Total joint arthroplasty versus trapeziectomy in the treatment of trapeziometacarpal joint arthritis: a randomized controlled trial.

The aim of this double anonymized, randomized controlled trial was to determine whether total joint arthroplasty has superior outcomes than trapeziectomy 1 year after surgery for trapeziometacarpal osteoarthritis. A total of 62 women aged 40 years and older, scheduled for surgery for stage II or III osteoarthritis of the trapeziometacarpal joint, were included and randomized to trapeziectomy or total joint arthroplasty. The primary outcome was the total score of the Michigan Hand Outcomes Questionnaire. Secondary outcomes were the Michigan Hand Outcomes Questionnaire subscale scores, Disability of the Arm, Shoulder and Hand Questionnaire, active range of motion, strength, return to work, patient satisfaction and complications. Data were collected at baseline and at 3 and 12 months. At 1 year, we found no superiority of total joint arthroplasty over trapeziectomy regarding the total score of the Michigan Hand Outcomes Questionnaire. The total joint arthroplasty did show a significant advantage in strength and range of motion.Level of evidence: I.

Validity and reliability of a portable handheld dynamometer compared to a fixed isokinetic dynamometer to assess forearm torque strength.

To evaluate the effect of treatment on forearm rotation, torque muscle strength can be assessed using an isokinetic device (IKD) or a wrist dynamometer (WD). The aims of this study were 1) to determine concurrent validity and intra- and inter-rater reliability using the WD, and to examine correlations between WD and IKD in different positions; and 2) subsequently, to establish the intermethod reproducibility between WD as a handheld (HHD) or fixed device. We conducted a cross-sectional study in which torque strength was measured in healthy participants by two observers using an IKD and a WD. Study endpoints were concurrent validity (Pearson's r), intra- and inter-rater reliability, intermethod reproducibility (intraclass correlation coefficient: ICC) and measurement error (limits of agreement: LoA). Concurrent validity ranged, in the 2 studies assessing it, from r 0.37 to 0.52 for pronation and from r 0.50 to 0.82 for supination, with wide 95% confidence intervals. ICC for intra-rater reliability for pronation ranged from 0.85 to 0.91 and for supination from 0.91 to 0.95. ICC for inter-rater reliability for pronation ranged from 0.84 to 0.96 and for supination from 0.92 to 0.96. Despite the excellent intra- and inter-rater reliability and intermethod reproducibility for the WD-HHD and fixed WD, validity was low when compared to IKD and wide LoA indicated a high measurement error of approximately 20%. These results suggest that the WD cannot replace the IKD isometric mode for pronation and supination. LEVEL OF EVIDENCE: 2.

Subcellular localization of hippocampal ryanodine receptor 2 and its role in neuronal excitability and memory.

Ryanodine receptor 2 (RyR2) is abundantly expressed in the heart and brain. Mutations in RyR2 are associated with both cardiac arrhythmias and intellectual disability. While the mechanisms of RyR2-linked arrhythmias are well characterized, little is known about the mechanism underlying RyR2-associated intellectual disability. Here, we employed a mouse model expressing a green fluorescent protein (GFP)-tagged RyR2 and a specific GFP probe to determine the subcellular localization of RyR2 in hippocampus. GFP-RyR2 was predominantly detected in the soma and dendrites, but not the dendritic spines of CA1 pyramidal neurons or dentate gyrus granular neurons. GFP-RyR2 was also detected within the mossy fibers in the stratum lucidum of CA3, but not in the presynaptic terminals of CA1 neurons. An arrhythmogenic RyR2-R4496C+/- mutation downregulated the A-type K+ current and increased membrane excitability, but had little effect on the afterhyperpolarization current or presynaptic facilitation of CA1 neurons. The RyR2-R4496C+/- mutation also impaired hippocampal long-term potentiation, learning, and memory. These data reveal the precise subcellular distribution of hippocampal RyR2 and its important role in neuronal excitability, learning, and memory.

The role of routine radial styloidectomy in proximal row carpectomy: a retrospective review of 120 patients.

