The absence of real-time pulmonary vein isolation during cryoballoon ablation is associated with atrial fibrillation recurrence and pulmonary vein reconnection : Insights from the Middelheim-PVI Registry 2.

BACKGROUND: Absence of real-time pulmonary vein (PV) isolation (PVI) occurring in 15-40% of PVs during cryoballoon ablation (CBA) of atrial fibrillation (AF) raises doubt about adequate PVI. Aim of the present study is to determine whether real-time PVI during CBA is predictive of long-term clinical outcome and durability of PVI. METHODS: Eight hundred three AF patients (64 ± 10 years, 68% males) undergoing CBA were studied. The cohort was divided in 4 groups according to the number of PVs without real-time PVI: none (N = 252 [31.4%]), 1 (N = 255 [31.8%]), 2 (N = 159 [19.8%]), and 3-4 (N = 137 [17.1]). RESULTS: At 3 years, 279 (34.7%) patients had recurrence of AF of which 188 underwent repeat ablation. A vein without real-time PVI was associated with AF recurrence (HR = 1.275; 95% CI 1.134-1.433; p < 0.01), independent of persistent AF type (HR = 2.075; 95% CI 1.584-2.738; p < 0.01), left atrial diameter (HR = 1.050; 95% CI 1.028-1.072; p < 0.01), and diagnosis-to-ablation time (HR = 1.002; 95% CI 1.000-1.005; p = 0.04). Highest success was achieved with present real-time PVI in all veins (77.4%), gradually decreasing per increasing number of absent real-time PVI: 66.3% for 1 vein, 58.5% for 2, and 48.9% for 3-4 veins (p < 0.001). At repeat ablation (N = 188), PV reconnection was seen in 99/430 (23.0%) versus 83/288 (28.8%) veins with and without real-time PVI, respectively (p = 0.08). Right inferior PVs (RIPVs) with real-time PVI were less reconnected than RIPVs without real-time PVI: 29.7% versus 43.7% (p = 0.047). CONCLUSION: The absence of real-time PVI during CBA independently predicts AF recurrence with a 30% gradual decrease in outcome per increase in veins without real-time PVI. Real-time PVI is particularly important for the RIPV to achieve durable PVI.

Electroanatomical mapping improves procedural outcomes of cryoballoon pulmonary vein isolation (the Achieve Plus study).

BACKGROUND: Validation of pulmonary vein (PV) isolation (PVI) using only the Achieve catheter following cryoballoon ablation (CBA) is imperfect since pulmonary vein potentials (PVP) can be recorded in only 50-85% of the veins and residual PVP are found in up to 4.3-7.6% of the isolated veins in remapping studies. OBJECTIVE: To study if addition of electroanatomical mapping to Achieve catheter-guided CBA is superior for PVI. METHODS: One hundred patients were randomized between Achieve catheter-guided CBA (control group; N = 50) and Achieve catheter-guided CBA with additional EnSite voltage maps performed pre- and post-CBA (Achieve Plus group; N = 50). Confirmation of PVI was done by circular mapping catheter (CMC) and EnSite mapping by a second blinded operator. RESULTS: Despite apparent PVI in all PVs after CBA, incomplete PVI was present in 0 out of 50 patients (0%) and 0 out of 204 PVs in the Achieve Plus group versus 6 patients out of 50 (12%; P = 0.012) and 6 out of 203 PVs (3%; P = 0.013) in the control group. All 6 non-isolated PVs could be successfully isolated by additional cryoapplications. Procedure time was longer in the Achieve Plus group (75.76 ± 21.65 vs 66.06 ± 16.83 min; P = 0.014) with equal fluoroscopy times (14.85 ± 6.41 vs 14.33 ± 8.55; P = 0.732). CONCLUSION: The addition of electroanatomical EnSite mapping to the Achieve catheter improves the PVI rate of CBA and could be considered for future use. Design and Results of the Achieve Plus study. The Achieve Plus study shows that the addition of electro-anatomical EnSite mapping to the Achieve catheter improves PVI rate of CBA and could be considered for future use. See text for further explanation. ABBREVIATIONS: CBA: cryoballoon ablation; PVI: pulmonary vein isolation.

Diagnosis-to-ablation time as a predictor of success: early choice for pulmonary vein isolation and long-term outcome in atrial fibrillation: results from the Middelheim-PVI Registry.

