Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis.

BACKGROUND: The efficacy of thrombolytic therapy in patients with submassive pulmonary embolism (PE) remains unclear. Previous meta-analyses have not separately reported the proportion of patients with submassive PE. OBJECTIVE: We assessed the effect of thrombolytic therapy on mortality, recurrent PE, clinical deterioration requiring treatment escalation and bleeding in patients with submassive PE. METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched to identify all relevant randomized controlled trials comparing adjunctive thrombolytic therapy with heparin alone as initial treatments in patients with acute submassive PE, and reported 30-day mortality or in-hospital clinical outcomes. RESULTS: A total of 1510 patients were enrolled in this meta-analysis. No significant differences were apparent in the composite endpoint of all-cause death or recurrent PE between the adjunctive thrombolytic therapy arm and the heparin-alone arm (3.1% vs. 5.4%; RR, 0.64 [0.32-1.28]; P = 0.2). Adjunctive thrombolytic therapy significantly reduced the incidence of the composite endpoint of all-cause death or clinical deterioration (3.9% vs. 9.4%; RR, 0.44; P < 0.001). There were no statistically significant associations for major bleeding when adjunctive thrombolytic therapy was compared with heparin therapy alone (6.6% vs. 1.9%; P = 0.2). CONCLUSIONS: This meta-analysis shows that adjunctive thrombolytic therapy does not significantly reduce the risk of mortality or recurrent PE in patients with acute submassive PE, but that adjuvant thrombolytic therapy prevents clinical deterioration requiring the escalation of treatment in patients with acute submassive PE. Bleeding risk assessment might be the most successful approach for improving clinical outcomes and patient-specific benefit.

Genetic polymorphisms and haplotypes of the human cardiac sodium channel alpha subunit gene (SCN5A) in Japanese and their association with arrhythmia.

Genetic variations in cardiac ion channels have been implicated not only as the causes of inherited arrhythmic syndromes, but also as genetic risk factors for some acquired arrhythmias. To elucidate the potential roles of genetic polymorphisms of the alpha subunit of the voltage-gated sodium channel type V (SCN5A) in cardiac rhythm disturbance, the entire SCN5A coding exons and their flanking introns were sequenced in 166 Japanese arrhythmic patients and 232 healthy controls. We detected 69 genetic variations, including 54 novel ones. Out of the 12 novel nonsynonymous single nucleotide polymorphisms (SNPs), p.Leu1988Arg was found at a frequency of 0.015. The other 11 SNPs were rare (0.001), with 6 found in arrhythmic patients and 5 in healthy controls. The frequency of a novel intronic SNP, c.703+130G>A, was significantly higher in the patients than in the controls, suggesting this SNP is associated with an unknown risk factor for arrhythmia. Following linkage disequilibrium analysis, the haplotype structure of SCN5A was inferred using high-frequency SNPs. The frequency of the haplotype harbouring both p.Leu1988Arg and the common SNP p.His558Arg (haplotype GG) was significantly lower in the patients than in the controls. This finding suggests that this haplotype (GG) might have been positively selected in the controls because of its protective effect against arrhythmias. This study provides fundamental information necessary to elucidate the effect of genetic variations in SCN5A on channel function and cardiac rhythm in Japanese, and probably in the Asian population.

Identifying patterns of spatial current dispersion that characterise and separate the Brugada syndrome and complete right-bundle branch block.

The aim of the study was to detect patterns of spatial-current distribution in the late QRS and early ST-segments that distinguish Brugada-syndrome cases from complete right-bundle branch block (CRBBB). Magnetocardiograms (MCGs) were recorded from Brugada-syndrome patients (n = 6), CRBBB patients (n = 4) and the members of a control group (n = 33). The current distributions at six time points from Q-onset were estimated by producing current-arrow maps (CAMs). The angle of the current arrow of maximum amplitude at each time point was calculated. In the Brugada cases, the characteristic ST elevation was seen above the upper right chest, and abnormal currents appeared to be present in the right-ventricular outflow tract (RVOT). The angles of the abnormal arrows were -78 degrees +/- 51 degrees at 100 ms and -50 degrees +/- 61 degrees at 110 ms. In the cases of CRBBB, wide S- and R-waves were recorded above the upper right and lower right chest, respectively. The angles of the abnormal arrows for CRBBB were 152 degrees +/- 19 degrees at 100 ms, 159 degrees +/- 20 degrees at 110 ms, and 157 degrees +/- 19 degrees at 120 ms. The findings suggest that an abnormal current from the RVOT to the upper left chest may be a feature of the Brugada syndrome, and that the direction of this current is completely different from that seen in CRBBB.

