Guanggen Cui

Atrial Extracellular Matrix Remodeling and the Maintenance of Atrial Fibrillation

Background—Remodeling occurs in both ventricle and atrium in dilated cardiomyopathy and heart failure. However, the alteration of atrial extracellular matrix components during remodeling and its effect on the electrical remodeling and atrial arrhythmia have never been explored. Methods and Results—Atrial tissue samples of 53 explanted hearts from patients with dilated cardiomyopathy and end-stage heart failure who underwent heart transplantation were examined. Nineteen patients had permanent atrial fibrillation (PmAF), 18 had persistent AF (PsAF), and 16 had no documented AF (NAF). Sixteen donor left atria (LA) were used as controls (CNs). Western Blot analysis revealed a selective downregulation of tissue inhibitor of metalloproteinase (TIMP)-2 in PmAF and PsAF groups compared with the NAF and CN groups and an upregulation of atrial metalloproteinase (MMP)-2 that was most pronounced in the PmAF group followed by the PsAF and NAF groups. Immunofluorescent staining revealed that in the LA, type I collagen volume fraction (CVF-I) increased significantly in the PmAF group followed by the PsAF and NAF groups compared with that in CN. LA CVF-I significantly correlated with LA dimension and TIMP-2 to MMP-2 ratio. In the PsAF group, CVF-I/CVF-III ratio was significantly correlated with AF duration and the frequency of AF recurrence. Conclusions—Atrial extracellular matrix remodeling manifested by the selective downregulation of TIMP-2 along with upregulation of MMP-2 and CVF-I in the atrium is associated with the development of sustained atrial fibrillation in patients with cardiomyopathy and heart failure.

Effects of amiodarone, sematilide, and sotalol on QT dispersion

To study the effects of class III agents on QT/QTc dispersion in patients with heart disease and cardiac arrhythmias, QT dispersion and QRS and RR intervals were compared in patients before and after treatment with amiodarone (n = 26), sematilide (n = 26), and sotalol (n = 26). QT, QRS, and RR intervals, and QTc values were calculated for each complex, and their mean values were calculated for each lead. QT and QTc dispersions were defined as differences between the minimal and maximal QT or QTc values in each of the 12 leads studied. Amiodarone, sematilide, and sotalol all significantly prolonged the QT interval and the QTc value. Significant reductions in QT and QTc dispersions were only found in the amiodarone group (QT dispersions: 79 +/- 13 vs 49 +/- 14 ms; p < 0.001; QTc dispersions: 0.08 +/- 0.02 vs 0.05 +/- 0.01 s1/2; p < 0.001). The mean RR interval was significantly increased in patients after treatment with amiodarone (p < 0.001) and sotalol (p < 0.001), but not in patients receiving sematilide treatment (p > 0.2). The baseline QT and QTc dispersions were significantly greater in patients with than without myocardial infarction before treatment (p < 0.001). The mean baseline values for QT/QTc dispersions were not significantly different among all 3 groups. However, only amiodarone significantly reduced the QT dispersion (from 76 +/- 10 to 46 +/- 11 ms; p < 0.001) and QTc dispersion (from 0.09 +/- 0.02 to 0.05 +/- 0.01 s1/2; p < 0.001) in patients with myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased Incidence of Atrial Flutter Associated With the Rejection of Heart Transplantation

