Renal Denervation for Treating Hypertension: Current Scientific and Clinical Evidence.

Initial studies of catheter-based renal denervation (RDN) for uncontrolled HTN using radiofrequency ablation in the main renal arteries showed that RDN was effective in lowering office blood pressure (BP). However, the first randomized sham-controlled trial, SYMPLICITY-HTN-3, did not show significantly lower office or 24-h ambulatory systolic BP compared with sham treatment. Subsequent studies in both animals and humans demonstrated the potential importance of more distal and branch renal artery radiofrequency ablation, and a second-generation multielectrode system became available. Two recent randomized sham-controlled trials in patients not taking antihypertensive drugs (SPYRAL HTN-OFF MED) or continuing to take drugs (SPYRAL HTN-ON MED) performed RDN with the second-generation radiofrequency ablation system using an ablation protocol that included treatment of the distal renal artery as well as the branch renal arteries. These studies showed that RDN significantly reduced office and 24-h ambulatory BP compared with sham treatment. Another recent randomized sham-controlled trial in patients not receiving medications showed that RDN with catheter-based ultrasound (RADIANCE-HTN SOLO) applied in just the main renal arteries significantly lowered daytime ambulatory and office BP compared with sham treatment. These trials have renewed clinical and scientific interest in defining the appropriate role of RDN in hypertension treatment. In addition, other important issues will need to be addressed in the future such as the development of tests to determine the extent of RDN at the time of the procedure and the potential of renal nerve fibers to regain their patency at some later stage following the ablation procedure.

Utility of adjunctive single oral bolus propafenone therapy in patients with atrial defibrillators.

AIMS: Previous studies have demonstrated that ambulatory atrial defibrillation shocks delivered by an implantable cardioverter-defibrillator (ICD) are safe and effective, but poorly tolerated. Separate studies have demonstrated the utility of single oral bolus propafenone for conversion of recent-onset atrial fibrillation (AF); however, most patients were hospitalized, had no structural heart disease, were taking no other antiarrhythmic drugs, and were not exposed to concomitant shock. We hypothesized that a single oral bolus dose of propafenone given early after onset would be a safe and effective adjunct to ICD-based AF therapy and improve overall therapy tolerance. METHODS AND RESULTS: A randomized three-way crossover study design was used to compare three strategies, deployed in the ambulatory setting early after AF episode onset in 35 ICD patients with advanced, drug refractory episodic/persistent syndromes, many of whom had structural heart disease and were taking other antiarrhythmic drugs: (i) single oral bolus propafenone (600 mg), followed by ICD shock if necessary; (ii) single oral bolus placebo, followed by ICD shock if necessary; and (iii) no oral bolus therapy and ICD shock if necessary (no bolus). Antiarrhythmic efficacy, defined by the restoration of sinus rhythm within 24 h, was similar during propafenone (81%) and no-bolus strategies (84%); both were significantly higher than during placebo strategy (62%). Propafenone was well tolerated and not associated with proarrhythmia. Shock use was significantly lower during propafenone strategy (19%) than during no-bolus strategy (55%); this was correlated with improved patient tolerance. CONCLUSION: Adjunctive use of single oral bolus propafenone is safe and effective in patients with an ICD and improves patient tolerance of device-based AF therapy.

Serial evaluation of atrial tachyarrhythmia burden and frequency after implantation of a dual-chamber cardioverter-defibrillator.

UNLABELLED: Serial evaluation of AT burden and frequency after implantation of D-ICD. BACKGROUND: We sought to characterize atrial tachyarrhythmia (AT) burden and frequency after implantation of a dual-chamber implantable cardioverter-defibrillator (D-ICD). METHODS AND RESULTS: A total of 149 subjects underwent implantation of a D-ICD (Jewel AF model 7250, Medtronic, Inc.) for the primary indication of drug-resistant AT, and were followed for at least 12 months during which device programming was constant. The device employed atrial overdrive pacing as well as shocks to terminate episodes of AT. Arrhythmia burden and frequency were evaluated during the 0- to 6-month follow-up and and 6- to 12-month follow-up intervals. A majority of subjects (62%) received a type I/III antiarrhythmic drug during follow-up. The median arrhythmia burden decreased from 8.2 hours/month during 0-6 months to 3.3 hours/month during 6-12 months (P=0.004); this result was driven primarily by the subgroup with persistent AT prior to device implantation. There was no significant change in the median AT frequency (2.2 vs 1.0 episodes/month). There was a significant decrease in the median shock frequency (0.32 vs 0.00 shocks/month, P=0.003) and an increase in shock efficacy (85.5% vs 94.9%, P=0.01). CONCLUSIONS: Device-based treatment of AT, in association with antiarrhythmic drugs, yields a significant time-dependent decrease in AT burden but not frequency.

