Individualized or fixed approach to pulmonary vein isolation utilizing the fourth-generation cryoballoon in patients with paroxysmal atrial fibrillation: the randomized INDI-FREEZE trial.

AIMS: Cryoballoon (CB) based pulmonary vein isolation (PVI) is a widely used technique for treatment of atrial fibrillation (AF); however the ideal energy dosing has not yet been standardized. This was a single-centre randomized clinical trial aiming at assessing the safety, acute efficacy, and clinical outcome of an individualized vs. a fixed CB ablation protocol using the fourth-generation CB (CB4) guided by pulmonary vein (PV) potential recordings and CB temperature. METHODS AND RESULTS: Patients were randomized in a 1:1 fashion to two different dosing protocols: INDI-FREEZE group (individualized protocol): freeze-cycle duration of time to effect plus 90 s or interruption of the freeze-cycle and repositioning CB if a CB temperature of -30°C was not within 40 s. Control group (fixed protocol): freeze-cycle duration of 180 s. No-bonus freeze-cycle was applied in either patient group. The primary endpoint was freedom from atrial tachyarrhythmia at 12 months. Secondary end points included procedural parameters and complications. A total of 100 patients with paroxysmal AF were prospectively enrolled. No difference was seen in the primary endpoint [INDI-FREEZE group: 38/47 (81%) vs. control group: 40/47, (85%), P = 0.583]. The total freezing time was significantly shorter in the INDI-FREEZE group (157 ± 56 s vs. 212 ± 83 s, P < 0.001), while procedure duration (57.9 ± 17.9 min vs. 63.2 ± 20.2 min, P = 0.172) was similar. No differences were seen in the minimum CB and oesophageal temperatures as well as in periprocedural complications. CONCLUSION: Compared to the fixed protocol, the individualized approach provides a similar safety profile and clinical outcome, while reducing the total freezing time.

Initial experience and procedural efficacy of pulmonary vein isolation using the fourth-generation cryoballoon - a step forward?

Background: Cryoballoon (CB)-based pulmonary vein isolation (PVI) is an established treatment modality for patients suffering from paroxysmal or persistent atrial fibrillation (AF). Recently, the novel fourth-generation cryoballoon (CB4) was introduced which mainly provides a 40% shorter distal tip as compared to the second-generation cryoballoon (CB2). This two-centre analysis sought to assess the primary efficacy of the 28 mm CB4 for PVI and the feasibility of real-time signal recordings from the PVs considering the time-to-isolation (TTI).Methods and results: Eighty-four patients with paroxysmal or short-standing persistent AF underwent CB4-based PVI at two different hospitals. Individual freeze-cycle duration was set at TTI + 120 seconds. No bonus freeze was applied. A total of 331 pulmonary veins (PVs) including five left common PVs were identified and all PVs were successfully isolated. Mean freeze-cycle duration was 165.7 ± 31.5 seconds. The mean minimal CB temperature was -45.6 ± 7.6 °C with a real-time PVI visualisation rate of 78% (67/84 (79.8%) RSPVs, 55/84 (65.5%) RIPVs, 67/79 (84.8%) LSPVs, 66/79 (83.5%) LIPVs and 2/5 (40%) LCPV). Transient phrenic nerve palsy occurred in 2/84 (2.4%) patients during cryo-application along the RSPV.Conclusions: The novel CB4 provides both, a high acute efficacy and a high rate of real time electrical PV-recordings, thus facilitating individual ablation strategies based on TTI.

Dosing of the second-generation cryoballoon using acute time-to-pulmonary vein isolation as an indicator of durable ablation in a canine model.

BACKGROUND: Rigid time-based dosing protocol(s) currently used in the clinic for cryoballoon ablation of atrial fibrillation may be inadequate to guide the circumferential and transmural cryothermal energy transfer across the pulmonary vein (PV) and may result in injury to collateral tissues or electrical gaps between the PV and left atrium (LA). OBJECTIVE: A physiologic endpoint (e.g., acute time-to-PV isolation a.k.a. time-to-effect; TTE) may be effective in the determination of a transmural lesion formation and may allow for individualized ablation dosing across each PV. METHODS: Thirty PVs from 15 dogs were randomized into five dosing protocols, including (1) TTE + 60 s, (2) TTE + 90 s, (3) TTE + 120 s, (4) TTE + 150 s, and (5) 2 × 180 s. Ablations were conducted with a 23-mm second-generation cryoballoon, and TTE was assessed during a freeze by pacing from an inner balloon-lumen circular diagnostic catheter to a quadripolar diagnostic catheter in the coronary sinus. After ablation, animals were survived for 30 to 34 days, and repeat electrophysiology assessment of PV isolation was conducted after which animals were euthanized for gross anatomy and histological examination. RESULTS: At study termination, efficacy endpoint evaluations were based on maintenance of PV electrical isolation, gross anatomy assessment of PV lesions, and histological examination of PVs. Five efficacy endpoint failures were noted, including the following: 1 PV in the TTE + 90 sec group; 2 PVs in the TTE + 120 sec group; 1 PV in the TTE + 150 s group; and 1 PV in the 2 × 180 s group. Regarding safety, one phrenic nerve injury was observed in the 2 × 180 s cohort. No other complications were observed. CONCLUSIONS: In a canine model, effective PV isolation could be found even in the shortest duration dosing cohort (TTE + 60 s). One complication (phrenic nerve injury) was observed in the longest duration dosing group (2 × 180 s). Further studies will be required to correlate these results to a 28-mm cryoballoon (more commonly used in the cryoablation of a human LA); however, to date, this is the first reporting of a successful cryoablation using TTE + 60 s dosing (approximately 90 s total duration of freezing).

