Vernakalant in an Experimental Model of Pacing-Induced Heart Failure: Lack of Proarrhythmia Despite Prolongation of Repolarization

BackgroundThe present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible proarrhythmic effects of vernakalant in an experimental model of heart failure (HF).Methods and ResultsIn 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 μmol/L and 30 μmol/L) increase of action potential duration (APD₉₀) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD₉₀ was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 μmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K⁺ concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias.ConclusionIn the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts.     

Effect of ranolazine on ventricular vulnerability and defibrillation threshold in the intact porcine heart

Introduction: Extensive in vitro studies and clinical evidence (MERLIN trial) indicate an antiarrhythmic potential of ranolazine, a novel antianginal agent. Programmed electrophysiologic testing was performed to quantify ranolazine's effects on ventricular vulnerability and defibrillation thresholds and to gain insights into mechanisms. Methods and Results: Effects of ranolazine (9.2 ± 2.1 μM, plasma level) on surface ECG, right ventricular effective refractory period (ERP), and repetitive extrasystole (RE), ventricular fibrillation (VF), and defibrillation (DFT) thresholds were determined in 29 normal closed‐chest anesthetized pigs. The single extrastimulus method was employed for ERP and for RE and VF thresholds. DFT₅₀ was determined using an up‐down testing protocol with an implantable cardioverter‐defibrillator. Ranolazine increased rate‐corrected QT interval from 490 ± 30 to 527 ± 24 ms (P < 0.05) but did not alter T_peak‐T_end interval (59 ± 8 to 62 ± 11, P = 0.65). ERP increased by 40 ± 6 ms (P < 0.001). Compared with baseline, ranolazine raised RE threshold from 20 ± 6 to 34 ± 9 mA (P < 0.001) and VF threshold from 38 ± 4 to 48 ± 10 mA (P < 0.05). DFT₅₀ was unchanged (baseline: 14 ± 2 J; ranolazine: 14 ± 2 J; P = 0.6), whereas diastolic pacing threshold increased from baseline pulse width of 0.07 ± 0.03 to 0.17 ± 0.07 ms (P < 0.01) with 1V pulse amplitude. Conclusions: Ranolazine, at therapeutic concentrations, produces a mild increase in QT interval and a marked increase in both RE and VF thresholds. Thus, ranolazine does not augment and may improve dispersion of ventricular repolarization, suggesting a potential antiarrhythmic action. Ranolazine is unlikely to affect the margin of safety of defibrillation, given no significant effect on DFT, but could result in a mild increase in pacing threshold.     

Hemodynamic Effects of Late Sodium Current Inhibitors in a Swine Model of Heart Failure

ObjectivesTo evaluate possible treatment-related hemodynamic changes, we administered ranolazine or mexiletine to swine with heart failure (HF) and to controls.BackgroundRanolazine and mexiletine potently inhibit depolarizing late Na⁺ current (I_Na,late) and Na⁺ entry into cardiomyocytes_. Blocking Na⁺ entry may increase forward-mode Na/Ca exchange and reduce cellular Ca⁺² load, further compromising systolic contraction during HF.Methods and ResultsAnesthetized tachypaced HF swine received ranolazine (n = 9) or mexiletine (n = 7) as boluses, then as infusions; the same experiments were performed in 10 nonpaced controls. The swine with HF had characteristic elevated left ventricular end-diastolic pressure (LVEDP) and reduced maximal left ventricular pressure rise (+dP/dt_max) and left ventricular peak systolic pressure (LVSP). No significant change occurred after ranolazine dosing for any parameter: LVEDP, +dP/dt_max, LVSP, heart rate, maximal LV pressure fall rate (–dP/dt_max), or time constant for isovolumic relaxation. Similar results seen in additional swine with HF: 7 were given mexiletine, and 7 others were given ranolazine after a 27% rate decrement to maximize I_Na,late. Patch-clamped HF cardiomyocytes confirmed drug-induced I_Na,late blockade.ConclusionsRanolazine or mexiletine blocking I_Na,late neither worsened nor improved hemodynamics during advanced HF. Although results must be clinically confirmed, they suggest inhibition of I_Na,late by ranolazine or mexiletine may not exacerbate HF in patients.     