Impingement between the radial styloid and the trapezium can occur after a proximal row carpectomy (PRC). We hypothesized that a PRC with primary radial styloidectomy reduces the risk of radial impingement, without affecting clinical or functional outcomes. In this retrospective cohort study, 120 patients were divided into two groups: PRC with or without primary radial styloidectomy. Patient-related outcome, strength and range of motion after proximal row carpectomy were measured in a subgroup. The occurrence of radial impingement was significantly lower in the group with primary radial styloidectomy versus those without (p = 0.002). Five patients in the latter group were subsequently treated by a secondary radial styloidectomy, as compared with one patient who underwent primary radial styloidectomy (p = 0.034). There were no significant differences in range of motion or patient-related outcome observed between the two groups. From our study, a radial styloidectomy is recommended as a routine part of the PRC procedure to prevent radial impingement without negatively impacting on function.Level of evidence: IV.

Impaired myosin isoform shift and calcium transients contribute to cellular pathogenesis of rat cirrhotic cardiomyopathy.

BACKGROUND & AIMS: Cirrhotic cardiomyopathy is a recently recognized entity, but detailed cellular and molecular mechanisms remain unclarified. We aimed to elucidate the role of myosin heavy chain isoform shifts and their relation to calcium transients in the contractile kinetics of cirrhotic rats. METHODS: Cirrhosis was induced in male Lewis Brown-Norway rats by bile duct ligation (BDL). Myosin heavy chain (MHC) isoform distribution was evaluated by gel electrophoresis. Contractile force, Ca2+ transients and cell shortening were studied at varied frequency and extracellular [Ca2+ ]. T-tubular integrity was analysed by power spectrum analysis of images of myocytes stained with di-8-ANEPPS. RESULTS: Compared with sham controls, the phenotypes of cirrhotic rats were as follows: (a) alpha-myosin heavy chain shifted to beta-MHC isoform; (b) mild loss of T-tubular integrity in myocytes; (c) a reduced maximum and rate of rise of the Ca2+ transient (max F/Fo ); (d) a reduction in both the rate of rise and fall of contraction; (e) decreased maximal force-generating capacity; (f) loss of the inotropic effect of increased stimulus frequency; (g) unchanged sensitivity of force development to varied extracellular [Ca2+ ] and (h) increased spontaneous diastolic sarcomere length fluctuations. CONCLUSION: Cardiomyocytes and ventricular trabeculae in a cirrhotic rat model showed features of typical heart failure including systolic and diastolic prolongation, impaired force-frequency relation and decreased force-generating capacity. Impaired myosin isoform shift and calcium transients are important contributory mechanisms underlying the pathogenesis of the heart failure phenotype seen in cirrhosis.

A first-principles study on magnetic properties of the intrinsic defects in wurtzite ZnO.

Since the origin of magnetism in ZnO-based diluted magnetic semiconductors (DMSs) is still controversial, in this work, we presented a detailed study on the magnetic, structural, and electronic properties of wurtzite ZnO-based DMS systems with point and complex intrinsic defects. Two outer electrons from neutral oxygen vacancy (VO) occupy the a1 orbital, making the inducted magnetic moment to be zero, while a cluster including three VOs leads to a magnetic moment of ∼1 µB. The magnetic moment of the system with a Zn vacancy (VZn) is 1.65 µB. When two neutral VZns in different relative distances were created in respective supercells, the systems showed different magnetic moments induced by the unequal level between the highest electron occupied orbital of the defect state introduced by different VZn sites and the valence band maximum. The system of a neutral O occupying an octahedral site gives rise to a magnetic moment of 2 µB, while zinc interstitial and antisite defects do not cause spin polarization. The system with a complex defect of VO and VZn is magnetic when those vacancies are adjacent but still do not cause the compensation effect. The oxygen interstitial defect is unstable, and VZn easily turns into the complex defect. We suggest that VO clusters and VZn complex defects could likely be the origin of ferromagnetism in undoped ZnO.

Alternative Approaches to the Assessment of the Systemic Circulation and Left Ventricular Performance: A Proof-of-Concept Study.