Brugada syndrome: a decade of progress.

The Brugada syndrome has gained wide recognition throughout the world and today is believed to be responsible for 4% to 12% of all sudden deaths and approximately 20% of deaths in patients with structurally normal hearts. The incidence of the disease is on the order of 5 per 10 000 inhabitants and, apart from accidents, is the leading cause of death of men under the age of 50 in regions of the world where the inherited syndrome is endemic. This minireview briefly summarizes the progress made over the past decade in our understanding of the clinical, genetic, cellular, ionic, and molecular aspects of this disease.

Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome.

AIMS: Differences in the sensitivity of the genotype of the congenital long QT syndrome to sympathetic stimulation have been suggested. This study compared the influence of sympathetic stimulation on continuous corrected QT (QTc) intervals between LQT1, LQT2 and LQT3 forms of the congenital long QT syndrome. METHODS AND RESULTS: We recorded a 12-lead electrocardiogram continuously before and after bolus injection (0.1 microg x kg(-1)) of epinephrine followed by continuous infusion (0.1 microg x kg(-1) min(-1)) in 12 LQT1, 10 LQT2, 6 LQT3, and 13 control patients. The QT intervals and previous RR intervals of all beats were measured semi-automatically, and the QTc intervals of all beats were calculated by Bazett's method. The dynamic response of the RR interval to epinephrine was no different between the four groups. The QTc was prolonged remarkably (477+/-42 to 631+/- 59 ms; P<0.0005, % delta prolongation =+32%) as the RR was maximally decreased (at peak of epinephrine), and remained prolonged at steady state conditions of epinephrine (556+/-56 ms; P<0.0005 vs baseline, +17%) in LQT1 patients. Epinephrine also prolonged the QTc dramatically (502+/-23 to 620+/-39 ms; P<0.0005, +24%) at peak of epinephrine in LQT2 patients, but this shortened to baseline levels at steady state (531+/-25 ms; P=ns vs baseline, +6%). The QTc was much less prolonged at peak of epinephrine in LQT3 (478+/-44 to 532+/-41 ms; P<0.05, +11%) and controls (394+/-21 to 456+/-18 ms; P<0.0005, +16%) than in LQT1 and LQT2 patients, and shortened to the baseline levels (LQT3; 466+/-49 ms, -3%, controls; 397+/-16 ms, +1%; P=ns vs baseline) at steady state. CONCLUSION: Our data suggest that the dynamic response of ventricular repolarization to sympathetic stimulation differs between LQT1, LQT2 and LQT3 syndromes, and may explain why the trigger of cardiac events differs between the genotypes.

Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure.

Ghrelin is a novel GH-releasing peptide that may also induce vasodilation and a positive energy balance through GH-independent mechanisms. However, the hemodynamic, renal, and hormonal effects of ghrelin in patients with chronic heart failure (CHF) remain unknown. Accordingly, 12 patients with CHF were given an iv infusion of human ghrelin (0.1 microg/kg.min) or placebo. Ghrelin significantly decreased mean arterial pressure (-9 mm Hg, P < 0.05) without a significant change in heart rate. Ghrelin significantly increased cardiac index (+25%, P < 0.05) and stroke volume index (+30%, P < 0.05), although it did not significantly alter mean pulmonary arterial pressure or pulmonary capillary wedge pressure. Infusion of ghrelin induced a marked increase in serum GH level (15-fold), associated with slight increases in circulating epinephrine, ACTH, cortisol, and PRL. Infusion of ghrelin did not significantly alter urine volume, urinary sodium excretion, or creatinine clearance. These hemodynamic, renal and hormonal parameters remained unchanged during placebo infusion. In summary, iv infusion of ghrelin, a potent GH-releasing peptide, had beneficial hemodynamic effects in patients with CHF in the absence of renal effects.