Effects of cromakalim or pinacidil on pacing- and ischemia-induced ventricular fibrillation in the anesthetized pig

Summary The effects of the potassium channel openers (KCO), cromakalim or pinacidil, were evaluated in an anesthetized porcine model of pacing- and ischemia-induced ventricular fibrillation (VF). Hearts were paced at 180 bpm and the left anterior descending coronary artery was occluded until VF was induced.Reproducible times to VF (in seconds) were obtained allowing at least 20 min recovery following defibrillation. Cromakalim (0.3 mg/kg) or pinacidil (3 mg/kg) produced equivalent drops in mean arterial blood pressure. At these doses, cromakalim reduced monophasic action potential duration measured at 90% repolarization (APD₉₀). Although time to VF in the cromakalim group was significantly greater than the vehicle treated group, it was not significantly different from its predrug value. In contrast, pinacidil reduced APD₉₀, and significantly increased time to VF from 134±5 to 322±62 s (p<0.05). Neither cromakalim nor pinacidil affected whole-cell calcium currents recorded in guinea pig myocytes. During ischemia, cromakalim or pinacidil further reduced APD₉₀; however, pinacidil had a two-fold greater effect than did cromakalim. The Class III antiarrhythmic agent, dofetilide, prolonged APD₉₀, but did not increase time to VF.In conclusion, the increased time to VF observed with pinacidil coincides with its ability to shorten APD, and is consistent with activation of ATP-sensitive K⁺ channels (K⁺ _ATP). It is suggested that indirect reduction of calcium influx through K⁺ _ATP activation and APD shortening is sufficient to increase time to VF in this model. However, the inability of dofetilide to be effective suggests that this model would not be useful to test for Class III antiarrhythmic agents.     

Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation

The goal of this study was to test the hypothesis that the novel anti-ischemic drug ranolazine, which is known to inhibit late I_Na, could reduce intracellular [Na⁺]_i and diastolic [Ca²⁺]_i overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na⁺]_i and elevated diastolic [Ca²⁺]_i. Increased Na⁺ influx through voltage-gated Na⁺ channels (late I_Na) has been suggested to contribute to elevated [Na⁺]_i in HF. In isometrically contracting ventricular muscle strips from end-stage failing human hearts, ranolazine (10 µmol/L) did not exert negative inotropic effects on twitch force amplitude. However, ranolazine significantly reduced frequency-dependent increase in diastolic tension (i.e., diastolic dysfunction) by ~ 30% without significantly affecting sarcoplasmic reticulum (SR) Ca²⁺ loading. To investigate the mechanism of action of this beneficial effect of ranolazine on diastolic tension, Anemonia sulcata toxin II (ATX-II, 40 nmol/L) was used to increase intracellular Na⁺ loading in ventricular rabbit myocytes. ATX-II caused a significant rise in [Na⁺]_i typically seen in heart failure via increased late I_Na. In parallel, ATX-II significantly increased diastolic [Ca²⁺]_i. In the presence of ranolazine the increases in late I_Na, as well as [Na⁺]_i and diastolic [Ca²⁺]_i were significantly blunted at all stimulation rates without significantly decreasing Ca²⁺ transient amplitudes or SR Ca²⁺ content. In summary, ranolazine reduced the frequency-dependent increase in diastolic tension without having negative inotropic effects on contractility of muscles from end-stage failing human hearts. Moreover, in rabbit myocytes the increases in late I_Na, [Na⁺]_i and [Ca²⁺]_i caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na⁺]_i and diastolic [Ca²⁺]_i.     