The impact of atrial prevention and termination therapies on atrial tachyarrhythmia burden in patients receiving a dual-chamber defibrillator for ventricular arrhythmias.

INTRODUCTION: This prospective, multicenter, randomized trial evaluated the effects of atrial prevention and termination therapies on atrial tachyarrhythmia (ATA) burden in patients with a standard indication for an implantable cardioverter defibrillator (ICD). METHODS: A Jewel AF or GEM III AT ICD was implanted in 451 patients. At 1-month post-implant, patients were randomized to atrial prevention and termination therapies ON ( n = 199) or OFF ( n = 206) and followed for 6 additional months. Automatic atrial shocks were enabled in only 14% of the ON group. The follow-up time after randomization was 6.9 +/- 2.4 months ON versus 6.8 +/- 2.3 months OFF. RESULTS: There were 126/405 (31.1%) patients who had AT/AF episodes during follow-up. Only four patients received a shock to treat ATA's during follow-up. The median ATA burden was 0 hours/month in both the ON and OFF groups ( P = 0.40). The mean ATA burden was 4.3 +/- 20.0 hours/month ON versus 9.0 +/- 50.0 hours/month OFF ( P = 0.11). In a subgroup of 192 patients with a history of ATA's, the median burden was 0 hours/month in the both groups ( P = 0.23). However, the mean burden in this subgroup was 7.6 +/- 27.1 hours/month ON versus 19.2 +/- 73.7 hours/month OFF ( P = 0.056). CONCLUSIONS: In patients receiving an ICD for ventricular arrhythmias, no significant change in ATA burden was observed when atrial prevention and termination therapies were enabled. This may have been due to the low ATA burden in this population. In a subgroup of patients with history of ATA's, there was a trend towards a reduction in mean burden.

Association of cholesterol levels and occurrence of angiographically detectable endothelial disruption during coronary angioplasty.

BACKGROUND: Disruption of the atherosclerotic plaque is a common feature of both acute coronary syndromes and balloon dilatation of coronary artery stenoses. HYPOTHESIS: The study was undertaken to evaluate whether the known association of cholesterol levels and acute coronary syndromes also exists for the occurrence of angiographically detectable endothelial disruption (ED) following coronary angioplasty. METHODS: For this purpose, we examined 79 consecutive patients (men/women 58/21; mean age: 62 +/- 11 years), with a noncalcified, de novo, significant stenosis in a single native coronary artery, undergoing elective coronary intervention because of stable effort angina. Coronary angioplasty was performed using regular balloon catheters, aiming for a balloon/ artery ratio of 1, with stent implantation allowed only provisionally. Following balloon dilatation, patients were divided into two groups according to the presence or absence of angiographically detectable ED. RESULTS: Endothelial disruption occurred in 28 patients (35%). The two groups with and without ED were comparable with respect to clinical, angiographic, and procedural parameters. A history of hypercholesterolemia was significantly more frequent in patients with ED (93 vs. 2%; p < 0.001). Total and low-density lipoprotein (LDL) cholesterol levels were significantly higher in the group with ED (230.1 +/- 46.5 vs. 204.4 +/- 30.2 mg/dl, p < 0.05; and 150.6 +/- 39.2 vs. 125.8 +/- 26 mg/dl, p < 0.03, respectively). A cut-off value of LDL cholesterol > or = 135 mg/dl identified patients at higher risk of developing ED. CONCLUSION: High cholesterol levels appear to favor the occurrence of ED during coronary angioplasty. Aggressive lipid-lowering therapy and a more careful procedural approach may be warranted in patients with hypercholesterolemia undergoing coronary interventions in order to decrease the occurrence of ED and the associated clinical (acute ischemia) and procedural (stent implantation) consequences.

The effect of atrial pacing therapies on atrial tachyarrhythmia burden and frequency: results of a randomized trial in patients with bradycardia and atrial tachyarrhythmias.