Atrial fibrillation (AF) and atrial flutter (Afl) are common dysrhythmias that occur after orthotopic heart transplantation (OHT); however, their etiology and clinical significance have not been defined. To determine the precise incidence of sustained AF and Afl and their association with cardiac rejection, 892 consecutive patients who underwent OHT were studied. A total of 104 patients had 113 episodes of Afl; 102 patients had 117 episodes of AF. The incidence of Afl (12.7%) was the same as AF (13.1%). Sixty-nine AF episodes occurred in first 2 weeks after transplantation, and 22 of which were associated with rejection. In contrast, only 20 Afl episodes occurred the first 2 weeks after OHT, 10 of which were associated with rejection. Fifty-two episodes of Afl occurred during from the third week to 6 months after transplantation, 34 of which were associated with moderate to severe cellular or humoral rejection and/or transplant coronary artery disease (TCAD). All 41 Afl episodes that occurred 6 months after transplantation were associated with cellular and humoral rejection, and/or TCAD. The prevalence of Afl was significantly higher in biatrial than bicaval anastomosis. Atrial conduction defect, manifested by the increase of terminal force of the P wave in lead V(1) of the surface electrocardiogram, predicted the occurrence of Afl and AF associated with rejection in OHT with a sensitivity of 89% and specificity of 92%. These results demonstrate that the incidence of Afl increased after OHT, which might be a consequence of cellular and humoral rejection, and coronary vasculopathy of the transplanted hearts.

Localized interleukin-10 gene transfer induces apoptosis of alloreactive T cells via FAS/FASL pathway, improves function, and prolongs survival of cardiac allograft.

We hypothesized that localized IL-10 gene transfer can induce alloreactive T cell apoptosis and tested this hypothesis with liposome-mediated ex vivo intracoronary IL-10 gene transfer using a functional heterotopic allograft heart transplant model in rabbits. Localized IL-10 overexpression prolonged cardiac allograft survival over three folds. In parallel with the time-course of IL-10 overexpression, the percentage of apoptotic CD3+ cells among total CD3+ cells was significantly increased in the gene therapy group (36.5±3.9%) compared with that in the control group (6.2±2.6%, P <0.01) on postoperative day (POD) 3–6, and it was further increased (45.8±5.7%) on POD7–10. Apoptotic CD4+ and CD8+ cells were also significantly increased in the gene group (P <0.01). In contrast, the percentage of apoptotic myocytes significantly decreased from 10.1±0.8% in the control group to 3.5±0.4% in the gene group on POD7–10 (P <0.01). This reduction was inversely correlated with the increase in the percentages of apoptotic CD4+ and CD8+ cells (P <0.01). The percentage of caspase-3 positive myocytes was significantly reduced, although percentages of caspase-3 positive CD4+ and CD8+ cells were markedly increased in the gene group (P <0.01). Moreover, about 60–80% of apoptotic T lymphocytes expressed Fas in the gene group compared with less than 10% in the control group (P <0.01). These results suggest that localized IL-10 gene transfer induces alloreactive T cell apoptosis via the Fas/FasL pathway that may contribute to the alleviated acute rejection, improved cardiac function, and prolonged survival in the IL-10 gene-treated cardiac allografts.

Localized immunosuppression in the cardiac allograft induced by a new liposome-mediated IL-10 gene therapy

BACKGROUND Overexpression of interleukin 10 (IL-10) in the donor heart prolongs allograft survival in animals. Interleukin-10 has many immunosuppressive effects; however, the mechanism(s) of its protective effect on allograft rejection remains unknown. METHODS Recently, we optimized an ex vivo, intracoronary infusion of the GAP:DLRIE, liposome-mediated, IL-10 gene method using a rabbit, cervical, heterotopic heart transplant model. RESULTS The efficiency of this new-generation, liposome-mediated, IL-10 gene transfer to the donor hearts was 15% in hypothermic conditions, which represents a 30% increase from the efficiency of other liposomes, such as DOSPA/DOPE, DOGS/DOPE, and DMRIE/DOPE. Cardiac allograft survival was prolonged from 6.0 +/- 0.7 days to 14.3 +/- 1.8 days. Infiltrating lymphocyte sub-populations CD3+, CD4+, and CD8) decreased significantly in the gene therapy group compared with the control group. Local IL-10 overexpression correlated significantly with decreased CD4+ and CD8+ responsiveness and Type-1 helper (Th1) cytokine gene (IL-2, interferon-gamma, and tumor necrosis factor alpha) expression level and correlated inversely with the allograft rejection grade. In the gene therapy group, the cytotoxic activity of infiltrating T cells in the allograft decreased greatly, but the time course of this decrease did not parallel the rejection process. CONCLUSION We conclude that GAP:DLRIE is the best cationic liposome for ex vivo gene transfection in hypothermic conditions. The effects of IL-10 gene therapy on antigen-specific T-lymphocyte proliferation and Th1-cytokine expression may play an important role in localized immunosuppression and tolerance induction.