Acute effects of different atrial pacing sites in patients with atrial fibrillation: comparison of single site and biatrial pacing.

It has been reported that a trial single site or biatrial pacing can suppress the occurrence of AF. However, its mechanism remains unclear. The study population included 32 patients with AF (n = 20: AF group), or without paroxysmal AF (n = 12: control group). The mechanism and efficacy of atrial pacing were investigated by electrophysiological studies to determine which was more effective for suppressing AF induction; single site pacing of the right atrial appendage (RAA) or distal coronary sinus (CS-d), or biatrial (simultaneous BAA and CS-d) pacing. In the AF group, AF inducibility was significantly higher with BAA extrastimulus during RAA (12/20; P < 0.0001) or biatrial paced drive (7/20; P < 0.01) than during CS-d paced drive (0/20). In the control group, AF was not induced at any site paced. In the AF group, the conduction delay and other parameters of atrial vulnerability significantly improved during CS-d paced drive. The atrial recovery time (ART) at RAA and CS-d was measured during each basic pacing mode. ART was defined as the sum of the activation time and refractory period, and the difference between ARTs at RAA and CS-d was calculated as the ART difference (ARTD). The ARTD was significantly longer during BAA pacing in the AF group than in control group (155.0 +/- 32.8 vs 128.8 +/- 32.9 ms, P < 0.05). In the AFgroup, ARTDs during biatrial (52.0 +/- 24.2 ms) and CS-d pacing (51.7 +/- 26.0 ms) were significantly shorter than ARTD during RAA pacing. The CS-d paced drive was more effective for suppressing AF induction than biatrial or RAA paced drive by alleviating conduction delay. CS-d and biatrial pacing significantly reduced ARTD compared with RAA pacing.

Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome.

OBJECTIVES: The study compared the influence of sympathetic stimulation on transmural and spatial dispersion of repolarization between LQT1 and LQT2 forms of congenital long QT sYndrome (LQTS). BACKGROUND: Cardiac events are more associated with sympathetic stimulation in LQT1 than in LQT2 or LQT3 syndrome. Experimental studies have suggested that the interval between Tpeak and Tend (Tp-e) in the electrocardiogram (ECG) reflects transmural dispersion of repolarization across the ventricular wall. METHODS: We recorded 87-lead body-surface ECGs before and after epinephrine infusion (0.1 microg/kg/min) in 13 LQT1, 6 LQT2, and 7 control patients. The Q-Tend (QT-e), Q-Tpeak (QT-p), and Tp-e were measured automatically from 87-lead ECGs, corrected by Bazett's method (QTc-e, QTc-p, Tcp-e), and averaged among all 87-leads and among 24-leads, which reflect the potential from the left ventricular free wall. As an index of spatial dispersion of repolarization, the dispersion of QTc-e (QTc-eD) and QTc-p (QTc-pD) were obtained among 87-leads and among 24-leads, and were defined as the interval between the maximum and the minimum of the QTc-e and the QTc-p, respectively. RESULTS: Epinephrine significantly increased the mean QTc-e but not the mean QTc-p, resulting in a significant increase in the mean Tcp-e in both LQT1 and LQT2, but not in control patients. The epinephrine-induced increases in the mean QTc-e and Tcp-e were larger in LQT1 than in LQT2, and were more pronounced when the averaged data were obtained from 24-leads than from 87-leads. Epinephrine increased the maximum QTc-e but not the minimum QTc-e, producing a significant increase in the QTc-eD in both LQT1 and LQT2 patients, but not in control patients. The increase in the QTc-eD was larger in LQT1 than in LQT2 patients. CONCLUSIONS: Our data suggest that sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than in LQT2 syndrome, and this may explain why LQT1 patients are more sensitive to sympathetic stimulation.

Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors.

