Design and results of the antiarrhythmics vs implantable defibrillators (AVID) registry. The AVID Investigators.
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BACKGROUND: The Antiarrhythmics Versus Implantable Defibrillators (AVID) Study compared treatment with implantable cardioverter-defibrillators versus antiarrhythmic drugs in patients with life-threatening ventricular arrhythmias (VAs). AVID maintained a Registry on all patients, randomized or not, with any VA or unexplained syncope who could be considered for either of the treatment strategies. Trial-eligible arrhythmias were the categories of VF cardiac arrest, Syncopal VT, and Symptomatic VT, below. METHODS AND RESULTS: Of 5989 patients screened, 4595 were registered and 1016 were randomized. Mortality follow-up through 1996 was obtained on the 4219 Registry patients enrolled before 1997 through the National Death Index. Crude mortality rates (mean+/-SD, follow-up, 16.9+/-11.5 months) were: VF cardiac arrest, 17.0% (n=1399, 238 deaths); Syncopal VT, 21.2% (n=598, 127 deaths); Symptomatic VT, 15.8% (n=1065, 168 deaths); Stable (asymptomatic) VT, 19.7% (n=497, 98 deaths); VT/VF with transient/correctable cause, 17.8% (n=270, 48 deaths); and Unexplained syncope, 12.3% (n=390, 48 deaths). CONCLUSIONS: Patients with seemingly lower-risk or unknown-risk VAs (asymptomatic VT, and VT/VF associated with a transient factor) have a (high) mortality similar to that of higher-risk, AVID-eligible VAs. The similar (and poor) prognosis of most patients with VT/VF suggests the need for reevaluation of a priori risk grouping and raises the question of the appropriate arrhythmia therapy for a broad range of patients. (+info)
Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction: importance of microvascular reperfusion injury on clinical outcome.
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BACKGROUND: Despite early recanalization of an occluded infarct artery, reperfusion at the level of the microcirculation may remain impaired owing to a process of microvascular reperfusion injury. METHODS AND RESULTS: Microvascular reperfusion injury was studied in 91 patients with acute myocardial infarction (AMI) by evaluation of the resolution of ST-segment elevation after successful PTCA. Impaired microvascular reperfusion, defined as the presence of persistent (>/=50% of initial value) ST-segment elevation (ST >/=50%) at the end of coronary intervention, was observed in 33 patients (36%) and was independently correlated with low systolic pressure on admission and high age. Patients >/=55 years of age with systolic pressures /=50% versus ST <50%, P=0.01); nonfatal MI rate, 9% versus 2% (P=0.1); and total major adverse cardiac event (MACE) rate, 45% versus 15% (P<0.005). ST >/=50% was the most important independent determinant of MACE with an adjusted risk ratio of 3.4. CONCLUSIONS: Impaired microvascular reperfusion, as evidenced by ST >/=50% after successful recanalization, occurs in more than one third of our AMI patients, especially in older patients with low systolic pressure. Its detrimental implications on clinical outcome reinforce the need to develop adjunctive agents that attenuate the process of reperfusion injury. (+info)
Diagnostic cardiac catheterisation in a hospital without on-site cardiac surgery.
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OBJECTIVE: To assess the feasibility, safety, and clinical impact of diagnostic cardiac catheterisation in a multipurpose laboratory in a district general hospital without cardiac surgery. METHODS: A prospective audit of the first 2000 consecutive cases between September 1992 and March 1997. Unstable patients were referred to a surgical centre for investigation, in line with subsequently published British Cardiac Society (BCS) guidelines, but all other patients requiring cardiac catheterisation were investigated locally and are included in this report. The function of the laboratory was also compatible with the BCS guidelines regarding staffing, operators, equipment, number of cases, and locally available vascular surgery. RESULTS: Of the 2000 cases, 1988 studies were completed (99%), 1985 (99%) included coronary angiography, and 1798 (90%) were performed as day cases. Left main stem disease was present in 157 (8%), three vessel disease in 683 (34%), two vessel disease in 387 (19%), single vessel disease in 424 (21%), and normal coronary arteries in 494 (25%). Of the latter, 284 (14% of the total) had another cardiac diagnosis for which they were investigated (for example, valvar heart disease). Referral for cardiac intervention following catheterisation was made in 1172 of the 2000 cases (intervention rate 59%; catheter:intervention ratio 1. 7:1). The interventions performed were coronary artery bypass grafting (CABG) in 736 of the 1172 cases (63%), other types of cardiac surgery in 122 (10%), combined CABG and other cardiac surgery in 71 (6%), and percutaneous transluminal coronary angioplasty in 243 (21%). There were two catheter related deaths (0. 1%), both of which occurred within 24 hours of the procedure, and a further nine major cardiovascular complications with residual morbidity (0.45%). These were myocardial infarction in two (0.1%), cerebrovascular events in two (0.1%), and surgical vascular complications in five (0.25%). In addition, there were eight successfully treated, life threatening arrhythmias (0.4%). CONCLUSIONS: Diagnostic cardiac catheterisation can be performed safely and successfully in a local hospital. When BCS guidelines are followed, the mortality is similar to published pooled data from regional centres (0.1% v 0.12%). The high intervention rate indicates a persistent unmet demand in the districts, which will continue to affect surgical and interventional services. (+info)
Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs.