BACKGROUND: The purpose of this article is to examine the systemic circulation and left ventricular (LV) performance by alternative, nonconventional approaches: systemic vascular conductance (G SV ) and the head-capacity relation (ie, the relation between LV pressure and cardiac output), respectively; in so doing, we aspired to present a novel and improved interpretation of integrated cardiovascular function. METHODS: In 16 open-chest, anaesthetized pigs, we measured LV pressure (P LV ), central aortic pressure (P Ao ), and central venous pressure (P CV ) and aortic flow (Q Ao ). We calculated heart rate (HR), stroke volume, cardiac index (CI = cardiac output/body weight), mean PLV ( P ¯ LV ) , and the average arteriovenous pressure difference ( Δ P = P ¯ Ao - P ¯ CV ); G SV  = CI/( P ¯ Ao - P ¯ CV ). We studied the effects of changing loading conditions with the administration of phenylephrine (Δ P ¯ Ao ≥ +25 mm Hg), isoproterenol (ΔHR ∼+25%), sodium nitroprusside (Δ P ¯ Ao ≥ -25 mm Hg), and proximal aortic constriction (to maximize developed P LV and minimize Q Ao ). RESULTS: Sodium nitroprusside and isoproterenol increased G SV compared with phenylephrine and constriction. A maximum head-capacity curve was derived from pooled data using nonlinear regression on the maximum P ¯ LV values in Q Ao bins 12.5 mL/min/kg wide. The head-capacity relation and the plots of conductance were combined using CI as a common axis, which illustrated that CI is the output of the heart and the input of the circulation. CONCLUSIONS: Thus, at a given CI, G SV determines the driving pressure and, thereby, P Ao . We also demonstrated how decreases in G SV compensate for arterial hypotension by restoring the arteriovenous pressure difference and arterial pressure.

CONTEXTE: Le présent article examine l'efficacité de la circulation générale et la fonction ventriculaire gauche à l'aide de paramètres de rechange non conventionnels, soit la conductance vasculaire systémique (G VS ) pour l'une et la relation pression-volume (c.-à-d. la relation entre la pression ventriculaire gauche et le débit cardiaque) pour l'autre, dans le but de présenter une interprétation nouvelle et améliorée de la fonction cardiovasculaire intégrée. MÉTHODOLOGIE: Chez 16 porcs anesthésiés, nous avons mesuré à thorax ouvert la pression ventriculaire gauche (P VG ), la pression aortique centrale (P AC ), la pression veineuse centrale (P VC ) et le flux aortique (Q A ). Nous avons établi la fréquence cardiaque (FC), le volume d'éjection systolique, l'index cardiaque (IC; rapport entre le débit cardiaque et le poids corporel), la P VG moyenne ( P ¯ VG ) et la différence de pression artérioveineuse moyenne ( Δ P = P ¯ A C − P ¯ V C ); G VS  = IC/( P ¯ AC − P ¯ VC ). Nous avons aussi étudié les effets d'une modification des conditions de charge cardiaque provoquée par l'administration de phényléphrine (Δ P ¯ AC ≥ + 25 mmHg), d'isoprotérénol (ΔFC d'environ + 25 %) ou de nitroprussiate de sodium (Δ P ¯ AC ≥ − 25 mmHg) et par la constriction de l'aorte proximale (pour maximiser la P VG développée et réduire le plus possible le Q A ). RÉSULTATS: Le nitroprussiate de sodium et l'isoprotérénol ont augmenté la G VS comparativement à la phényléphrine et à la constriction. Une courbe de la relation pression-volume maximale a été dérivée à partir des données groupées, au moyen d'une régression non linéaire sur les valeurs maximales de la P ¯ VG réparties dans des classes de Q A de 12,5 ml/min/kg d'amplitude. La courbe de la relation pression-volume et le tracé de la conductance ont été superposés en utilisant l'IC comme axe commun, ce qui a permis de constater que l'IC correspond au débit cardiaque et au volume entrant dans la circulation. CONCLUSIONS: Pour un IC donné, la G VS détermine la pression motrice et donc, la P AC . Nous avons aussi démontré comment une diminution de la G VS compense l'hypotension artérielle en rétablissant la différence de pression artérioveineuse et la pression artérielle.

Dynamic and Irregular Distribution of RyR2 Clusters in the Periphery of Live Ventricular Myocytes.