Aims: The aim of the study is to define long-term outcome of pulmonary vein isolation (PVI) in atrial fibrillation (AF) and to determine whether time window between AF diagnosis and PVI affects outcome. Methods and results: Consecutive AF patients undergoing PVI (2006-14) were followed for 5 years. Primary outcome was clinical success, defined as freedom of documented AF without anti-arrhythmic drugs respecting a 1-month blanking period. A 1000 patients were included (age 60 ± 10 years, CHA2DS2-VASc score 1 ± 1). The cohort was divided in four quartiles (Q) according to the diagnosis-to-ablation time (DAT): Q1 DAT 0-11 months (N = 244), Q2 DAT 12-≤33 months (N = 254), Q3 DAT 34-≤70 months (N = 252) and Q4 DAT 71-360 months (N = 250). Mean follow-up was 44.3±21.0 months. At 5 years, clinical success was achieved in 45.2 ± 2.0% of patients. Independent predictors of clinical success were AF type (HR = 0.61; 95%CI 0.50-0.74; P < 0.0001), left atrial size (HR = 1.03; 95%CI 1.02-1.05; P < 0.0001), DAT (HR = 1.00; 95%CI 1.00-1.00; P = 0.001), ablation technique (P = 0.012), and year of ablation (HR = 0.93; 95%CI 0.86-1.00; P = 0.045) in multivariable-adjusted analysis. The highest clinical success was achieved when PVI was performed within the first year, and gradually declined with increasing DAT: 55.9 ± 4.6% for Q1, 46.9 ± 4.0% for Q2, 45.5 ± 3.6% for Q3, and 35.5 ± 3.6% for Q4 (P < 0.001). Conclusion: Long-term success rate of PVI is 45.2 ± 2.0%. Shorter diagnosis-to-ablation times are associated with better clinical success. Our data advocate for early PVI following diagnosis of AF.

Duty-cycled multi-electrode radiofrequency vs. conventional irrigated point-by-point radiofrequency ablation for recurrent atrial fibrillation: comparative 3-year data.

AIMS: Pulmonary vein isolation (PVI) is an accepted treatment to relieve symptoms in patients with atrial fibrillation (AF). We studied 3 year outcome after PVI guided by duty-cycled multi-electrode radiofrequency (RF) ablation (pulmonary vein ablation catheter, PVAC) and provided comparative data to outcome after conventional PVI (CPVI) using mapping with irrigated, point-per-point RF ablation. METHODS AND RESULTS: One hundred and sixty-one consecutive patients with symptomatic paroxysmal or persistent AF and minimal heart disease underwent PVI (PVAC, n = 79 vs. CPVI, n = 82). Follow-up (with symptom-guided rhythm monitoring) was truncated at 3 years in all patients. Success was defined as freedom of documented arrhythmia after a single procedure and without antiarrhythmic drug treatment (ADT). Baseline characteristics did not differ between both groups. At 3 years follow-up, single-procedure success without ADT was comparable between PVAC and CPVI (65% vs. 55%, P = NS). The majority of recurrences occurred during the first year (PVAC 79% vs. CPVI 70%, P = NS). The annual rate of very late recurrence (i.e. beyond 1 year) was similar in both groups (10.5% vs. 15%, P = NS). CONCLUSION: At 3 years follow-up, outcome after PVAC-guided PVI is comparable to conventional isolation by irrigated point-by-point RF ablation. In both strategies, the majority of recurrences occurred in the first year of ablation.

Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy.

An important feature of cancer is dysregulation of gene activity and gene expression, which is driven by a combination of acquired genetic and epigenetic alterations. Here, we will highlight how insights into the epigenetic processes underpinning tumor biology have led to the emerging field of cancer pharmaco-epigenomics. First, we will discuss how interference with the epigenetic machinery in cancer is leading to novel promising therapies, with several DNA methyltransferase and histone deacetylase inhibitors being approved for cancer treatment. Second, we will discuss how epigenetic markers in cancer may increasingly be used as complementary diagnostic tools, prognostic markers of disease progression, and predictive markers of treatment response. Although the anti-tumoral activities of epigenetic therapies have thus far been attributed to reactivation of silenced tumor-suppressor and/or apoptotic genes, they may also influence the tumor environment by directly affecting stromal cells. As an example, we will discuss how tumor-endothelial cells are regulated at the epigenetic level and are affected by methyltransferase and histone deacetylase inhibitors.

Genetic evidence for a role of IL33 in nasal polyposis.