OBJECTIVES: The Atrial Therapy Efficacy and Safety Trial (ATTEST) was a prospective, randomized study to evaluate preventive pacing and antitachycardia pacing (ATP) in patients with symptomatic atrial fibrillation (AF) or atrial tachycardia (AT). BACKGROUND: The effect of the combination of atrial prevention and termination algorithms on AT/AF burden and frequency in pacemaker patients is unknown. METHODS: A DDDRP pacemaker (AT500, Medtronic Inc., Minneapolis, Minnesota) with three atrial preventive pacing algorithms and two ATP algorithms was implanted in 368 patients. Patients were randomized one-month post-implant to all prevention and ATP therapies ON or OFF and followed for three months. The OFF group had DDDR pacing at a lower programmed rate of 60 ppm. The AT/AF burden and frequency were determined from daily device counters in 324 patients treated according to protocol. RESULTS: In 17,018 episodes with stored electrograms, appropriate detection was confirmed in 17,004 (99.9%). The median percentage of atrial pacing was 98% in the ON group versus 75% in the OFF group (p < 0.001). Using device-defined criteria for successful termination, ATP terminated 8,590 (54%) of 15,789 treated episodes. The median AT/AF burden during the three-month study period was 4.2 h/month ON versus 1.1 h/month OFF (p = 0.20). The median AT/AF frequency was 1.3 episodes/month ON versus 1.2 episodes/month OFF (p = 0.65). System-related, complication-free survival at four months was 90.2% (Kaplan-Meier estimate). CONCLUSIONS: This DDDRP pacemaker is safe, has accurate AT/AF detection, and provides ATP with 54% efficacy as defined by the device. The atrial prevention and termination therapies combined did not reduce AT/AF burden or frequency in this patient population.

Effectiveness of rapid atrial pacing for termination of drug refractory atrial fibrillation: results of a dual chamber implantable cardioverter defibrillator trial.

There is increasing interest in the use of an implantable cardioverter defibrillator (ICD) to manage atrial tachyarrhythmias. Although device-based shock therapy is highly effective in terminating persistent atrial tachyarrhythmias, atrial overdrive pacing may also be useful, particularly when this therapy is applied early after the onset of an arrhythmia. A dual-chamber ICD (Medtronic 7250 Jewel AF(R)) has been studied in 267 patients with drug-refractory symptomatic AF. The patients were enrolled as part of multicenter clinical trial to evaluate the safety and efficacy of the device to manage atrial tachyarrhythmias in the absence of a standard ventricular ICD indication. The device discriminates atrial tachycardia (AT) from atrial fibrillation (AF) based on cycle length and regularity, and employs multiple methods of atrial overdrive pacing as well as shocks to terminate tachyarrhythmia episodes. Patients were followed for an average of 15.8 +/- 9.3 months. A majority (63%) of patients presented with a history of persistent AF and 34% presented with a history of paroxysmal AF. The pacing therapies terminated 54% of AT episodes and 27% of AF episodes. In patients with persistent AF, 75% of the AT/AF episodes that were successfully terminated by pacing lasted

Atrial arrhythmia burden as an endpoint in clinical trials: is it the best surrogate? Lessons from a multicenter defibrillator trial.

Therapies to treat atrial tachyarrhythmias need to be evaluated in controlled, randomized clinical trials in order to optimize patient outcomes. If the maintenance of sinus rhythm is the ultimate goal, then atrial tachyarrhythmia burden may serve as a useful endpoint. Atrial tachyarrhythmia burden is defined as the total duration of all atrial tachyarrhythmias divided by the follow-up time and includes asymptomatic as well as symptomatic episodes. The measurement of atrial tachyarrhythmia burden is more practical now than in the past because of the availability of implantable devices capable of monitoring atrial tachyarrhythmia episodes. The advantage of burden over other endpoints is that it is not subject to investigator bias and it does not have the sampling error associated with episodic rhythm monitoring or the monitoring of patient symptoms. The use of burden as a surrogate endpoint for clinical outcome facilitates the demonstration of a biological effect of a therapy on the triggers or substrates responsible for the arrhythmia. Therapies that reduce burden can then be further studied to assess more traditional endpoints. A recent multicenter trial examined the effect of device-based atrial therapies on burden in patients receiving an implantable cardioverter defibrillator (Medtronic 7250 Jewel AF) to treat ventricular tachyarrhythmias. Patients were randomized to 3-month periods of atrial therapies "ON" or "OFF" and subsequently crossed over. The atrial therapies resulted in a reduction of atrial tachyarrhythmia burden from a mean of 58.5 hours/month to 7.8 hours/month (P = 0.007). Based on the evidence of a biological effect of the atrial therapies (burden reduction) studies to determine of the effects of AT/AF prevention and termination algorithms on morbidity and quality of life in ICD recipients are underway.

Atrial pacing lead location alters the effects of atrioventricular delay on atrial and ventricular hemodynamics.