Cardiac ryanodine receptors (RyR2s) are Ca2+ release channels clustering in the sarcoplasmic reticulum membrane. These clusters are believed to be the elementary units of Ca2+ release. The distribution of these Ca2+ release units plays a critical role in determining the spatio-temporal profile and stability of sarcoplasmic reticulum Ca2+ release. RyR2 clusters located in the interior of cardiomyocytes are arranged in highly ordered arrays. However, little is known about the distribution and function of RyR2 clusters in the periphery of cardiomyocytes. Here, we used a knock-in mouse model expressing a green fluorescence protein (GFP)-tagged RyR2 to localize RyR2 clusters in live ventricular myocytes by virtue of their GFP fluorescence. Confocal imaging and total internal reflection fluorescence microscopy was employed to determine and compare the distribution of GFP-RyR2 in the interior and periphery of isolated live ventricular myocytes and in intact hearts. We found tightly ordered arrays of GFP-RyR2 clusters in the interior, as previously described. In contrast, irregular distribution of GFP-RyR2 clusters was observed in the periphery. Time-lapse total internal reflection fluorescence imaging revealed dynamic movements of GFP-RyR2 clusters in the periphery, which were affected by external Ca2+ and RyR2 activator (caffeine) and inhibitor (tetracaine), but little detectable movement of GFP-RyR2 clusters in the interior. Furthermore, simultaneous Ca2+- and GFP-imaging demonstrated that peripheral RyR2 clusters with an irregular distribution pattern are functional with a Ca2+ release profile similar to that in the interior. These results indicate that the distribution of RyR2 clusters in the periphery of live ventricular myocytes is irregular and dynamic, which is different from that of RyR2 clusters in the interior.

Myomectomies for massive hemoperitoneum from spontaneous bleeding of a uterine myoma.

Massive hemoperitoneum from spontaneous bleeding of uterine myoma is an extremely rare condition, that needs urgent surgical exploration. We report a 40-year-old woman, admitted for acute onset of abdominal pain. Physical examination revealed hypovolemic shock. The hemoglobin level was of 5 g/dL. Ultrasonography revealed hemoperitoneum. Emergency surgical exploration was planned. There was hemoperitoneum of 3 L, uterine myomas with multiple subserous myomas, bleeding from superficial ruptured varice overlying the most largest subserous myoma, which measured 15 cm. Glove adapted as a tourniquet, was applied at the base of the uterus, and myomectomies were performed with removal of around twenty myomas. The postoperative course was uneventful. Myomectomies can be safely and effectively performed by using a tourniquet, for massive hemoperitoneum with precarious hemodynamic status due to subserous myoma bleeding, despite the number and the size of myomas.

Influence of Therapeutic Approach in the TENS-induced Hypoalgesia.

INTRODUCTION: The present study aimed to determine how the therapist's approach about intervention may influence transcutaneous electrical nerve stimulation (TENS)-induced hypoalgesia. METHODS: One hundred and sixty-one pain-free individuals agreed to participate in this study and had their demographics, perceived pain intensity, pressure pain threshold, anxiety level, and the state of anxiety inventory score measured. Subsequently, participants were randomly assigned into 6 study groups, 3 active and 3 placebo TENS associated with positive, negative, or neutral approaches about electrical stimulation, as given by the investigator. After the treatment, all parameters were reassessed. RESULTS: Active TENS-treated participants receiving either positive or neutral expectations about intervention showed a significant increase in pressure pain threshold (P<0.02) compared with pretreatment; however, this was not observed in the active TENS group when associated with negative expectations. The intensity of perceived pain was significantly reduced (P<0.02) only in the active TENS groups in association with either positive or neutral expectations. There was no significant difference in any of the variables assessed in the groups receiving placebo TENS intervention. DISCUSSION: The negative expectations induced prior to the proposed intervention promoted unfavorable outcomes with respect to the analgesic properties of TENS, suggesting that the approach taken by the physical therapist should be used to convey positive expectations and avoid those negatives, to promote more efficacious treatment.

Distribution and Function of Cardiac Ryanodine Receptor Clusters in Live Ventricular Myocytes.

The cardiac Ca(2+) release channel (ryanodine receptor, RyR2) plays an essential role in excitation-contraction coupling in cardiac muscle cells. Effective and stable excitation-contraction coupling critically depends not only on the expression of RyR2, but also on its distribution. Despite its importance, little is known about the distribution and organization of RyR2 in living cells. To study the distribution of RyR2 in living cardiomyocytes, we generated a knock-in mouse model expressing a GFP-tagged RyR2 (GFP-RyR2). Confocal imaging of live ventricular myocytes isolated from the GFP-RyR2 mouse heart revealed clusters of GFP-RyR2 organized in rows with a striated pattern. Similar organization of GFP-RyR2 clusters was observed in fixed ventricular myocytes. Immunofluorescence staining with the anti-α-actinin antibody (a z-line marker) showed that nearly all GFP-RyR2 clusters were localized in the z-line zone. There were small regions with dislocated GFP-RyR2 clusters. Interestingly, these same regions also displayed dislocated z-lines. Staining with di-8-ANEPPS revealed that nearly all GFP-RyR2 clusters were co-localized with transverse but not longitudinal tubules, whereas staining with MitoTracker Red showed that GFP-RyR2 clusters were not co-localized with mitochondria in live ventricular myocytes. We also found GFP-RyR2 clusters interspersed between z-lines only at the periphery of live ventricular myocytes. Simultaneous detection of GFP-RyR2 clusters and Ca(2+) sparks showed that Ca(2+) sparks originated exclusively from RyR2 clusters. Ca(2+) sparks from RyR2 clusters induced no detectable changes in mitochondrial Ca(2+) level. These results reveal, for the first time, the distribution of RyR2 clusters and its functional correlation in living ventricular myocytes.

