A randomized study to compare ramp versus burst antitachycardia pacing therapies to treat fast ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators: the PITAGORA ICD trial.

BACKGROUND: In patients with implantable cardioverter-defibrillators (ICDs), antitachycardia pacing (ATP) is highly effective in terminating fast ventricular tachycardias (FVTs) and lowers the use of high-energy shocks, without increasing the risk of arrhythmia acceleration or syncope. METHODS AND RESULTS: The aim of the PITAGORA ICD trial was to randomly compare 2 ATP strategies (88% coupling interval burst versus 91% coupling interval ramp, both 8 pulses) in terms of ATP efficacy, arrhythmia acceleration, and syncope. Two hundred six ICD patients (83% male, 67+/-11 years) were enrolled. FVT episodes with cycle lengths between 240 and 320 ms were treated by 1 ATP sequence and, in the event of failure, by shocks. Over a median follow-up of 36 months, 829 spontaneous ventricular tachyarrhythmia episodes were detected in 79 patients. Episode review identified 595 episodes as true ventricular arrhythmias in 72 patients; devices classified 111 (18.7%) episodes as VF, 216 (36.3%) as FVT, and 268 (45.0%) as VT. Fifty-six patients had 214 treated FVT episodes-2 FVTs self-terminated before ATP release; 44 (79%) of these had at least 1 effective ATP intervention, and 34 (61%) were spared ICD shocks. Burst terminated 100 of 133 (75.2%) FVT episodes, whereas ramp terminated 44 of 81 (54.3%; P=0.015). Acceleration occurred in 9 of 214 (4.2%) FVT episodes treated: 6 episodes in 3 ramp patients and 3 episodes in 3 burst patients. Two patients-1 in each group-suffered 1 syncopal event associated to a nonterminated FVT episode. CONCLUSIONS: Burst is significantly more efficacious than ramp in terminating FVT episodes. As the first therapy for FVT episodes, ATP carries a low risk of acceleration or syncopal events.

A randomized comparison of amiodarone and class IC antiarrhythmic drugs to treat atrial fibrillation in patients paced for sinus node disease: the Prevention Investigation and Treatment: A Group for Observation and Research on Atrial arrhythmias (PITAGORA) trial.

BACKGROUND: Rhythm control is an important goal in the treatment of recurrent atrial tachyarrhythmias (AT). The PITAGORA study was a randomized trial in patients paced for sinus node disease (SND), designed to test the noninferiority of class IC antiarrhythmic drugs (AADs) to amiodarone in terms of a primary end point composed of death, permanent AT, cardiovascular hospitalization, atrial cardioversion, or AAD change. METHODS: Randomization was stratified to assign 2 patients to amiodarone and 2 patients to class IC AADs: propafenone or flecainide. One hundred seventy-six patients (46% men, 72 +/- 8 years) were enrolled. Device diagnostics continuously monitored AT recurrences and duration. RESULTS: In a mean follow-up of 20 +/- 9 months, the primary end point occurred in 23 (30.7%) of 75 class IC patients and in 28 (40.0%) of 70 amiodarone patients. The absolute difference in the end point incidence (-9.3%; 95% CI between 3.7% and -22.3%) confirmed the noninferiority of class IC to amiodarone (P = .007). Kaplan-Meier 1-year freedom from AT episodes >10 minutes, 1 day, and 7 days was 40%, 73%, and 91% for amiodarone and 28%, 78%, and 86% for class IC AADs (P = nonsignificant). CONCLUSIONS: In patients paced for SND and suffering from AT, class IC AADs proved not to be inferior to amiodarone in terms of the primary composite end point described or end points which were differently composed of mortality, efficacy, or AAD side effects. The AADs studied also showed similar results in terms of symptoms, quality of life, and freedom from AT recurrences.

Randomized comparison between Ramp and Burst+ atrial antitachycardia pacing therapies in patients suffering from sinus node disease and atrial fibrillation and implanted with a DDDRP device.