G-CSF therapy reduces myocardial repolarization reserve in the presence of increased arteriogenesis, angiogenesis and connexin 43 expression in an experimental model of pacing-induced heart failure

G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10?μg/kg G-CSF s.c. over 17?±?4?days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33?±?12?ms; p?相似文献   

Piceatannol facilitates conduction block and ventricular fibrillation induction in ischemia-reperfused rabbit hearts with pacing-induced heart failure

Background

Piceatannol, a hydroxystilbene natural product, has been reported to exert antiarrhythmic action via I_Na inhibition and slow I_Na inactivation in ischemia-reperfused (IR) rat hearts. The present study aimed to clarify the proarrhythmic property of piceatannol during regional IR injury in failing rabbit hearts.

Methods

Heart failure (HF) was induced by rapid right ventricular pacing for 4 weeks. The IR model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo. Simultaneous voltage and intracellular Ca^2 + (Ca_i) optical mapping was then performed in isolated Langendorff-perfused hearts (n = 11 in each HF and control group). Action potential duration (APD) restitution, arrhythmogenic alternans and VF inducibility were evaluated by a dynamic pacing protocol. Conduction velocity was measured along lines across the IR and non-IR zones during pacing. Piceatannol (10 μM) was administered after baseline studies.

Results

In the HF group, piceatannol decreased conduction velocity, induced rate-dependent regional inhomogeneity of conduction delay and wavelength shortening, slowed Ca_i decay, and facilitated arrhythmogenic alternans instead of APD prolongation to increase VF inducibility. In the control group, the proarrhythmic effects of piceatannol on APD restitution, arrhythmogenic alternans and conduction delay were offset by its antiarrhythmic effects (APD and wavelength prolongation), resulting in a neutral effect on VF inducibility.

Conclusions

Piceatannol (10 μM) is proarrhythmic in failing rabbit hearts with regional IR injury. The increased VF inducibility by piceatannol in HF suggests that its undesirable effects are more pronounced than its benefits in failing hearts.     

Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease

The aim of the study was to determine the characteristics of the late Na current (I_NaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, I_NaL and the action potential duration (APD₉₀) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and slowed I_NaL decay time which could be normalized by addition of the I_NaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD₉₀ could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of I_NaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of I_NaL and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest. This article is part of a Special Issue entitled “Na⁺ Regulation in Cardiac Myocytes”.     

Ranolazine Exerts Potent Effects on Atrial Electrical Properties and Abbreviates Atrial Fibrillation Duration in the Intact Porcine Heart

Introduction: In vitro studies and ambulatory ECG recordings from the MERLIN TIMI-36 clinical trial suggest that the novel antianginal agent ranolazine may have the potential to suppress atrial arrhythmias. However, there are no reports of effects of ranolazine on atrial electrophysiologic properties in large intact animals.
Methods and Results: In 12 closed-chest anesthetized pigs, effects of intravenous ranolazine (∼9 μM plasma concentration) on multisite atrial effective refractory period (ERP), conduction time (CT), and duration and inducibility of atrial fibrillation (AF) initiated by intrapericardial acetylcholine were investigated. Ranolazine increased ERP by a median of 45 ms (interquartile range 29–50 ms; P < 0.05, n = 6) in right and left atria compared to control at pacing cycle length (PCL) of 400 ms. However, ERP increased by only 28 (24–34) ms in right ventricle (P < 0.01, n = 6). Ranolazine increased atrial CT from 89 (71–109) ms to 98 (86–121) ms (P = 0.04, n = 6) at PCL of 400 ms. Ranolazine decreased AF duration from 894 (811–1220) seconds to 621 (549–761) seconds (P = 0.03, n = 6). AF was reinducible in 1 of 6 animals after termination with ranolazine compared with all 6 animals during control period (P = 0.07). Dominant frequency (DF) of AF was reduced by ranolazine in left atrium from 11.7 (10.7–20.5) Hz to 7.6 (2.9–8.8) Hz (P = 0.02, n = 6).
Conclusions: Ranolazine, at therapeutic doses, increased atrial ERP to greater extent than ventricular ERP and prolonged atrial CT in a frequency-dependent manner in the porcine heart. AF duration and DF were also reduced by ranolazine. Potential role of ranolazine in AF management merits further investigation.     