The combined role of atrial pacing lead location and AV timing on cardiovascular performance has not been defined. This study tested the hypothesis that atrial pacing lead location can change the dependence of LA and LV hemodynamics on AV timing in vivo. Dogs anesthetized with isoflurane (n = 8) were instrumented for measurement of hemodynamics including LA pressure, LA volume, and pulmonary venous bloodflow. Data were recorded during normal sinus rhythm, and atrial overdrive pacing from the right atrial appendage (RAA), proximal coronary sinus (CS), and LA lateral wall (LAW). The AV node was then ablated and measurements repeated during synchronous ventricular pacing and during dual chamber pacing from each atrial lead location at various AV delays (20, 60, 120, 180, 240, and 350 ms). Hemodynamics during intrinsic sinus rhythm and overdrive atrial pacing from different sites were similar. In contrast, ventricular or dual chamber pacing caused significant (P < 0.05) changes in cardiac output with different AV timing during RAA (3.5 +/- 0.2 vs 2.9 +/- 0.2 L/min at 120 and 350 ms, respectively) and LAW pacing but not CS pacing. A significant interaction between atrial lead location and AV delay was observed for changes in stroke volume, pulmonary venous blood transport, LA volume, and LV preload. The results indicate that the atrial contribution to cardiac output depends on AV timing and atrial lead location in isoflurane-anesthetized dogs with AV nodal conduction block.

Intrapericardial therapeutics: a pharmacodynamic and pharmacokinetic comparison between pericardial and intravenous procainamide delivery.

INTRODUCTION: Procainamide delivery into the pericardial space may produce a greater and more prolonged electrophysiologic effect, particularly in thin superficial atrial tissue, compared with intravenous delivery. METHODS AND RESULTS: Swine were randomized to sequential procainamide doses delivered intravenously (n = 6) or into the pericardial space (n = 7). The cumulative pericardial doses were 0.5, 1.5, and 3.5 mg/kg, and the intravenous doses were 2, 10, and 26 mg/kg. Pericardial procainamide prolonged right atrial effective refractory period from baseline by 22% (P < 0.01) but only at the 3.5 mg/kg cumulative dose. This dose slowed interatrial conduction time by 14% (P < 0.05) and raised atrial fibrillation threshold by 70 mA (P < 0.05). Pericardial procainamide had minimal effect on ventricular electrophysiology. Similar results occurred with a single 2 mg/kg pericardial dose in a closed chest model. Intravenous 10 and 26 mg/kg cumulative doses prolonged atrial effective refractory period from baseline by 24% and 18% (P < 0.01), respectively. The 26 mg/kg cumulative intravenous dose slowed interatrial and atrial-ventricular conduction times by 27% and 17%, respectively (P < 0.05), raised atrial fibrillation threshold, and slowed ventricular conduction time by 29% (P < 0.05). Pericardial procainamide produced pericardial fluid concentrations ranging from 250 to 1,500 microg/mL, but plasma concentrations were <1 microg/mL. Intravenous procainamide doses produced pericardial fluid concentrations similar to plasma trough concentrations 0 to 12 microg/mL. CONCLUSION: The single 2 mg/kg and 3.5 mg/kg cumulative pericardial procainamide doses prolonged atrial refractoriness and raised atrial fibrillation threshold similar to the 26 mg/kg cumulative intravenous dose, but the duration of effect was similar between delivery methods. Pericardial procainamide did not affect global or endocardial ventricular electrophysiology nor was it associated with ventricular proarrhythmia.

Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients?

OBJECTIVES: This study was designed to analyze the incidence of "dual tachycardia"-ventricular tachycardia (VT) or ventricular fibrillation (VF) preceded by paroxysmal atrial tachycardia (AT) or atrial fibrillation (AF)-in patients receiving dual-chamber implantable cardioverter defibrillators (ICDs). BACKGROUND: Paroxysmal AT/AF occurs commonly in patients who receive ICDs for the treatment of life-threatening VT/VF. Although AF is associated with an adverse prognosis in the setting of structural heart disease, the relationship between AT/AF and VT/VF is unclear. METHODS: We followed 537 patients undergoing implantation of the Jewel AF ICD (Model 7250, Medtronic, Minneapolis, Minnesota) for 11.4 +/- 8.2 months. These included 398 patients with a history of at least two episodes of AT or AF during the preceding year as well as 139 patients enrolled because of VT/VF alone. RESULTS: There were 233 dual tachycardia episodes in 45 patients during follow-up. Overall, 8.9% of episodes detected as VT/VF were dual tachycardias, and 20.3% of patients with VT/VF had at least one dual tachycardia episode. The median duration of AT/AF preceding the first VT/VF detection was 1.09 h (25% to 75% quartile 0.24 to 33.4 h). When AT/AF continued between two consecutive VT/VF detections, the median interdetection interval was 11 min. When AT/AF terminated either because of a ventricular therapy or spontaneously, the median interdetection interval was prolonged to 71 h (p < 0.001). CONCLUSIONS: Dual tachycardia is common in ICD recipients with a history of AT/AF. The duration of AT/AF preceding the first VT/VF detection is < or =1 h about 50% of the time. Termination of the AT/AF significantly delays the time to the next VT/VF detection.