or Pulmonary Veins Disconnection?
A. PROCLEMER1, D. PAVONI1, D. FACCHIN1, M. CROSATO1, R. OMETTO1, M. BONANNO2
Introduction
Radiofrequency (RF) ablation of the atrioventricular node followed by pace- maker implantation, so-called ablate and pace (AP), is now a well-accepted therapy in patients with disabling or medically refractory atrial fibrillation (AF). This therapy is used in patients affected by both paroxysmal and chronic or persistent AF [1].
This review will consider first the intermediate and long-term outcomes of AP [2, 3], followed by a description of the pulmonary veins (PVs) electri- cal disconnection techniques, analysing in detail the immediate and interme- diate outcomes and the possible complications.
Treatment of Atrial Fibrillation by Ablate and Pace
Fifteen years after its introduction into clinical practice, a substantial amount of data (long-term outcomes, identification of the best candidates for this therapy, short-term complications and those occurring during follow-up) on AP therapy for refractory AF have accumulated. The following is a synopsis of some representative studies based on large multicentre pop- ulations and meta-analyses.
Wood et al. [2] quantified the effects on the main clinical outcomes and survival with a large meta-analysis that included 21 AP studies comprising a total of 1181 patients, 97% with refractory AF and 3% with flutter or atrial tachycardia. The outcome analysis consisted of 642 patients who were enrolled in 15 studies and followed-up for a period of time that ranged from
1U.O. Cardiologia Ospedale S.M. Misericordia, Udine;2U.O. Cardiologia Ospedale S.
Bortolo, Vicenza, Italy
48 days to 2.3 years. The mortality analysis included 1073 patients in 16 studies who were followed for 3 months to 2.3 years. The authors concluded that in patients with refractory atrial tachyarrhythmias AP therapy signifi- cantly decreased symptoms and the need for health care resources, while improving quality of life (QOL), ejection fraction, and exercise tolerance.
Also, total and sudden mortality rates, (6.3%/year and 2%/year, respectively) were similar to, if not better than, those reported in other trials that included AF patients who did not undergo AP.
Gasparini et al. [3] reported similar results in a multicentre retrospective study that measured the long-term incidence of sudden death following treatment with AP. This study included 585 patients (mean age 66 years) with paroxysmal AF (n = 308) or chronic, symptomatic, refractory AF (n = 277), with associated organic heart disease in 71% of the patients. Mean fol- low up was 33.6 months; total mortality at 1 year was 4.88%, and sudden mortality 1.04% (predictive factors for these events were underlying heart disease and ejection fraction < 45%). The authors concluded that patients who had AP therapy for refractory atrial tachyarrhythmias had a lower risk of sudden death during follow-up. It was also noted that left ventricular dys- function secondary to the underlying heart disease appeared to be the main predictive variable for such an event.
At the Mayo Clinic, Ozcan et al. [4] analysed a population of 350 consecu- tive patients (mean age 68 years) treated with AP between 1990 and 1998, and compared their survival to that of a subgroup of consecutive patients (mean age 67 years) treated pharmacologically for AF in the same institu- tion, and with another subgroup (control) made up of Minnesota residents matched for age and gender. Mean follow up was 37 months and total mor- tality rate was 22%. The survival curve for the AP group was significantly worse than that of the control group (general population) (P < 0.001), while it was similar to that of the patients treated pharmacologically (P = 0.044).
Factors predicting death, without which the observed survival would have been similar to that of the control population, were found to be history of previous myocardial infarction (P < 0.001), congestive heart failure (P = 0.02), and t reat ment w ith cardiac dr ugs af ter ablat ion (P = 0.03).
Notwithstanding the limitation due to the retrospective nature of the study, the authors concluded that control of the ventricular rate and symptoms improvement in patients undergoing AP therapy did not influence negatively the prognosis and that AP was at least as safe as the traditional pharmaco- logical treatment for AF.
Our study population consisted of 103 consecutive patients who under- went AP in our unit from January 1, 1994 to December 31, 1998 for atrial tachyarrhythmias (mean age 67 ±1 0 years; 45 males); 61% had a docu- mented organic heart disease (14% ischaemic heart disease). At the time of
the AP procedure, 13.6% of the patients were in NYHA III or IV functional class, and 14.6% had a ≤ 40% ejection fraction (EF). In terms of type of arrhythmia, AF was present in 81 patients (79%) – paroxysmal in 23%, and chronic in 56% of these patients. The indications for AP in the remaining 22 patients (21%) were atypical atrial flutter or atrial tachycardia (Table 1).