Time-limited cryomapping during tachycardia: improved long-term outcomes for cryoablation of AVNRT.

PURPOSE: Cryothermal ablation (CTA) for atrioventricular nodal reentrant tachycardia (AVNRT) is considered safer than radiofrequency ablation (RFA) since it eliminates the risk of inadvertent AV block. However, it has not been widely adopted due to high late recurrence rate (LRR). In an effort to improve LRR, we evaluated a new approach to cryothermal mapping (CTM): "time to tachycardia termination" (TTT). METHODS: This single-center study had 88 consecutive patients who underwent CTA using TTT for AVNRT. The CTA catheter was positioned in sinus rhythm at the posteroseptal tricuspid annulus, and then AVNRT was induced. The CTA target site was identified by prompt tachycardia termination in ≤20 s during CTM. Procedural success was defined as no inducible AVNRT and ≤1 single AV nodal echoes. RESULTS: Acute procedural success was achieved in 87 of 88 patients (98.9 %) and was similar to prior studies for both CTA and RFA. No permanent AV block was observed. LRR was 3.7 % at a mean follow-up of 19.7 months. LRR was equivalent to that commonly reported for RFA and improved when compared to conventional CTA. CONCLUSION: TTT for CTA of AVNRT provides enhanced safety and similar long-term efficacy when compared to RFA. Based upon this experience, TTT provides an enhancement to conventional CTA that appears to result in improved long-term outcomes. In light of these findings, it seems reasonable to undertake additional randomized trials to determine whether RFA or CTA using TTT is the optimal approach for the catheter ablation of AVNRT.

Relationships between the risk of cardiovascular disease in type 2 diabetes patients and both visit-to-visit variability and time-to-effect differences in blood pressure.

AIMS: To determine whether visit-to-visit blood pressure (BP) variability can predict cardiovascular disease (CVD) incidence in type 2 diabetes patients independently of mean BP, and to analyze the time-to-effect relationship between BP and CVD risk. METHODS: We retrospectively enrolled 629 type 2 diabetes patients with no history of CVD who first visited our hospital between 1995 and 1996, made at least one hospital visit per year, were followed-up for at least 1 year, and had undergone four or more BP measurements. The patients were followed until June 2012 at the latest. RESULTS: CVD occurred in 66 patients. Variability in systolic or diastolic BP (SBP and DBP, respectively) was a significant predictor of CVD incidence, independent of mean SBP or DBP. CVD incidence was significantly associated with SBP during the preceding 3-5 years, with the highest risk occurring during the preceding 3 years. CONCLUSIONS: Visit-to-visit BP variability independently predicts CVD incidence in type 2 diabetes patients. Increased SBP over the preceding 3-5 years indicated a significant CVD risk. To prevent CVD, BP management should focus on stable and well-timed control. In particular, BP stabilization at an early phase and BP control during late phases are important.

Time-to-effect relationships between systolic blood pressure and the risks of nephropathy and retinopathy in patients with type 2 diabetes.

AIMS: To analyze time-to-effect relationships between systolic blood pressure (SBP) and the risks of development of nephropathy and retinopathy in patients with type 2 diabetes. METHODS: We retrospectively enrolled 647 patients with type 2 diabetes who first visited our hospital between 1995 and 1996, made ≥1 hospital visit per year, had been followed-up for ≥1year, and had undergone ≥4 SBP measurements. Of these, 352 with normoalbuminuria and 516 without retinopathy were followed through June 2012. RESULTS: Nephropathy developed in 90 patients and retinopathy in 113. Hazard ratios (HRs) for time-dependent SBP-associated nephropathy and retinopathy were the highest during 1year preceding each endpoint or censoring. The HRs for nephropathy had been steadily lower during the preceding 1-17 years, while that for retinopathy had been lower during the preceding 1-5 years and constant during the preceding 5-17 years. CONCLUSIONS: The time-to-effect relationship with SBP differed for the development of nephropathy and retinopathy. The long-term effect was obvious for nephropathy and borderline for retinopathy, while the short-term effect was stronger and evident for both. Continuous SBP lowering is necessary to prevent nephropathy, whereas SBP control during the preceding 5years seems to be important to prevent retinopathy.