BACKGROUND: Little is known about the genetic factors that contribute to nasal polyposis (NP). A genome-wide association study identified 10 single nucleotide polymorphisms (SNPs) associated with eosinophilia. As eosinophils play a key role in the pathogenesis of NP, we assessed if any of these SNPs contribute to genetic susceptibility of NP. METHODS: We recruited 284 patients with NP in four participating hospitals in Belgium and 427 healthy controls, and genotyped 10 SNPs affecting eosinophilia (rs1420101 in IL1RL1, rs12619285 in IKZF2, rs4431128 in GATA2, rs4143832 in IL5, rs3184504 in SH2B3, rs2416257 in WDR36, rs2269426 in MHC, rs9494145 in MYB, rs748065 in GFRA2, and rs3939286 in IL33) using MALDI-TOF. A two-stage design was used while correcting for multiple testing. RESULTS: First stage analysis, involving 150 NP patients and 250 controls, identified rs3939286 nearby IL33 as a susceptibility factor for NP. Per at-risk A-allele, rs3939286 increased the risk for NP with an odds ratio (OR) of 1.60 (95% CI = 1.16-2.22; P = 0.0041). Second stage replication analysis in another 123 NP patients and 165 controls confirmed this association (OR = 1.43; CI = 1.00-2.06; P = 0.046). The combined analysis of both stages revealed an OR of 1.53 (CI = 1.21-1.96; P = 0.00041). Given the association of IL33 with NP, we also investigated rs1420101 in IL1RL1, which is the receptor for IL33. Although rs1420101 itself failed to associate with NP, a combined risk assessment of rs3939286 and rs1420101 further increased the risk for NP. CONCLUSION: We provide unprecedented genetic evidence suggesting a role for the IL33 pathway in the pathogenesis of NP.

Beneficial effects of prolonged systemic administration of PlGF on late outcome of post-ischaemic myocardial performance.

Recent evidence indicates that an imbalance between cardiomyocyte hypertrophy and blood vessel growth in the remote myocardium may contribute to heart failure in ischaemic heart disease. It remains, however, largely unknown which angiogenic factors are capable of stimulating vessel growth in the remote myocardium after myocardial infarction (MI) and whether systemic, rather than local, administration of such factors suffices to ameliorate post-MI cardiac recovery. We therefore analysed the effect of systemic placental growth factor (PlGF) delivery on myocardial recovery post-MI in mice. MI was induced by permanent ligation of the left anterior descending coronary (LAD) artery in C57Bl6/J mice, followed by systemic injection of a PlGF adenovirus, resulting in elevated circulating levels of PlGF for 4 weeks. Functional and morphological analysis revealed that PlGF treatment induced cardiomyocyte hypertrophy and improved cardiac recovery at day 28 post-MI. PlGF stimulated angiogenesis in the infarct border and vessel enlargement in the remote myocardium. In this mouse model, capillary-to-cardiomyocyte ratios in the remote myocardium were maintained post-MI, but PlGF increased the vascular perfusion area in balance with the cardiomyocyte hypertrophy. Overall, systemic delivery of PlGF improves cardiac performance and promotes adaptive remodelling of the post-MI heart.

Clinical and fundamental aspects of angiogenesis and anti-angiogenesis.

Insight into the fundamental physiological mechanisms of blood vessel development and neoformation has led to the discovery of multiple angiogenic growth factors and inhibitors. To date, at least 5 angiogenesis inhibitors are readily available for clinical use, mainly in the treatment of cancers and age-related macular degeneration. More inhibitors are yet to come and the indications for their clinical use are expected to broaden. Conversely, the use of angiogenic stimulators, although initially promising in animal models and in small uncontrolled pilot studies in patients with ischaemic heart disease or peripheral arterial occlusive disease, could thus far not show any convincing therapeutic improvement. Challenges still remain as to which angiogenic factor or combination of factors should be administered and in which form (protein versus gene), and what route and duration of administration should be used. Further clinical perspective might come from the recent identification of vascular endothelial growth factor (VEGF) as a modifier of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), and as a promising therapy in the treatment of ALS in preclinical animal models. This review discusses the different clinical trials of angiogenic inhibitors and stimulators, preceded by some fundamental aspects of angiogenesis, giving the clinician a brief overview of the most relevant angiogenic topics.

Brown tumour: presenting symptom of primary hyperparathyroidism.

The skeletal lesions of primary hyperparathyroidism, including brown tumour, are rare nowadays, with the practice of checking serum calcium levels leading to an earlier diagnosis of hyperparathyroidism. Clinical, laboratory, radiographic and histological investigations can lead to a correct diagnosis. Treatment of brown tumour focuses on the hyperparathyroidism, and is usually followed by a regression of the brown tumour. The diagnosis of hyperparathyroidism and brown tumour should be considered in patients with hypercalcaemia and an osteolytic expansive bone lesion. We present a patient where a brown tumour of the mandible was the presenting symptom of primary hyperparathyroidism.