Liposome-Mediated Combinatorial Cytokine Gene Therapy Induces Localized Synergistic Immunosuppression and Promotes Long-Term Survival of Cardiac Allografts

Localized gene transfer has the potential to introduce immunosuppressive molecules only into the transplanted allograft, which would limit systemic side effects, and prolong allograft survival. However, an applicable gene transfer strategy is not available, and the feasible therapeutic gene(s) has not yet been determined. We developed an ex vivo liposome-mediated gene therapy strategy that is able to intracoronary deliver the combination of IL-4 and IL-10 cDNA expression vectors to the allograft simultaneously. We examined the efficiency, efficacy, and cardiac adverse effects of this combinatorial gene therapy protocol using a rabbit functional cervical heterotopic heart transplant model. Although the efficiency was moderate, the expression of both transgenes was long lasting and localized only in the target organ. The mean survival of cardiac allograft was prolonged from 7 to >100 days. Synergism of overexpressed IL-4 and IL-10 in the inhibition of T lymphocyte infiltration and cytoxicity, and modulation of Th1/Th2 cytokine production promote long-term survival of cardiac allografts.

Cause of atrioventricular block in patients after heart transplantation.

Background. The precise incidence and cause of atrioventricular block (AVB) after heart transplantation remain uncertain. Methods and Results. After surgery, immediate and follow‐up electrocardiograms from 1,047 consecutive patients who underwent heart transplantation were reviewed for AVB and correlated with clinical symptoms, laboratory data, rejection grade, and echocardiogram and coronary angiography findings. A total of 113 patients demonstrated various kinds of AVB; the incidence was 10.8%. First‐degree AVB occurred in 87 patients, 37 of whom also demonstrated persistent atrial tachyarrhythmias (ATAs). In 30 patients, firstdegree AVB occurred 7 days to 120 months after heart transplantation. Among those, 88% demonstrated cellular rejection, and 20% developed transplant coronary artery disease (TCAD). Fifty patients demonstrated first‐degree AVB without ATA, 32 of whom developed AVB from operative day 7 to 156 months. The incidence of cellular rejection was significantly lower (36%, P<0.01), and the rejection was less severe. In 18 patients, AVB occurred early postoperatively (0‐7 days), and most were secondary to surgical injury. Second‐degree AVB Mobitz I occurred in six patients (four patients with TCAD and two patients undergoing percutaneous transluminal coronary angioplasty). One patient developed Mobitz II during coronary artery stenting. Complete AVB (CAVB) occurred in 19 patients. Nine episodes of CAVB occurred during endomyocardial biopsy or coronary angiography, and four occurred immediately after heart transplantation as the result of surgical insult. Conclusion. These results indicate that first‐degree AVB is causatively related to cellular rejection and TCAD‐induced atrial conduction disturbance. Seconddegree AVB and CAVB were mainly the consequences of surgical and catheter intervention injury.