BACKGROUND: Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, that may also cause a positive energy balance by stimulating food intake and inducing adiposity. We sought to investigate the pathophysiology of ghrelin in the cachexia associated with chronic heart failure (CHF). METHODS AND RESULTS: Plasma ghrelin was measured in 74 patients with CHF and 12 control subjects, together with potentially important anabolic and catabolic factors, such as GH and tumor necrosis factor (TNF-alpha). Patients with CHF were divided into two groups, those with cachexia (n=28) and those without cachexia (n=46). Plasma ghrelin did not significantly differ between all CHF patients and controls (181+/-10 versus 140+/-14 fmol/mL, P=NS). However, plasma ghrelin was significantly higher in CHF patients with cachexia than in those without cachexia (237+/-18 versus 147+/-10 fmol/mL, P<0.001). Circulating GH, TNF-alpha, norepinephrine, and angiotensin II were also significantly higher in CHF patients with cachexia than in those without cachexia. Interestingly, plasma ghrelin correlated positively with GH (r=0.28, P<0.05) and TNF-alpha (r=0.31, P<0.05) and negatively with body mass index (r=-0.35, P<0.01). CONCLUSIONS: Plasma ghrelin was elevated in cachectic patients with CHF, associated with increases in GH and TNF-alpha and a decrease in body mass index. Considering ghrelin-induced positive energy effects, increased ghrelin may represent a compensatory mechanism under catabolic-anabolic imbalance in cachectic patients with CHF.

Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure.

BACKGROUND: Ghrelin is a novel growth hormone (GH)-releasing peptide that may also induce vasodilation and stimulate feeding through GH-independent mechanisms. We investigated whether ghrelin improves left ventricular (LV) dysfunction and attenuates cardiac cachexia in rats with chronic heart failure (CHF). METHODS AND RESULTS: Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, rat ghrelin (100 microg/kg SC BID) or saline was administered for 3 weeks. Echocardiography and cardiac catheterization were performed. Serum GH and insulin-like growth factor-1 were significantly higher in both CHF and sham rats treated with ghrelin than in those given placebo (P<0.05 for both). CHF rats given placebo showed an impaired increase in body weight compared with sham rats given placebo (P<0.05). CHF rats treated with ghrelin, however, showed a significantly greater increase in body weight than those given placebo (+10% versus +3%, P<0.05). They showed significantly higher cardiac output (315+/-49 versus 266+/-31 mL. min(-1). kg(-1), P<0.05) and LV dP/dt(max) (5738+/-908 versus 4363+/-973 mm Hg/s, P<0.05) than CHF rats given placebo. Ghrelin increased diastolic thickness of the noninfarcted posterior wall, inhibited LV enlargement, and increased LV fractional shortening in CHF rats (from 15+/-3% to 19+/-3%, P<0.05). CONCLUSIONS: Chronic subcutaneous administration of ghrelin improved LV dysfunction and attenuated the development of LV remodeling and cardiac cachexia in rats with CHF.

[Chemoradiotherapy and salvage surgery in a patient with advanced esophageal cancer].

We report a case of advanced esophageal cancer, which was treated by chemoradiotherapy combined with surgical treatment. Moreover, 14 advanced esophageal cancer patients treated by chemoradiotherapy are discussed. The chemoradiotherapy showed beneficial control of the tumor; however, it sometimes leads to esophageal stenosis and ulcer. We conclude that additional salvage surgery is needed for such complications.

Utility of serum CA 19-9 monitoring in preoperative radiotherapy for pancreatic cancer.

BACKGROUND/AIMS: Pancreatic cancer is extremely refractory even to aggressive treatments including surgery, resulting in early metastasis and/or local recurrence. We investigated changes in serum tumor marker CA 19-9 levels during preoperative radiotherapy in conjunction with initial treatment failure. METHODOLOGY: Twenty-three patients presenting with localized disease and an increased serum CA 19-9 level, who were slated to undergo pancreatectomy and/or intraoperative radiotherapy following preoperative radiotherapy were reviewed. CA 19-9 response, the ratio of post-radiotherapy level before laparotomy to pre-radiotherapy level, was analyzed in relation to disease-control time and survival. RESULTS: Eleven patients revealed metastasis at restaging or laparotomy; 12 patients (52%) completed aggressive treatments. Initial failure was identified at the liver (52%), peritoneum (52%), or local site (26%) with a median disease-control time of 91 days; 7 patients showed combined failure. All but 1 patient died of cancer with a median survival time of 264 days. CA 19-9 response (range: 0-1185%) did not correlate with disease-control time or survival; 8 progressive-disease patients (> 140% response), however, showed significantly shorter disease-control time than 15 nonprogressive-disease patients (< or = 140% response). CONCLUSIONS: CA 19-9 monitoring is useful in preoperative radiotherapy for identifying patients who will not benefit by succeeding aggressive treatments by predicting early metastasis.