AIMS: Atrial tachycardia and flutter frequently occur in association with atrial fibrillation and may be treated by overdrive pacing in patients who receive pacemakers with antitachycardia pacing (ATP) capabilities. The PITAGORA trial was a multi-centre, randomized, cross-over study aimed at comparing two different ATP modes for atrial tachyarrhythmia (AT) termination in patients suffering from sinus node disease (SND). METHODS AND RESULTS: One hundred and seventy-six patients (72 M, age 71+/-9 years) received a Medtronic AT500 pacemaker. All patients were on class IC or III antiarrhythmic drugs. After a 5-month observation period, 170 patients were randomized to either Ramp or Burst+ ATP therapy; 4 months later they crossed over. One hundred and fifty-seven patients completed the 13 months of follow-up; 114 (72.6%) suffered 6088 AT episodes. In 75 patients, 1904 AT episodes were treated and 934 (49.1%) successfully terminated. The median value of individual patients' ATP efficacy was 60%. Burst+ terminated 387 out of 873 AT episodes (44%) in 58 patients. Ramp terminated 547 out of 1031 AT episodes (53%, P<0.001) in 56 patients. Ramp efficacy was significantly (P<0.01) and directly correlated with AT cycle length (ATCL), whereas Burst+ efficacy was not. Ramp showed higher (P<0.001) termination efficacy than Burst+ for ATCL >240 ms. Quality of life, as measured by the EuroQoL questionnaire, and number of symptoms significantly improved in the overall population. This improvement was significantly higher in patients with ATP efficacy >60%. CONCLUSION: In patients suffering from SND and AT, Ramp therapy shows higher termination efficacy than Burst+ therapy in AT episodes with ATCL >240 ms. Further studies are required to show the impact of ATP on clinical outcomes.

Design and rationale of a randomized study to compare amiodarone and Class IC anti-arrhythmic drugs in terms of atrial fibrillation treatment efficacy in patients paced for sinus node disease: the PITAGORA trial.

AIMS: Many sinus node disease (SND) patients suffer from atrial fibrillation (AF). Anti-arrhythmic drugs (AADs) are the therapeutic mainstay for AF prophylaxis. The PITAGORA trial has a multicentre, prospective, randomized, single blind design to compare amiodarone with Class IC AADs in patients who have an AF history and are paced for SND. METHODS AND RESULTS: Starting from January 2001, 176 patients received a Medtronic AT500 pacemaker. AADs were randomly assigned with a 3 : 2 ratio between Class III and Class IC. Randomization was stratified in order to assign two patients to amiodarone and one patient to sotalol every three Class III AAD patients. After a 5-month observational period, Ramp or Burst+ ATP therapies were enabled in a randomized way, maintained for 4 months, and then crossed over. Total follow-up period is 21 months. The primary long-term objective is to show the non-inferiority of IC AADs compared with amiodarone in terms of time to first occurrence of a composite endpoint (death, atrial cardioversion, hospitalizations due to AF or heart failure, or change of AADs). Data will be analysed on an intention-to-treat basis. The primary short-term objective is to compare Ramp vs. Burst+ efficacy in terminating atrial tachyarrhythmias treated by the device. Secondary endpoints are major clinical events, medication toxicity, symptoms, AF burden, and quality-of-life. CONCLUSION: Given the high morbidity and healthcare costs associated with AF, new therapeutic strategies are needed. The results of the PITAGORA trial may help in guiding AADs therapy and ATP programming in SND patients suffering from AF.

Early EPS/ICD strategy in survivors of acute myocardial infarction with severe left ventricular dysfunction on optimal beta-blocker treatment. The BEta-blocker STrategy plus ICD trial.