Impact of detubulation on force and kinetics of cardiac muscle contraction.

Action potential-driven Ca(2+) currents from the transverse tubules (t-tubules) trigger synchronous Ca(2+) release from the sarcoplasmic reticulum of cardiomyocytes. Loss of t-tubules has been reported in cardiac diseases, including heart failure, but the effect of uncoupling t-tubules from the sarcolemma on cardiac muscle mechanics remains largely unknown. We dissected intact rat right ventricular trabeculae and compared force, sarcomere length, and intracellular Ca(2+) in control trabeculae with trabeculae in which the t-tubules were uncoupled from the plasma membrane by formamide-induced osmotic shock (detubulation). We verified disconnection of a consistent fraction of t-tubules from the sarcolemma by two-photon fluorescence imaging of FM4-64-labeled membranes and by the absence of tubular action potential, which was recorded by random access multiphoton microscopy in combination with a voltage-sensitive dye (Di-4-AN(F)EPPTEA). Detubulation reduced the amplitude and prolonged the duration of Ca(2+) transients, leading to slower kinetics of force generation and relaxation and reduced twitch tension (1 Hz, 30°C, 1.5 mM [Ca(2+)]o). No mechanical changes were observed in rat left atrial trabeculae after formamide shock, consistent with the lack of t-tubules in rodent atrial myocytes. Detubulation diminished the rate-dependent increase of Ca(2+)-transient amplitude and twitch force. However, maximal twitch tension at high [Ca(2+)]o or in post-rest potentiated beats was unaffected, although contraction kinetics were slower. The ryanodine receptor (RyR)2 Ca-sensitizing agent caffeine (200 µM), which increases the velocity of transverse Ca(2+) release propagation in detubulated cardiomyocytes, rescued the depressed contractile force and the slower twitch kinetics of detubulated trabeculae, with negligible effects in controls. We conclude that partial loss of t-tubules leads to myocardial contractile abnormalities that can be rescued by enhancing and accelerating the propagation of Ca(2+)-induced Ca(2+) release to orphan RyR2 clusters.

Evoked centripetal Ca(2+) mobilization in cardiac Purkinje cells: insight from a model of three Ca(2+) release regions.

Despite strong suspicion that abnormal Ca(2+) handling in Purkinje cells (P-cells) is implicated in life-threatening forms of ventricular tachycardias, the mechanism underlying the Ca(2+) cycling of these cells under normal conditions is still unclear. There is mounting evidence that P-cells have a unique Ca(2+) handling system. Notably complex spontaneous Ca(2+) activity was previously recorded in canine P-cells and was explained by a mechanistic hypothesis involving a triple layered system of Ca(2+) release channels. Here we examined the validity of this hypothesis for the electrically evoked Ca(2+) transient which was shown, in the dog and rabbit, to occur progressively from the periphery to the interior of the cell. To do so, the hypothesis was incorporated in a model of intracellular Ca(2+) dynamics which was then used to reproduce numerically the Ca(2+) activity of P-cells under stimulated conditions. The modelling was thus performed through a 2D computational array that encompassed three distinct Ca(2+) release nodes arranged, respectively, into three consecutive adjacent regions. A system of partial differential equations (PDEs) expressed numerically the principal cellular functions that modulate the local cytosolic Ca(2+) concentration (Cai). The apparent node-to-node progression of elevated Cai was obtained by combining Ca(2+) diffusion and 'Ca(2+)-induced Ca(2+) release'. To provide the modelling with a reliable experimental reference, we first re-examined the Ca(2+) mobilization in swine stimulated P-cells by 2D confocal microscopy. As reported earlier for the dog and rabbit, a centripetal Ca(2+) transient was readily visible in 22 stimulated P-cells from six adult Yucatan swine hearts (pacing rate: 0.1 Hz; pulse duration: 25 ms, pulse amplitude: 10% above threshold; 1 mm Ca(2+); 35°C; pH 7.3). An accurate replication of the observed centripetal Ca(2+) propagation was generated by the model for four representative cell examples and confirmed by statistical comparisons of simulations against cell data. Selective inactivation of Ca(2+) release regions of the computational array showed that an intermediate layer of Ca(2+) release nodes with an ~30-40% lower Ca(2+) activation threshold was required to reproduce the phenomenon. Our computational analysis was therefore fully consistent with the activation of a triple layered system of Ca(2+) release channels as a mechanism of centripetal Ca(2+) signalling in P-cells. Moreover, the model clearly indicated that the intermediate Ca(2+) release layer with increased sensitivity for Ca(2+) plays an important role in the specific intracellular Ca(2+) mobilization of Purkinje fibres and could therefore be a relevant determinant of cardiac conduction.