Relative biological effectiveness of the 235 MeV proton beams at the National Cancer Center Hospital East.

A therapy-dedicated cyclotron was installed in the National Cancer Center Hospital East (NCCHE) at Kashiwa in 1997. Prior to the start of clinical use, we investigated the biological effectiveness of therapeutic proton beams for cell lethality. The proton beams accelerated up to 235 MeV were horizontally extracted from the cyclotron, and scattered by a bar-ridge filter to produce a Spread-Out-Bragg-Peak (SOBP) of 10-cm width. The biological systems used here were mouse intestinal crypt cells and three in vitro cell lines, including SCC61 human squamous cell carcinoma, NB1RGB human fibroblasts and V79 Chinese hamster cells. The dose responses after irradiation at either the entrance plateau or the middle portion of SOBP were compared with those after linac 6 MV X-ray irradiation. The fit of a linear quadratic model to survival curves showed that proton irradiation increased the alpha value of SCC61 and the beta value of V79 cells with a least change for alpha/beta ratio of NB1RGB cells. The isoeffect dose that reduces either cell survivals to 10% or mouse jejunum crypts to 10 per circumference was termed D10. The relative biological effectiveness (RBE) of protons obtained by comparing the D10 values between protons and X-rays ranged from 0.9 to 1.2. The depth distribution of cell lethality was measured by replating V79 cells after irradiation from a "cell stack chamber" that received a single dose of 7 Gy at the middle position of SOBP. The thus-obtained cell survivals at various depths coincided well with the estimated survivals, but tended to decrease at the distal end of SOBP. We conclude that an RBE of 1.1 would be appropriate for 235 MeV proton beams at the NCCHE.

Localized right ventricular morphological abnormalities detected by electron-beam computed tomography represent arrhythmogenic substrates in patients with the Brugada syndrome.

AIMS: This study was designed to determine, using electron-beam CT, whether there are morphological abnormalities in patients with the Brugada syndrome and to elucidate the relationship between those abnormalities and arrhythmogenesis. METHODS AND RESULTS: Twenty-six consecutive patients with the Brugada syndrome and 23 age- and gender-matched control subjects (controls) were evaluated for morphological abnormalities using electron beam CT. Electron beam CT demonstrated morphological abnormalities of the right ventricle in 21 (81%) of 26 patients, but in only two (9%) of 23 controls. The sites of morphological abnormalities were the right ventricular outflow tract area in 17 patients and the inferior wall of the right ventricle in four patients. Of the seven patients with monoform premature ventricular contractions recorded only in the acute phase, four of the five patients with premature ventricular contractions from the right ventricular outflow tract area had morphological abnormalities in the right ventricular outflow tract area, and the other two patients with premature ventricular contractions from the inferior wall of the right ventricle had morphological abnormalities in the inferior wall of the right ventricle. CONCLUSION: The sites of morphological abnormalities detected by electron beam CT in patients with the Brugada syndrome were related to the origins of premature ventricular contractions recorded only in the acute phase, which may trigger ventricular fibrillation. These morphological abnormalities may be related to arrhythmogenic substrates in patients with the Brugada syndrome.

Clinical usefulness of a multielectrode basket catheter for idiopathic ventricular tachycardia originating from right ventricular outflow tract.

