Malcolm M. Bersohn

Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices.

AIMS Atrial tachyarrhythmias (ATs) detected by implanted devices are often atrial fibrillation or flutter (AF) associated with stroke. We hypothesized that introduction and termination of anticoagulation based upon AT monitoring would reduce both stroke and bleeding. METHODS AND RESULTS We randomized 2718 patients with dual-chamber and biventricular defibrillators to start and stop anticoagulation based on remote rhythm monitoring vs. usual office-based follow-up with anticoagulation determined by standard clinical criteria. The primary analysis compared the composite endpoint of stroke, systemic embolism, and major bleeding with the two strategies. The trial was stopped after 2 years median follow-up based on futility of finding a difference in primary endpoints between groups. A total of 945 patients (34.8%) developed AT, 264 meeting study anticoagulation criteria. Adjudicated atrial electrograms confirmed AF in 91%; median time to initiate anticoagulation was 3 vs. 54 days in the intervention and control groups, respectively (P < 0.001). Primary events (2.4 vs. 2.3 per 100 patient-years) did not differ between groups (HR 1.06; 95% CI 0.75-1.51; P = 0.732). Major bleeding occurred at 1.6 vs. 1.2 per 100 patient-years (HR 1.39; 95% CI 0.89-2.17; P = 0.145). In patients with AT, thromboembolism rates were 1.0 vs. 1.6 per 100 patient-years (relative risk -35.3%; 95% CI -70.8 to 35.3%; P = 0.251). Although AT burden was associated with thromboembolism, there was no temporal relationship between AT and stroke. CONCLUSION In patients with implanted defibrillators, the strategy of early initiation and interruption of anticoagulation based on remotely detected AT did not prevent thromboembolism and bleeding. CLINICAL TRIAL REGISTRATION IMPACT ClinicalTrials.gov identifier: NCT00559988 ( http://clinicaltrials.gov/ct2/show/NCT00559988?term=NCT00559988&rank=1 ).

Multicenter randomized study of anticoagulation guided by remote rhythm monitoring in patients with implantable cardioverter-defibrillator and CRT-D devices: Rationale, design, and clinical characteristics of the initially enrolled cohort. The IMPACT study

Atrial fibrillation and atrial flutter are common cardiac arrhythmias associated with an increased risk of stroke in patients with additional risk factors. Anticoagulation ameliorates stroke risk, but because these arrhythmias may occur intermittently without symptoms, initiation of prophylactic therapy is often delayed until electrocardiographic documentation is obtained. The IMPACT study is a multicenter, randomized trial of remote surveillance technology in patients with implanted dual-chamber cardiac resynchronization therapy defibrillator (CRT-D) devices designed to test the hypothesis that initiation and withdrawal of oral anticoagulant therapy guided by continuous ambulatory monitoring of the atrial electrogram improve clinical outcomes by reducing the combined rate of stroke, systemic embolism, and major bleeding compared with conventional clinical management. For those in the intervention group, early detection of atrial high-rate episodes (AHRE) generates an automatic alert to initiate anticoagulation based on patient-specific stroke risk stratification. Subsequently, freedom from AHRE for predefined periods prompts withdrawal of anticoagulation to avoid bleeding. Patients in the control arm are managed conventionally, the anticoagulation decision prompted by incidental detection of atrial fibrillation or atrial flutter during routine clinical follow-up. The results will help define the clinical utility of wireless remote cardiac rhythm surveillance and help establish the critical threshold of AHRE burden warranting anticoagulant therapy in patients at risk of stroke. In this report, we describe the study design and baseline demographic and clinical features of the initial cohort (227 patients).

Verapamil protection of ischemic isolated rabbit heart: Dependence on pretreatment

Verapamil may protect ischemic myocardium by several mechanisms: prevention of Ca overload as a direct effect of blocking Ca influx through slow channels, coronary vasodilatation, decreased contractility, or cardioplegia produced by high doses. We manipulated the experimental situation to ask whether the first mechanism alone could be protective. We studied isovolumically contracting rabbit hearts perfused at 37 degrees C, paced at 150/min, and maximally vasodilated by dipyridamole. Hearts were subjected to 60 min of low flow ischemia followed by 60 min reperfusion. Two groups were exposed to verapamil 0.5 microM beginning either 2 to 4 min before ischemia or 10 min after the onset of ischemia (when pressure development had ceased) and continuing until reperfusion. Developed pressure recovered during reperfusion to 70 +/- 4% of its initial value in hearts treated with verapamil before ischemia compared to 40 +/- 5% for control hearts and 35 +/- 11% for hearts treated with verapamil 10 min after the onset of ischemia. There was significant preservation of phosphocreatine at 10 min of ischemia and of ATP at 60 min in the early verapamil group compared to the other two. When verapamil was present before ischemia, pressure development during early ischemia was reduced to about 50% of control. Consequently there was substantial sparing of high energy phosphates and enhanced recovery of mechanical function. If verapamil was added 10 min after the onset of ischemia, when it no longer could affect cardiac work, there was no protection. Therefore, in the isolated rabbit heart, verapamil had an important protective effect only by reducing contractility of ischemic myocardium.