The velocity of cardiac sarcomere shortening: mechanisms and implications.

A classical paper published by Michael Barany almost 50 years ago demonstrated a tight correlation between the mechanical parameter of maximal velocity of shortening and the biochemical parameter of myosin ATPase activity in a wide spectrum of species. Here, we review the determinants of muscle dynamics by mechanical load and the relation between sarcomere shortening velocity and cross-bridge dynamics in rat myocardium containing a range of fast and slow myosin. Observations from molecular level to mechanics of the intact human heart suggest that cardiac actin-myosin kinetic properties are matched so as to optimize myocardial strain rate and allow for the maximum rate of hydraulic energy output observed during ejection in the whole ventricle.

The interaction of Ca2+ with sarcomeric proteins: role in function and dysfunction of the heart.

The hallmarks of the normal heartbeat are both rapid onset of contraction and rapid relaxation as well as an inotropic response to both increased end-diastolic volume and increased heart rate. At the microscopic level, Ca(2+) plays a crucial role in normal cardiac contraction. This paper reviews the cycle of Ca(2+) fluxes during the normal heartbeat, which underlie the coupling between excitation and contraction and permit a highly synchronized action of cardiac sarcomeres. Length dependence of the response of the regulatory sarcomeric proteins mediates the Frank-Starling Law of the heart. However, Ca(2+) transport may go astray in heart disease such as in congestive heart failure, and both jeopardize systole and diastole and triggering arrhythmias. The interaction between weak and strong segments in nonuniform cardiac muscle allows partial preservation of force of contraction but may further lead to mechanoelectric feedback or reverse excitation-contraction coupling mediating an early diastolic Ca(2+) transient caused by the rapid force decrease during the relaxation phase. These rapid force changes in nonuniform muscle may cause arrhythmogenic Ca(2+) waves to propagate by the activation of neighboring sarcoplasmic reticulum by diffusing Ca(2+) ions.

Role of cardiac myofilament proteins titin and collagen in the pathogenesis of diastolic dysfunction in cirrhotic rats.

BACKGROUND & AIMS: Significance of diastolic dysfunction in cirrhotic cardiomyopathy has been brought to the forefront with several reports of unexpected heart failure following liver transplantation and transjugular intrahepatic portosystemic stent-shunt, but the etiology remains unclear. The present study investigated the role of passive tension regulators - titin and collagen - in the pathogenesis of this condition. METHODS: Cirrhosis was induced by bile duct ligation (BDL) in rats, while controls underwent bile duct inspection with no ligation. Four weeks after operation, cardiac mRNA and protein levels of titin, collagen, and protein kinase A (PKA) were determined. Diastolic function was examined in isolated right ventricular cardiomyocytes, while passive tension was examined in right ventricular trabeculae muscles. RESULTS: In BDL animals, diastolic return velocity was significantly decreased, relaxation time increased and passive tension increased. However, no significant difference in mRNA and protein levels of titin was observed. PKA mRNA and protein levels were significantly decreased in BDL animals. Collagen levels were also significantly altered in the BDL group. CONCLUSIONS: Therefore, diastolic dysfunction exists in cirrhosis with alterations in titin modulation, PKA levels, and collagen configuration contributing to the pathogenesis of this condition.

Electromechanical coupling in the cardiac myocyte; stretch-arrhythmia feedback.