Electrocardiological effects of ranolazine and lidocaine on normal and diabetic rat atrium

Purpose

Cellular changes occurring in diabetic cardiomyopathy include disturbances of calcium and sodium homeostasis. Voltage-gated sodium channels are responsible for the initiation of cardiac action potentials, and the excitability would create relevance. The effect of ranolazine as a sodium channel blocker on atrium electromechanical parameters is investigated and compared with lidocaine in streptozocin-treated diabetic rats.

Methods

After an 8-week induction of diabetes type I, the effect of cumulative concentrations of ranolazine and lidocaine on the electrophysiology of isolated atrium was studied. Ranolazine’s effects were evaluated on cardiac sodium current in normal- and high-glucose medium, with whole-cell patch-clamp technique.

Results

Ranolazine at therapeutic concentrations had no significant statistical effect on refractory period in normal and diabetic isolated heart. Ranolazine (10 μM) caused a hyperpolarizing shift of V_1/2 for steady-state inactivation in normal media, while it significantly elicited a depolarizing shift in high-glucose media (p?<?0.05).

Conclusion

It is concluded that in the isolated rat atrium preparation, ranolazine and lidocaine have no beneficial on diabetic cardiomyopathy. Although refractoriness and contractility were not much different in normal and diabetic atria, there was a definite effect of ranolazine and lidocaine on sodium current in varying concentrations. This may have significance in future therapeutics.

     

Effects of hypokalemia on transmural dispersion of ventricular repolarization in left ventricular myocardium

ObjectiveTo observe effects of hypokalemia on transmural heterogeneity of ventricular repolarization in left ventricular myocardium of rabbit, and explore the role of hypokalemia in malignant ventricular arrhythmia (MVA).MethodsA total of 20 rabbits were randomly divided into control group and hypokalemic group. Isolated hearts in the control group were simply perfused with modified Tyrode's solution, and were perfused with hypokalemic Tyrode's solution in hypokalemic group. Ventricular fibrillation threshold (VFT), 90% monophasic action potential repolarization duration (APD₉₀) of subepicardial, midmyocardial and subendocardial myocardium, transmural dispersion of repolarization (TDR) and C×43 protein expression in three layers of myocardium were measured in both groups.ResultsVFT in the control group and the hypokalemic group were (13.40±2.95) V, and (7.00±1.49) V, respectively. There was a significant difference between two groups (P<0.01). APD₉₀ of three myocardial layers in the hypokalemic group were significantly prolonged than those in the control group (P<0.01). ΔAPD₉₀ in the hypokalemic group and the control group were (38.10±10.29) ms and (23.70±5.68) ms, and TDR were (52.90±14.55) ms and (36.10±12.44) ms, respectively. ΔAPD₉₀ and TDR in the hypokalemic group were significantly higher than those in the control group (P<0.05), and the increase in APD₉₀ of midmyocardium was more significant in the hypokalemic group. Cx43 protein expression of all three myocardial layers were decreased significantly in the hypokalemic group (P<0.01), and ΔCx43 was significantly increased (P<0.05). Reduction of Cx43 protein expression was more significant in the midmyocardium.ConclusionsHypokalemic can increase transmural heterogeneity of C×43 expression and repolarization in left ventricular myocardium of rabbit, and decrease VFT and can induce MVA more easily.     