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AIMS: To quantify and compare the incidence of ventricular arrhythniias associated with the use of five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were also examined. METHODS: We carried out a cohort study with a nested case-control analysis using the UK-based General Practice Research database (GPRD). The study cohort included persons aged less than 80 years old who received their first prescription for any of the five study drugs between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as compared with non use. RESULTS: The study cohort included 197425 persons who received 513012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias were detected. Nine occurred during the current use of any antihistamine, resulting in a crude incidence of 1.9 per 10000 person-years (95%CI: 1.0-3.6) and a relative risk of 4.2 (95%CI: 1.5-11.8) as compared with non use. Astemizole presented the highest relative risk (RR= 19.0; 95%CI: 4.8-76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5-8.5) was in the range of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular arrhythmias (RR=7.4; 95%CI: 2.6-21.4) and seemed to increase the effect of antihistamines (RR=6.4; 95%CI: 1.7-24.8). The proportions of high dose terfenadine and the concomitant use with P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study period with no single case of ventricular arrhythmias occurring in the presence of these two risk factors. CONCLUSIONS: The use of nonsedating antihistamines increases the risk of ventricular arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low requiring 57000 prescriptions, or 5300 person-years of use for one case to occur. The risk associated with terfenadine was no different from that with other nonsedating antihistamines. (+info)
Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases.
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Bone marrow (BM) and/or peripheral blood progenitor cells (PBPC) given after high-dose chemo-radiotherapy are commonly cryopreserved. Re-infusion of the thawed product can cause cardiovascular and other complications. We compared two groups of adult patients receiving autologous BM or PBPC transplant to assess the incidence of adverse events occurring during infusion. Fifty-one patients received BM, and 75 PBPC. The two groups were comparable in respect of age, total volume infused, quantity of dimethylsulfoxide (DMSO) and number of polymorphonuclear neutrophils. Patients receiving PBPC had a higher number of nucleated cells per kg of body weight; those in the BM group received a significantly greater quantity of red cells. Non-cardiovascular complications occurred in 19% and 8% of patients rescued by BM and PBPC respectively. The incidence of hypertension was 21% in the BM and 36% in the PBPC group. Asymptomatic hypotension was more frequent in PBPC patients (P<0.001). Bradyarrhythmia was noticed in two of 75 PBPC patients and in 14 of 51 BM patients (P<0.001). In the former group one patient had heart block; he died of renal failure 10 days later. Bradycardia and hemoglobinuria were more common in patients receiving BM where a higher concentration of red cells was present (P<0.001). Since bradyarrhythmias may be a life-threatening complication we advise continuous careful monitoring during infusion of thawed BM. The strong correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content. (+info)
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
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A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors. (+info)
Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current.
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Although it is widely accepted that afterdepolarizations initiate arrhythmias when action potentials are prolonged, the underlying mechanisms are unclear. In this study, we tested the hypothesis that action potential prolongation would raise intracellular calcium and thereby activate the arrhythmogenic transient inward current (Iti). Furthermore, given that Iti can be activated by sarcoplasmic reticulum Ca2+ release, we tested the hypothesis that inhibition of calmodulin (CaM) kinase would prevent Iti. Isolated rabbit ventricular myocytes were studied with whole-cell-mode voltage clamp. Stimulation with a prolonged action potential clamp, under near-physiological conditions, increased [Ca2+]i. Iti was reproducibly induced in 60 of 60 cells, but Iti was not seen with the use of a shorter action potential waveform (n=12). Iti was associated with a secondary elevation in [Ca2+]i. When [Ca2+]i buffering was enhanced by dialysis with BAPTA (20 mmol/L, n=9), no Iti was present. The Na+/Ca2+ exchanger was likely responsible for Iti, because Iti was inhibited by the Na+/Ca2+ exchanger inhibitory peptide XIP (10 micromol/L, n=6), but not by an inactive scrambled peptide (10 micromol/L, n=5) or by the Cl- current antagonist niflumic acid (10 to 40 micromol/L, n=9). Activator Ca2+ from the sarcoplasmic reticulum was essential for development of Iti, because it was prevented by pretreatment with ryanodine (10 micromol/L, n=6) or thapsigargin (1 micromol/L, n=6). Two different CaM kinase inhibitory peptides (n=16) and a CaM inhibitory peptide (n=4) completely suppressed Iti. These results are consistent with the hypothesis that CaM kinase plays a role in arrhythmias related to increased [Ca2+]i. (+info)
Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel.
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BACKGROUND: The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go-related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (IKr), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. METHODS AND RESULTS: To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane. CONCLUSIONS: Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2. (+info)