The macroscopic hallmarks of the normal heartbeat are rapid onset of contraction and rapid relaxation and an inotropic response to both increased end diastolic volume and increased heart rate. At the microscopic level, the calcium ion (Ca(2+)) plays a crucial role in normal cardiac contraction. This paper reviews the cycle of Ca(2+) fluxes during the normal heartbeat, which underlie the coupling between excitation and contraction (ECC) and permit a highly synchronized action of cardiac sarcomeres. Length dependence of the response of the regulatory sarcomeric proteins mediates the Frank-Starling Law of the heart. However, Ca(2+) transport may go astray in heart disease and both jeopardize the exquisite mechanism of systole and diastole and triggering arrhythmias. The interplay between weakened and strong segments in nonuniform cardiac muscle may further lead to mechanoelectric feedback-or reverse excitation contraction coupling (RECC) mediating an early diastolic Ca(2+) transient caused by the rapid force decrease during the relaxation phase. These rapid force changes in nonuniform muscle may cause arrhythmogenic Ca(2+) waves to propagate by activation of neighbouring SR by diffusing Ca(2+) ions.

Nonuniform activation and the mechanics of myocardial trabeculae with fast or slow myosin.

Left ventricular (LV) wall motion abnormalities reflect regional nonuniform contraction which may be arrhythmogenic. We studied sarcomere mechanics and force development (F) in uniform and nonuniform trabeculae using a model in which half of the muscle can be rendered weak by exposure to low [Ca2+]o. Stretch allowed the weak muscle segment to generate a force that was four-fold higher than force when the whole muscle was exposed to low [Ca2+]o. The sarcomere force-velocity relationships (FSVR) and the force-sarcomere-length relationships (FSLR) explained the force increase in the weak segment and the decrease of force in the strong segment such that both carried the same force. Correction for muscle stiffness converted the FSVR into a [Ca2+]o-independent linear FVRXB for "the single cross-bridge (XB)." Stretch increased XB force<10% above FXB-max, but recruited more XBs by feedback of V to the rate of XB, weakening (g=g0+g1V). The g1 here was indistinguishable from g1 of XBs in slow myosin of aged animals. The mechanics of nonuniform muscle can be explained by a linear FVRXB combined with the effect of V on the XB weakening rate.

Effects of therapy using the Celacade system on structural and functional cardiac remodelling in rats following myocardial infarction.

BACKGROUND: Immune modulation by the Celacade system (Vasogen Inc, Canada) decreases mortality and hospitalization in human heart failure. OBJECTIVES: To study the effects of Celacade in rats on acute cytokine expression after coronary artery ligation, cardiac dimensions following myocardial infarction (MI), and systolic and diastolic function of cardiac muscle in MI. METHODS: Celacade treatment was administered 14 days before coronary artery ligation and monthly after the surgery. Cytokine expression in cardiac tissue was measured on days 1 and 7 by ELISA in sham rats and in rats with MI (with or without Celacade treatment). Echocardiograms were obtained serially for 16 weeks. Force and sarcomere length (SL) were measured by strain gauge and laser diffraction in isolated right ventricle trabeculas at 16 weeks. The inotropic effect of pacing on force was quantified as F5 Hz/0.5 Hz. Diastolic dysfunction was quantified as the root mean square of spontaneous SL fluctuations. RESULTS: Celacade inhibited transforming growth factor beta-1 production in the infarct area on day 7 (191.6+/-22.6 pg/mg versus 275.4+/-30.1 pg/mg; P<0.05), but did not attenuate cardiac dilation in MI. Celacade restored positive inotropism of pacing in MI (F5 Hz/0.5 Hz in Celacade, 219.1+/-46.7%; MI, 148.1+/-27.1% [P<0.05 compared with 211.4+/-37.9% in sham]). Celacade reduced diastolic dysfunction in MI (root mean square of spontaneous SL fluctuations: 121+/-15% and 143+/-19% with Celacade versus 184+/-19% and 190+/-26% without Celacade at 26 degrees C and 36 degrees C, respectively) compared with sham (100%; P<0.05). CONCLUSIONS: Celacade reduces the increase of transforming growth factor beta-1 expression during the acute stage of MI in rats, but does not prevent chronic cardiac dilation. Celacade restores the positive inotropic effect of increased pacing rate in trabeculas from rat right ventricles with large MIs and reduces diastolic dysfunction.