Antiarrhythmic effect of ischemic preconditioning during low-flow ischemia

Abstract. Short episodes of ischemia (ischemic preconditioning) protect the heart against ventricular arrhythmias during zero-flow ischemia and reperfusion. However, in clinics, many episodes of ischemia present a residual flow (low-flow ischemia). Here we examined whether ischemic preconditioning protects against ventricular arrhythmias during and after a low-flow ischemia and, if so, by what mechanism(s).Isolated rat hearts were subjected to 60 min of low-flow ischemia (12% residual coronary flow) followed by 60 min of reperfusion. Ischemic preconditioning was induced by two cycles of 5 min of zero-flow ischemia followed by 5 and 15 min of reperfusion, respectively. Arrhythmias were evaluated as numbers of ventricular premature beats (VPBs) as well as incidences of ventricular tachycardia (VT) and ventricular .brillation (VF) during low-flow ischemia and reperfusion. Ischemic preconditioning significantly reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. This antiarrhythmic effect of preconditioning was abolished by HOE 140 (100 nM), a bradykinin B₂ receptor blocker. Similar to preconditioning, exogenous bradykinin (10 nM) reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. Furthermore, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by glibenclamide (1 µM), a non-specific blocker of ATP-sensitive K⁺ (K_ATP) channels. Finally, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by HMR 1098 (10 µM), a sarcolemmal K_ATP channel blocker but not by 5-hydroxydecanoate (100 µM), a mitochondrial K_ATP channel blocker. In conclusion, ischemic preconditioning protects against ventricular arrhythmias induced by low-flow ischemia, and this protection involves activation of bradykinin B₂ receptors and subsequent opening of sarcolemmal but not of mitochondrial K_ATP channels.     

Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome

Introduction: One form of the hereditary long‐QT syndrome, LQT3‐ΔKPQ, is associated with sustained inward sodium current during membrane depolarization. Ranolazine reduces late sodium channel current, and we hypothesized that ranolazine would have beneficial effects on electrical and mechanical cardiac function in LQT3 patients with the SCN5A‐ΔKPQ mutation. Methods: We assessed the effects of 8‐hour intravenous ranolazine infusions (45 mg/h for 3 hours followed by 90 mg/h for 5 hours) on ventricular repolarization and myocardial relaxation in 5 LQT3 patients with the SCN5A‐ΔKPQ mutation. Changes in electrocardiographic repolarization parameters from before to during ranolazine infusion were evaluated by time‐matched, paired t‐test analyses. Cardiac ultrasound recordings were obtained before ranolazine infusion and just before completion of the 8‐hour ranolazine infusion. Results: Ranolazine shortened QTc by 26 ± 3 ms (P < 0.0001) in a concentration‐dependent manner. At peak ranolazine infusion, there was a significant 13% shortening in left ventricular isovolumic relaxation time, a significant 25% increase in mitral E‐wave velocity, and a meaningful 22% decrease in mitral E‐wave deceleration time compared with the baseline. No adverse effects of ranolazine were observed in the study patients. Conclusion: Ranolazine at therapeutic concentrations shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3‐ΔKPQ mutation, a genetic disorder that is known to cause an increase in late sodium current.     

Prolonged action potential durations,increased dispersion of repolarization,and polymorphic ventricular tachycardia in a mouse model of proarrhythmia

Introduction: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current I_Kr is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. Methods and results: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10^-5M and 2 × 10^-5M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 ± 1 to 48 ± 2 ms at 100 ms basic cycle length (BCL), from 38 ± 2 to 54 ± 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 ± 1 vs. 4 ± 1 ms, APD90max-min: 12 ± 1 vs. 5 ± 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K⁺ =3.0 mM and in 10 of 12 hearts at K⁺ = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 ± 3 ms; APD90max-min: 25 ± 3 ms; p < 0.05). Conclusions: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.     

Preserved norepinephrine reuptake but reduced sympathetic nerve endings in hypertrophic volume-overloaded rat hearts