Mean follow-up was 56 ± 23 months - one patient with valvular heart disease and EF 40%, experienced sudden death 17 months after AF. During follow- up, the study population showed a gradual and persistent clinical improve- ment; only 4.8% of the patients were in NYHA III or IV functional class at the last follow-up (Table 2, Fig. 1).
Table 1.Clinical characteristics at the moment of enrolment, of patients with atrial tachyarrhythmias treated with Ablate and Pace in Udine and Vicenza hospitals between 1994 and 1998
Total patients Alive patients Dead patients
(n = 103) (n = 86) (n = 17)
Sex
Male 57 47 10
Female 83 70 13
Age when treated (years) 67 ± 10 66 ± 10 71 ± 9
Ischaemic heart disease 18 15 3
Dilated cardiomyopathy 20 13 7
Valvular heart disease 29 25 4
Hypertension 14 11 3
Hypertrophic cardiomyopathy 4 4 0
Congenital heart disease 2 2 0
No heart disease 53 47 6
Ejection fraction
> 50% 88 80 8
40–50% 29 19 10
< 40% 33 18 5
NYHA class
I 91 75 16
II 35 30 5
III 12 10 2
IV 2 2 0
Type of arrhythmia
Paroxysmal atrial fibrillation 47 43 4
Chronic atrial fibrillation 57 43 14
Paroxysmal atrial flutter 14 12 2
Chronic atrial flutter 2 2 0
Paroxysmal atrial tachycardia 6 5 1
Sinus dysfunction 14 12 2
No. antiarrhythmic drugs 2.3 ± 2.0 2.5 ± 2.1 1.8 ± 1.4 Implanted PM type
VVIR 74 56 18
DDDR 66 61 5
Table 2.Events during the follow-up period in patients with atrial tachyarrhythmias treated with Ablate and Pace in Udine and Vicenza hospitals between 1994 and 1998
Total patients Alive patients Dead patients
(n = 103) (n = 86) (n = 17)
Follow-up (months) 56 ± 23 55 ± 22 27 ± 18
Mortality
(months from treatment) 27 ± 16 27 ± 16
Cause of death
Heart failure 2 2
Sudden death 1 1
Other 9 9
Unknown 11 11
Ventricular fibrillation 2 1 -
Admission for heart failure 21 18 3
Heart transplantation 3 3 -
NYHA class
I 80 68 12
II 18 14 4
III 5 4 1
IV 0 0 0
Drugs
Oral anticoagulant (OA) 73 60 13
Antiaggregation (AG) 16 16 0
No therapy AO/AG 14 10 4
Fig. 1.Event-free survival from total mortality, cardiac arrest, heart failure in patients with or without heart disease after Ablate and Pace
Comments on the AP Therapy
As demonstrated by observational and randomised studies [3, 5–7] and a recent meta-analysis [2], AP therapy in patients with highly symptomatic or medically refractory AF results in significant short-term and medium-term improvement of the QOL main indicators, a reduction in hospital admis- sions, a decrease in AF-related symptoms, an increase in left ventricular function, especially in patients with reduced EF, and an increased exercise tolerance [1, 8]. These results are likely due to heart rate control and normal- isation with the PM and, probably, to the reduction of the negative effects of the cardioactive drugs, such as the proarrhythmic or negative inotropic ones. In analysing the results obtained with AP therapy, it should be noted that the majority of patients presented with a major heart disease, decreased left ventricular function, a clearly enlarged left atrium, and advanced age (mean 65–70 years).