Defibrillation threshold testing fails to show clinical benefit during long-term follow-up of patients undergoing cardiac resynchronization therapy defibrillator implantation

BACKGROUND The utility of defibrillation threshold testing in patients undergoing implantable cardioverter-defibrillator (ICD) implantation is controversial. Higher defibrillation thresholds have been noted in patients undergoing implantation of cardiac resynchronization therapy defibrillators (CRT-D). Since the risks and potential benefits of testing may be higher in this population, we sought to assess the impact of defibrillation safety margin or vulnerability safety margin testing in CRT-D recipients. METHODS AND RESULTS A total of 256 consecutive subjects who underwent CRT-D implantation between January 2003 and December 2007 were retrospectively reviewed. Subjects were divided into two groups based on whether (n= 204) or not (n= 52) safety margin testing was performed. Patient characteristics, tachyarrhythmia therapies, procedural results, and clinical outcomes were recorded. Baseline characteristics, including heart failure (HF) severity, were comparable between the groups. Four cases of HF exacerbation (2%), including one leading to one death, were recorded in the tested group immediately post-implantation. No complications were observed in the untested group. After a mean follow-up of 32 ± 20 months, the proportion of appropriate shocks in the two groups was similar (31 vs. 25%, P = 0.49). There were three cases of failed appropriate shocks in the tested group, despite adequate safety margins at implantation, whereas no failed shocks were noted in the untested group. Survival was similar in the two groups. CONCLUSION Defibrillation efficacy testing during implant of CRT-D was associated with increased morbidity and did not predict the success of future device therapy or improve survival during long-term follow-up.

Molecular cloning and functional expression of the guinea pig cardiac Na+ -Ca2+ exchanger

The cDNA of the guinea pig cardiac Na(+)-Ca2+ exchanger was cloned from a lambda ZAP cDNA library. The deduced sequence of the protein corresponds to 970 amino acids and is 98% identical to the canine cardiac exchanger. The leader peptide region shows substantial variation among species. The cloned cDNA can induce Na(+)-Ca2+ exchange activity when in vitro transcribed cRNA is injected into Xenopus laevis oocytes.

Effect of temperature on sodium-calcium exchange in sarcolemma from mammalian and amphibian hearts

We have investigated temperature dependence of Ca2+ uptake by the cardiac sarcolemmal Na(+)-Ca2+ exchanger from dog, rabbit and bullfrog. In native rabbit sarcolemmal vesicles, Ca2+ affinity of the Na(+)-Ca2+ exchanger is unchanged from 7 to 37 degrees C; however, the initial velocity of Ca2+ uptake declines much more steeply below 22 degrees C than above 22 degrees C. In native dog sarcolemma, the temperature dependence of Na(+)-Ca2+ exchange velocity is similar to that of native rabbit. However, in frog heart the velocity of Na(+)-Ca2+ exchange declines much more slowly with decreasing temperature at both temperature ranges. Reconstitution of the Na(+)-Ca2+ exchanger into artificial lipid vesicles consisting of either asolectin or phosphatidylserine, phosphatidylcholine, and cholesterol has little effect on temperature dependence of Na(+)-Ca2+ exchange velocity in any of the three species. We conclude that the lesser temperature sensitivity of the cardiac sarcolemmal Na(+)-Ca2+ exchanger of a poikilothermic species is at least partly an intrinsic property of the transport protein.

Low referral rate for prophylactic implantation of cardioverter-defibrillators in a tertiary care medical center.

Background: Implantable cardioverter‐defibrillators (ICDs) for primary prevention became standard of care after the publication of the second Multicenter Automatic Defibrillator Implantation Trial (MADIT‐II) and Sudden Cardiac Death in Heart Failure Trial (SCD‐HeFT).