Acute Effects of Zatebradine on Cardiac Conduction and Repolarization

Zatebradine, a potent bradycardic agent, is believed to act selectively at the sinoatrial node. The selectivity of such a property relative to various electrophysiologic classes of action is not well defined. To characterize the electrophysiologic properties of zatebradine, the corrected sinus node recovery time, sinoatrial conduction time, conduction intervals, atrial effective refractory period and monophasic action potential duration in the ventricle were measured before and after incremental doses of zatebradine (0.1-1.5 mg/kg) in 15 anesthetized dogs. The electrophysiologic effects of zatebradine developed immediately after a single IV bolus dose, reaching steady-steady-state at 15 minutes with the maximum effect evident at 0.75 mg/kg. The IC50 was 0.23 mg/kg. There was no significant effect on the sinus node recovery time. The PR interval on the electrocardiogram was significantly increased when the dose was higher than 0.25 mg/kg. The duration of the P wave and the PA interval were not changed. Zatebridine greatly increased the AH (from 135 to 178 milliseconds) without changing the HH and HV intervals in His bundle recordings. The EC50 of this effect was 0.58 mg/kg. The QRS interval was not changed. The QTc was significantly increased from 0.43 to 0.56 s½ (P < 0.05). The action potential duration was significantly increased by high dose zatebradine (> 0.5 mg/kg), the EC50 for this effect was 0.76 mg/kg. The atrium effective refractory period was significantly increased (31%) with an EC50 0.69 mg/kg. These results indicate that zatebradine selectively inhibits sinus node automaticity at low doses. The inhibition of the AV nodal conduction and the lengthening of the refractory period and repolarization in the atria and the ventricles occur at higher dose.

Different Effects of Amiodarone and Quinidine on the Homogeneity of Myocardial Refractoriness in Patients With Intraventricular Conduction Delay

Background: Increases in QT and JT dispersion have been suggested as indicative of a proarrhythmic potential as a result of heterogeneity in myocardial refractoriness, the reduc tion of which by antiarrhythmic agents might be associated with a beneficial effect on the development of serious ventricular arrhythmias. Methods: To test the hypothesis that amiodarone reduces the heter-ogeneity of ventricular refractoriness to a significantly greater extent than quinidine in patients with intraventricu lar conduction defects under treatment for ventricular arrhythmias, the corrected and uncorrected QT and JT intervals and dispersions from 12-lead surface electrocardiograms were determined in 120 patients with intraventricular conduction defects with cardiac arrhythmias before and during treatment with amiodarone (n = 60) and quinidine (n = 60). Rcsults: Amiodarone increased QT from 403 ± 50 ms to 459 ± 47 ms (P < .001), with a sim ilar increase in the corrected QT interval (QTc) (P < .001). Amiodarone reduced QT disper sion by 40% (P < .001), whereas quinidine increased by 18% (P < .001). The net effects of both drugs were similar for QTc. Amiodarone, but not quinidine, reduced heart rate signifi cantly; amiodarone had no effect on the QRS; but quinidine increased it (P < .001). Quini dine as well as amiodarone increased the JT and JTc intervals significantly, but the effect of quinidine was quantitatively less striking. Amiodarone decreased the JT dispersion by 33% (P < .001) and JTc dispersion by 37% (P < .001). On the other hand, quinidine increased the corresponding values for JT and JTc by 18% (P < .001) and 21 % (P < .001), respectively. The overall data on QT and JT dispersions indicate an improvement in the homogeneity of myo cardial refractoriness with amiodarone treatment and the converse with quinidine treatment; this observation is consistent with a lower proarrhythmic propensity and mortality with amio darone than with quinidine. Quinidine increased the QRS interval more than amiodarone, and the data indicate that in patients with intraventricular conduction defects, the monitoring of the JT interval might more accurately reflect changes in myocardial repolarization. Conclusions: Amiodarone and quinidine both increased the corrected and uncorrected QT and JT intervals; amiodarone decreased and quinidine increased the dispersion of these intervals, and these results suggested an improvement in the homogeneity of myocardial refractoriness as a result of amiodarone treatment and the converse as a result of quinidine treatment. Quinidine increased the QTS interval more than amiodarone, and the data indi cate that in patients with intraventricular conduction defects, the monitoring of the JT inter val might more accurately reflect changes in myocardial repolarization.