BackgroundIn congestive heart failure (CHF), an activation of the cardiac sympathetic nervous system results in depleted cardiac norepinephrine (NE) stores. The underlying regulatory mechanisms are discussed controversially and were investigated in the present study in CHF resulting from volume overload.Methods and ResultsAorto-caval shunt (AVS) was performed in rats. Plasma NE levels were determined by radioenzymatic assay, left ventricular NE by high-performance liquid chromatography, endothelin-1 by enzyme-linked immunosorbent assay. Tyrosine-hydroxylase (TH)– and nerve growth factor (NGF)–mRNA was determined by Northern blot analysis and ribonuclease-assay. Cardiac [³H]-NE uptake was measured in isolated perfused hearts. Glyoxylic acid–induced histofluorescence was used to quantify cardiac sympathetic nerves. Compared with sham-operated animals (SH), AVS rats were characterized by depleted cardiac NE stores and enhanced NE plasma levels. Neither TH-mRNA levels in stellate ganglia, nor cardiac [³H]-NE-uptake were reduced in AVS. The left ventricular density of sympathetic nerves was markedly decreased. Gene expression of myocardial NGF (a positive regulator of NE reuptake and cardiac sympathetic nerve density) and left ventricular endothelin-1 (a negative regulator of NE reuptake and positive regulator of cardiac NGF expression) were unchanged.ConclusionIn volume-overloaded hypertrophic hearts, depletion of cardiac NE stores is caused by a reduction of the sympathetic nerve density, whereas cardiac NE reuptake is preserved.     

AntimiR-132 Attenuates Myocardial Hypertrophy in an Animal Model of Percutaneous Aortic Constriction

BackgroundPathological cardiac hypertrophy is a result of afterload-increasing pathologies including untreated hypertension and aortic stenosis. It features progressive adverse cardiac remodeling, myocardial dysfunction, capillary rarefaction, and interstitial fibrosis often leading to heart failure.ObjectivesThis study aimed to establish a novel porcine model of pressure-overload–induced heart failure and to determine the effect of inhibition of microribonucleic acid 132 (miR-132) on heart failure development in this model.MethodsThis study developed a novel porcine model of percutaneous aortic constriction by implantation of a percutaneous reduction stent in the thoracic aorta, inducing progressive remodeling at day 56 (d56) after pressure-overload induction. In this study, an antisense oligonucleotide specifically inhibiting miR-132 (antimiR-132), was regionally applied via intracoronary injection at d0 (percutaneous transverse aortic constriction induction) and d28.ResultsAt d56, antimiR-132 treatment diminished cardiomyocyte cross-sectional area (188.9 ± 2.8 vs. 258.4 ± 9.0 μm² in untreated hypertrophic hearts) and improved global cardiac function (ejection fraction 48.9 ± 1.0% vs. 36.1 ± 1.7% in control hearts). Moreover, at d56 antimiR-132-treated hearts displayed less increase of interstitial fibrosis compared with sham-operated hearts (Δsham 1.8 ± 0.5%) than control hearts (Δsham 10.8 ± 0.6%). Of note, cardiac platelet and endothelial cell adhesion molecule 1⁺ capillary density was higher in the antimiR-132–treated hearts (647 ± 20 cells/mm²) compared with in the control group (485 ± 23 cells/mm²).ConclusionsThe inhibition of miR-132 is a valid strategy in prevention of heart failure progression in hypertrophic heart disease and may be developed as a treatment for heart failure of nonischemic origin.     

Ranolazine Improves Right Ventricular Function in Patients With Precapillary Pulmonary Hypertension: Results From a Double-Blind,Randomized, Placebo-Controlled Trial

IntroductionA major outcome determinant in patients with precapillary pulmonary hypertension (PH) is right ventricular (RV) function. We studied the effect of ranolazine on RV function over 6 months using cardiovascular magnetic resonance (CMR) imaging in patients with precapillary PH (groups I, III, and IV).Methods and ResultsWe enrolled patients with PH and RV dysfunction (CMR imaging ejection fraction [EF] of <45%) in a longitudinal, randomized, double-blinded, placebo controlled, multicenter study of ranolazine treatment. All enrolled patients were on stable PH-specific therapy. Enrolled patients were assessed using CMR imaging, New York Heart Association functional class, N-terminal pro brain natriuretic peptide, 6-minute walk test, and quality of life health outcomes at baseline and repeated at the end of treatment. The primary outcome was change in RVEF after 6 months of treatment. Analysis of covariance was used to analyze the longitudinal changes taking into account baseline values, age, and sex, based on per protocol population. Twenty-two patients were enrolled, and 9 patients completed follow-up CMR imaging after ranolazine treatment and 6 completed placebo treatment. There was significant increase in RVEF at end of treatment compared with baseline in the ranolazine group adjusted for baseline values, age, and sex. There were no statistically significant changes in secondary outcomes such as changes in New York Heart Association functional class, 6-minute walk distance, N-terminal pro brain natriuretic peptide, or quality of life measures. Ranolazine treated patients experienced a higher number of adverse events, but only one was discontinued owing to side effects.ConclusionsRanolazine may improve RV function in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine.     