AIMS: This multicentre prospective randomised trial was undertaken to evaluate the usefulness of an electrophysiological study (EPS)-guided/implantable cardioverter defibrillator (ICD) strategy in patients at high risk of sudden death (SD) early after myocardial infarction (MI). Previous studies have shown the benefits of such a strategy only in high-risk patients late after MI. METHODS AND RESULTS: We enrolled 143 survivors of acute MI (<1 month) with left ventricular ejection fraction < or = 35% and either frequent (> or =10/h) premature ventricular complexes (PVCs), or depressed heart rate variability (SDNN < 70 ms) or abnormal signal-averaged ECG, who were able to tolerate optimised beta-blocker therapy (68 +/- 40 mg/day of metoprolol). Of these, 138 were randomised, in a 2:3 ratio, to two therapeutic strategies: conventional (CONV) strategy (n = 59) or EPS-guided/ICD strategy (n = 79). The latter resulted in ICD implantation in 24 inducible patients and in CONV therapy in the remaining 55. During a mean follow-up of 540 +/- 378 days, 26 patients (19%) died: nine (6.5%) SD, nine (6.5%) non-SD, and four (3%) non-cardiac death; in four patients (3%) the cause of death was unknown. The actuarial overall mortality for the CONV and EPS-guided/ICD arms was 18% vs 14% after 1 year and 29.5% vs 20% after 2 years, respectively (P = 0.3 and 0.2). CONCLUSIONS: Despite optimal therapy, mortality remains significant in high-risk patients following MI. Although there is a trend in favour of EPS-guided/ICD, our data are insufficient to demonstrate a survival benefit of this strategy early after MI.

Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: an alternative protective mechanism.

BACKGROUND: The concentration of peroxynitrite in the brain increases after central nervous system injuries. The authors hypothesized that propofol, because of its particular chemical structure, mitigates the effects of peroxynitrite-mediated oxidative stress and apoptosis by the induction of heme oxygenase (HO)-1 in primary cultured astroglial cells. METHODS: Primary cultured astroglial cells were incubated for 18 h with a known peroxynitrite donor (3 mm SIN-1) in the presence or absence of propofol (40 microm, 80 microm, 160 microm, and 1 mm). The protective effects of propofol were evaluated by 3(4,5-dimethyl-thiazol-2-yl)2,5-diphenyl-tetrazolium bromide cytotoxicity assay, lactic dehydrogenase release, DNA ladderization by Comet assay, and caspase-3 activation by Western blot analysis. RESULTS: Appropriate propofol concentrations (ranging from 40 microm to 1 mm) significantly increased HO-1 expression and attenuated SIN-1-mediated DNA ladderization and caspase-3 activation. The protective effects of propofol were mitigated by the addition of tin mesoporphyrin, a potent inhibitor of HO activity. The addition of a specific synthetic inhibitor of nuclear factor kappaB abolished propofol-mediated HO-1 induction, suggesting a possible role of this nuclear transcriptional factor in our experimental conditions. CONCLUSIONS: The antioxidant properties of propofol can be partially attributed to its scavenging effect on peroxynitrite as well as to its ability to increase HO-1 expression at higher concentrations, a property that might be relevant to neuroprotection during anesthesia.

Left ventricular function in acute hypothyroidism: a Doppler echocardiography study.