INTRODUCTION: It often is difficult to determine the optimal ablation site for idiopathic ventricular tachycardia (VT) originating from the right ventricular outflow tract (RVOT) when the VT or premature ventricular complex (PVC) does not occur frequently. The aim of our study was to evaluate the usefulness of a multielectrode basket catheter for ablation of idiopathic VT originating from the RVOT. METHODS AND RESULTS: Radiofrequency (RF) catheter ablation was performed using a 4-mm tip, quadripolar catheter in 50 consecutive patients with 81 VTs originating from the RVOT with (basket group = 25 patients with 45 VTs) or without (control group = 25 patients with 36 VTs) predeployment of a multielectrode basket catheter composed of 64 electrodes. Deployment of the multielectrode basket catheter was possible and safe in all 25 patients in the basket group. Ablation was successful in 25 (100%) of 25 patients in the basket group and in 22 (88%) of 25 patients in the control group. The total number of RF applications and the number of RF applications per PVC morphology did not differ between the two groups. However, both the fluoroscopic and ablation procedure times per PVC morphology were shorter in the basket group than in the control group (36.8+/-14.1 min vs 52.0+/-32.5 min, P = 0.04; 60.0+/-14.6 vs 81.5+/-51.2 min, P = 0.05). This difference was more pronounced in the 29 patients in whom VT or PVC was not frequently observed. CONCLUSION: The multielectrode basket catheter is safe and useful for determining the optimal ablation site in patients with idiopathic VT originating from the RVOT, especially in those without frequent VT or PVC.

The role of Purkinje and pre-Purkinje potentials in the reentrant circuit of verapamil-sensitive idiopathic LV tachycardia.

Although the mechanism of verapamil-sensitive idiopathic left ventricular tachycardia (ILVT) is usually reentry, the actual reentrant circuit is not clearly understood. This study examined the relationship between the Purkinje potential (PP) and a dull potential preceding PP (pre-PP) during ILVT to elucidate the roles of these potentials in the reentrant circuit of ILVT. Electrophysiological studies and radiofrequency catheter ablation were performed in ten patients (7 men, 3 women, mean age 29 years) who had an ILVT with a right bundle branch block configuration and left-axis deviation. Left ventricular endocardial mapping using an octapolar catheter and entrainment and resetting studies during VT was performed by pacing from the right ventricular outflow tract (RVOT) and each site of the left ventricular mapping catheter. PP and pre-PP were recorded simultaneously during VT in all patients. The earliest PP during VT was recorded at the inferoposterior septum, and PP was activated bidirectionally toward the proximal (basal) and distal (apical) sites along the left posterior fascicle. In contrast, pre-PP was recorded at sites slightly proximal to the earliest PP recording site, and was activated toward the earliest PP site. Pacing from RVOT confirmed manifest entrainment, and the stimulus to pre-PP interval was prolonged with a shorter pacing cycle length. Concealed entrainment was demonstrated by capture of the PPs of the left ventricular mapping catheter in six patients, and the postpacing interval at each PP site was equal to the tachycardia cycle length. The pre-PP was orthodromically activated from the proximal to the distal site during pacing. More rapid pacing also produced delay in activation from PP to pre-PP, indicating slow conduction in ILVT. Catheter ablation was performed at the pre-PP recording site during VT, and was successful in all patients. The reentrant circuit of ILVT could be constructed based on the pre-PP, PP, and slow conduction between the PP and pre-PP. Catheter ablation of ILVT was successful at the pre-PP recording site.

Paradoxic abbreviation of repolarization in epicardium of the right ventricular outflow tract during augmentation of Brugada-type ST segment elevation.

We report the case of a 53-year-old Japanese man with a typical Brugada-like ECG in whom epicardial and endocardial activation-recovery intervals (ARI) in the right ventricular outflow tract (RVOT) were simultaneously measured by recording unipolar electrograms from the Pathfinder catheter introduced in the great cardiac vein as well as from the multielectrode basket catheter deployed in the RVOT. Epicardial ARI in the RVOT was abbreviated paradoxically at the beat of augmented ST segment elevation in lead V2 after a long pause or after pilsicainide injection. Endocardial ARI in the RVOT and epicardial ARI in the left ventricle were prolonged or were not changed. Our data support the hypothesis that heterogenous response of repolarization across the ventricular wall in the RVOT is responsible for accentuation of ST segment elevation in the right precordial leads.