which got our criteria included in this study. QRS complexes in 9 cases (11.7%) were wider than normal and PR interval and corrected QT interval (QTc) were normal. There was no significant relationship between QT interval, QRS width and pulse rate changes with level of consciousness during 24 hours post admission, but blood pressure [systolic, diastolic and mean arterial blood pressure (MABP)] progressively decreased and PR interval changes progressively increased during this period. Further, there was negative correlation just between sever decrease of level of consciousness (coma) and blood pressure [systolic, diastolic and mean arterial blood pressure (MABP)], and positive correlation with QRS complexes widening at 12 hours after admission. There was no correlation between loss of consciousness and diastolic blood pressure, QT interval and PR interval on admission and 12 hours and 24 hours later. Regarding the relationship between level of consciousness and cardiovascular changes at 12 hours after admission, particular attention on cardiovascular changes and ECG monitoring particularly in intoxicated patients with severe loss of consciousness(coma), should considered; it will lead to prevent unexpected complication, mortality and to decrease the length of hospitalization.

Exploration and Suppression of Cardiac Amyloidosis Induced by Huntington's Disease-Causing Amyloid in the Drosophila Heart Model

Accumulation of amyloids is associated with cardiomyopathy; however, the precise mechanism that leads to defective heart structure and function is unknown. Amyloid-like inclusions have been detected in patients with Huntington's disease (HD), which is caused by an expanded polyglutamine (Poly-Q) repeat in the Huntington (HTT) protein. HD patients also demonstrate a greater occurrence of cardiovascular events, presumably as a result of toxic amyloid accumulation due to global protein misfolding and/or oxidative stress. To explore cardiac defects associated with HD-causing amyloid protein, we used the UAS-Gal4 system and a cardiac-specific driver (Hand-Gal4) to express mutant HTT with short (UAS-Httex1-PolyQ25) and disease-causing expanded (UAS-Httex1-PolyQ72) Poly-Q in the Drosophila heart. Expression of disease causing Poly-Q in 1 and 3 week old fly hearts resulted in severe cardiac defects as evidenced by prolonged diastolic and systolic intervals, a significantly increased incidence of arrhythmias and extreme cardiac dilation that was accompanied by a significant decrease in cardiac contractility (reduced fractional shortening). Structural analysis showed myocardial cells with noticeably reduced myofibrillar content, myofibrillar disorganization and the presence of amyloid-aggregates. No such physiological and structural defects were seen upon expression of short Poly-Q under similar conditions. To take advantage of our genetic model and to further explore the mechanism underlying the PolyQ-induced cardiac defects, we co-expressed expanded Poly-Q with either the antioxidant enzyme superoxide dismutase (SOD) or a chaperone protein UNC-45. Our preliminary results suggest that cardiac dilation is reduced and cardiac performance is enhanced upon co-expression of SOD or UNC-45. Thus we have developed a novel Drosophila model that allows us to explore cardiac defects associated with the accumulation of HD-causing amyloid and to elucidate the mechanisms underlying cardiac failure in HD patients.