Sodium pump inhibition in sarcolemma from ischemic hearts

Ischemic myocardial cells lose K+ and accumulate Na+. The role of the Na+/K(+)-pump in these changes was investigated by measuring both Na+/K(+)-ATPase activity and Na+ pumping in highly purified sarcolemmal vesicles from rabbit hearts made globally ischaemic for 1 h compared to non-ischemic controls. Purification of the sarcolemma was similar for control, 31 +/- 8-fold, and ischemia, 38 +/- 10-fold. The fraction of intact inside-out vesicles, in which Na+ pumping could be measured, was also the same for control, 60 +/- 16%, and ischemic, 56 +/- 8% as measured by 3H-ouabain binding in the presence and absence of detergent. Scatchard analysis of ouabain binding revealed a 26% increase in binding sites in ischemia compared to control. The Na+/K(+)-ATPase in the inside-out vesicles, measured as monensin-stimulated activity, was not affected by ischemia: 22 +/- 9 v 21 +/- 9 mumol Pi mg -1 h -1 for control and ischemic respectively. However, the initial velocity of ATP-dependent Na+ pumping into inside-out vesicles, assayed by subsequent exchange of Na+i for 45Ca2+ by the Na(+)-Ca2+ exchanger present in the vesicles was inhibited in ischemia. At 18 mM Na+o the velocity for control vesicles was 2.4 +/- 0.2 nmol mg -1 s -1 compared to 1.1 +/- 0.1 for ischemia vesicles. Passive sarcolemmal Na+ permeability was unchanged after 1 h of ischemia. The large reduction in Na+ pumping with unchanged Na+/K(+)-ATPase suggests uncoupling of the Na+/K(+)-pump in ischemia and a decreased ability to extrude Na+ despite the increase in number of pump sites in the sarcolemma.

Electropharmacology of amiodarone: Absence of relationship to serum, myocardial, and cardiac sarcolemmal membrane drug concentrations

Plasma concentrations are often of major consideration in the evaluation of therapeutic efficacy of cardiovascular drugs. This approach is based on the assumptions that the concentration of the drug in the cardiac muscle is in equilibrium with the plasma drug level and that pharmacologic efficacy is proportional to the myocardial drug concentration. The more pronounced pharmacologic efficacy of amiodarone following chronic administration, despite low plasma drug concentrations, and the lesser effects of the drug after acute intravenous administration, when drug levels are maximum, has not been explained on the basis of the pharmacokinetic behavior of the drug. Data obtained from the transmembrane action potential recordings from rabbit ventricular myocardium were therefore correlated with drug concentrations in the serum, myocardium, and myocardial sarcolemma following acute intravenous administration and after 4 weeks of oral administration of 20 mg/kg/day of amiodarone. Following 15 minutes of acute drug administration, when amiodarone concentrations were maximal in the serum (4.72 +/- 1.23 micrograms/ml), cardiac muscle (34.5 +/- 7.6 micrograms/gm), and sarcolemma (1.94 mg/gm protein), the electrophysiologic changes were insignificant. However, following chronic treatment, when levels of amiodarone were low in the serum (0.05 +/- 0.01 micrograms/ml amiodarone, 0.25 +/- 0.08 micrograms/ml desethylamiodarone), cardiac muscle (1.91 +/- 0.9 micrograms/gm amiodarone, 1.35 +/- 1.33 micrograms/gm desethylamiodarone), and myocardial membranes (0.043 mg/gm protein [amiodarone], 0.097 mg/gm protein [desethylamiodarone], there was a 54.3% increase in action potential duration at 90% repolarization (p less than 0.01) and 65% increase in the effective refractory period (p less than 0.01) of rabbit ventricular myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of safety and efficacy of pacemaker and defibrillator implantation by axillary incision in pediatric patients.

We successfully implanted 11 pacemakers, 6 defibrillators, and 1 biventricular pacemaker in 18 pediatric patients (15 female; 4 to 15 years, average age: 9) using the retropectoral transvenous approach with a hidden axillary incision. The average follow‐up period was 24 months (range 49 months). Eight patients had congenital structural heart conditions (d‐transposition of great arteries S/P Mustard operation, d‐transposition of great arteries S/P arterial switch operation, truncus arteriosus, right ventricular diverticula, ventricular septal defect, hypertrophic cardiomyopathy). Four patients had acquired heart conditions (dilated cardiomyopathy, myocarditis). Excellent sensing and pacing thresholds were achieved in all attempted implantations. There was no pneumothorax. There was one lead dislodgement. One lead fracture distant from the subclavian vein occurred 4 months after implantation. Implantation of pacemakers and defibrillators via axillary incisions can be safe and effective in pediatric patients. This approach avoids skin erosion when implanting large devices such as defibrillators or biventricular devices in small patients with limited muscle mass while achieving superior aesthetic results. The axillary or extrathoracic venous entry site avoids subclavian crush syndrome. (PACE 2004; 27:304–307)