慢性充血性心力衰竭时K_(ATP)通道与心室肌电生理特性变化的关系

探讨慢性充血性心力衰竭 (CHF)时三磷酸腺苷敏感性钾通道 (KATP通道 )在心室肌电生理特性改变和室性心律失常发生中的意义。采用阿霉素制作CHF兔模型。 2 9只兔分为健康对照组 (HC组 )和CHF实验组 ,后者包括CHF对照组 (CHFC组 )、CHF +KATP通道开放剂组 (P组 )、CHF +KATP通道阻断剂组 (G组 )、CHF +KATP通道开放剂和阻断剂组 (P +G组 )四个亚组。每组均予心房快速起搏 30min ,分别测定起搏前后 90 %单相动作电位时程(MAPD90 )、心室有效不应期 (VERP)及其离散度和兴奋时间 (AT)离散度 ,测定毕程序刺激诱发室性心动过速或心室颤动。结果 :快速起搏使MAPD90 、VERP延长 ,在CHFC组较HC组显著 (11.82± 10 .2 0vs 8.18± 6 .97ms,P <0 .0 5和14 .95± 12 .82vs 9.0 7± 8.79ms,P <0 .0 1) ,而G组和P +G组的MAPD90 、VERP延长更明显。各组快速起搏均未引起MAPD90 、VERP离散度变化 ,但CHFC组和P组都有AT离散度显著增大 (2 8.5 3± 8.6 3vs 36 .80± 6 .97ms ,P <0 .0 1和 2 6 .33± 5 .82vs 33.80± 9.5 0ms,P <0 .0 5 ) ,阻断剂可对抗AT离散度的增大。结论 :快速心房起搏可开放CHF心室肌KATP通道 ,一方面阻止MAPD90 、VERP的延长 ,另一方面又加大AT的非同步性 ,使室性心动过速易于诱发。     

Hemodynamic Effect and Safety of Intermittent Sequential Pneumatic Compression Leg Sleeves in Patients With Congestive Heart Failure

BackgroundPneumatic leg sleeves are widely used after prolonged operations for prevention of venous stasis. In healthy volunteers they increase cardiac function. We evaluated the hemodynamic effects and safety of intermittent sequential pneumatic compression (ISPC) leg sleeves in patients with chronic congestive heart failure (CHF).Methods and ResultsWe studied 19 patients with systolic left ventricular dysfunction and CHF. ISPC leg sleeves, each with 10 air cells, were operated by a computerized compressor, exerting 2 cycles/min. Hemodynamic and echocardiographic parameters were measured before, during, and after ISPC activation. The baseline mean left ventricular ejection fraction was 29 ± 9.2%, median 32%, range 10%–40%. Cardiac output (from 4.26 to 4.83 L/min; P = .008) and stroke volume (from 56.1 to 63.5 mL; P = .029) increased significantly after ISPC activation, without a reciprocal increase in heart rate, and declined after sleeve deactivation. Systemic vascular resistance (SVR) decreased significantly (from 1,520 to 1,216 dyne-s/cm⁵; P = .0005), and remained lower than the baseline level throughout the study. There was no detrimental effect on diastolic function and no adverse clinical events, despite increased pulmonary venous return.ConclusionsISPC leg sleeves in patients with chronic CHF do not exacerbate symptoms and transiently improve cardiac output through an increase in stroke volume and a reduction in SVR.