BACKGROUND: Acute changes in cardiac parameters may occur after L-thyroxine withdrawal in patients totally thyroidectomized for thyroid cancer. The literature data regarding cardiac function in acute hypothyroidism are limited and discordant. METHODS: In order to evaluate the effects of acute hypothyroidism on cardiac function, 20 athyreotic patients (3 males, 17 females, mean age 46.4 +/- 8.6 years, range 18-58 years) underwent Doppler echocardiography during L-thyroxine therapy (euthyroid phase) and 5 weeks after hormone therapy withdrawal (hypothyroid phase). RESULTS: Significant changes in the left ventricular mass (83 +/- 12 vs 93 +/- 17 g/m2, p = 0.004) and end-diastolic volume (56 +/- 9 vs 50 +/- 9 ml/m2, p = 0.01) were found. Among systolic function parameters, the pre-ejection period/left ventricular ejection time (PEP/LVET) ratio (0.33 +/- 0.07 vs 0.40 +/- 0.08, p = 0.0002), aortic peak flow velocity corrected for heart rate (3.9 +/- 0.7 vs 3.5 +/- 0.5 cm/s, p = 0.02) and mean aortic acceleration corrected for heart rate (45 +/- 15 vs 38 +/- 9 cm/s2, p = 0.007) showed significant variations, whereas the left ventricular fractional shortening (39 +/- 5 vs 40 +/- 6%, p = NS) and ejection fraction (69 +/- 6 vs 68 +/- 7%, p = NS) did not change. Among diastolic function parameters, only the E-wave velocity decreased (73 +/- 17 vs 65 +/- 12 cm/s, p = 0.01); no significant modification was found in the A-wave velocity (62 +/- 19 vs 58 +/- 14 cm/s, p = NS), E/A ratio (1.2 +/- 0.5 vs 1.1 +/- 0.3, p = NS), isovolumic relaxation time (93 +/- 16 vs 95 +/- 37 ms, p = NS) and E-wave deceleration time (233 +/- 48 vs 235 +/- 45 ms, p = NS). The pattern of left ventricular filling remained unchanged, except in 2 patients. The Suga-Sagawa's index, a known parameter of myocardial contractility, was unchanged (5.6 +/- 2 vs 6.1 +/- 2 mmHg/ml, p = NS). The systemic vascular resistance increased (1511 +/- 599 vs 2216 +/- 408 dynes-s-cm(-5), p = 0.002), while the stroke index (39 +/- 8 vs 33 +/- 7 ml/m2, p = 0.001) and cardiac index (2.74 +/- 0.6 vs 2.07 +/- 0.5 l/min/m2, p = 0.0001) significantly decreased. CONCLUSIONS: Acute hypothyroidism was associated with left ventricular systolic dysfunction, probably due to pre- and afterload alterations rather than to an impaired myocardial contractility. The diastolic function was not significantly modified. An increase in cardiac mass was also found, possibly a consequence of early interstitial myxedema. Unlike the PEP/LVET ratio, both the fractional shortening and ejection fraction may be unreliable indicators of left ventricular systolic dysfunction in patients with acute hypothyroidism.

Preclinical thalassemic cardiopathy: a study by acoustic densitometry.

BACKGROUND: The cardiac function in thalassemia major has never been studied at ultrasonic backscatter techniques. We assessed the utility of acoustic densitometry in thalassemic patients without clinical or echocardiographic signs of heart failure. METHODS: Three groups of subjects with comparable age, sex and body surface area were analyzed: 25 with beta-thalassemia major (group A), 14 with thalassemia intermedia (group B) and 10 healthy subjects (group C). All patients were asymptomatic and without conventional echocardiographic signs of systo-diastolic dysfunction. The left ventricular mass and volumes were echocardiographically evaluated. The ultrasonic myocardial integrated backscatter signal (IBS) was recorded and analyzed by means of acoustic densitometry in the parasternal long-axis view at the septum and posterior wall, both at the basal and intermediate levels. Both the average image intensity and the systo-diastolic variations of the IBS (cyclic variation index-CVIibs and peak-to-peak intensity-PPI), respectively related to the structure and contractility of the myocardium, were calculated. The serum ferritin and liver iron concentrations were also measured, as markers of tissue iron storage. RESULTS: The CVIibs was significantly lower in groups A and B than in group C at basal (22.7 +/- 8.4 vs 22.1 +/- 7.8 vs 31.8 +/- 10.2%; p = 0.001) and intermediate septum (24.4 +/- 7.6 vs 25.3 +/- 8.1 vs 30 +/- 9.8%; p = 0.03) and at basal (25.9 +/- 7.6 vs 24.5 +/- 6.1 vs 31.1 +/- 10.6%; p = 0.02) and intermediate posterior wall (25.1 +/- 5.1 vs 24.3 +/- 6.2 vs 30.2 +/- 6.6%; p = 0.02). The PPI was also significantly lower in groups A and B than in group C. Both CVIibs and PPI were comparable in groups A and B. The average image intensity and left ventricular mass and volumes were not significantly different in the three groups. No correlation was found between the densitometric findings and markers of tissue iron storage. CONCLUSIONS: In asymptomatic patients with thalassemia major with normal conventional indexes of systo-diastolic cardiac function, acoustic densitometry may show a reduced cyclic variation of the IBS as a possible marker of initial myocardial contractile deficiency. On the contrary, neither structural alterations nor the extent of myocardial iron stores are detectable by this technique in this type of patients.