There are, however, some negative aspects to be considered, such as life- long dependency on the PM, the nonphysiologic, electrically induced cardiac activation (right ventricular apical pre-excitation), and both the absence of preventive effects in terms of paroxysmal AF attacks and the evolution toward chronic AF due to the commonly used PMs without dedicate pacing algorithms. Moreover, a recent sub-analysis of the PA study [4] showed a sig- nificant increase in AF burden after AP therapy in patients with paroxysmal AF in spite of continued antiarrhythmic pharmacological therapy [9]. This increase has been attributed to the loss of AV and/or interventricular syn- chronism and to the subsequent increase in atrial wall stress, and to a neu- roendocrine negative balance. Also, this study observed a slight reduction in fractional shortening in patient with a baseline value > 30% (from 39.4 to 36.4%), while in subjects with baseline values ≤ 30% before AP therapy this parameter registered a significant increase (from 27 to 33.6%).
Patients with idiopatic tachyarrhythmias showed favourable survival rates compared to those with congestive heart failure, previous myocardial infarction and need for cardioactive drug therapy. Mortality in this group of patients was, however, comparable to that of subjects with less severe AF treated only with pharmacological therapy.
The rate of sudden death seemed to be rather low both in the short-term and long-term, and mostly due to the underlying heart disease rather than the AP procedure.
In our study, the results obtained with AP remain favourable even in the long-term (mean follow-up 52 months), as demonstrated by a persistently good functional class in most of the patients and the reduced number of admissions for heart failure. The long-term complications due to cardiac pacing appear to be negligible.
Electrical Isolation/Disconnection of the Pulmonary Veins
The evidence that paroxysmal AF (PAF) in patients without heart disease or with minor structural alterations, originates, most of the time, in the PVs has opened a new era in the non-pharmacological treatment of AF [10, 11].
Increasingly numerous studies have shown that PAF attacks can be eliminat- ed by suppressing the extra-systolic atrial triggers by RF ablation inside the PVs or by disconnecting these veins electrically by RF at the atriopulmonary junction [10, 11]. In the first case, the procedures were characterised by very long mapping times and a noticeable rate of PV stenosis, whereas in the sec- ond case the main endpoint used was the empirical elimination of all the electrical potentials inside each PV, obtained primarily during sinus rhythm or during right ventricle and coronary sinus pacing [12–15]. At the present, this procedure, defined as electrical disconnection of the PVs, is considered the most effective because it blocks, both at the entrance and at the exit, the venous impulses that could be responsible for the initiation and persistence of the AF.
Several mechanisms have been hypothesised to explain the clinical effec- tiveness of the electrical disconnection [16]: (1) formation of a complete, total-depth circumferential lesion with interruption of the veno-atrial con- necting muscle; (2) partial damage of the veno-atrial junction fibres to make both the activation, due to an intra-venous arrhythmogenic focus, and its propagation to the adjacent atrial muscle more difficult; (3) interruption at the junction level of the re-entry pathways that initiate or maintain AF; (4) interruption of the rotors or other arrhythmogenic foci located in the left atrial posterior wall; (5) interruption/modification of the fibres and parasympathetic ganglia situated at the PV ostia, considered decisive in the AF pathogenesis in apparently healthy hearts [17]. The presumption is that the achievement of points 3 and 4 is the reason for the operative successes reported with peri-venous circumferential ablation techniques performed on larger areas.
Short-Term Results
In patients with PAF, the rate of clinical success with RF ablation aimed at atriopulmonary junction electrical disconnection varied between 60 and 80% according to the data reported by the most important laboratories (Table 3). Often, however, it is necessary to perform multiple procedures for late AF recurrences, which occur in 6–54% of patients after 30–60 days from the first procedure. Early recurrences could be due to a local, transitory pro- arrhythmic irritation. In 10% of patients with late recurrences, there can be an improvement of symptoms by using anti-arrhythmic drugs previously considered ineffective. In this case, the class 1C drugs best extend the RF
ablation effectiveness, because, acting on the sodium channels, they decrease even further the already compromised conduction at the atriopulmonary junction and modify favourably the atrial substrate.
In a small number of patients it is also necessary to eliminate arrhythmo- genic foci located outside the PVs. In 4–11% of such cases triggers can be found inside the superior vena cava, while in an other 10–15% AF can origi- nate in the coronary sinus, near the crista terminalis in the right atrial poste- rior wall or in Marshall’s vein. The electrical isolation of these structures increases the ablation efficacy by another 10–20% [18]. It must be remem- bered that most of the patients treated had idiopathic AF, preserved left ven- tricular function, and left atrial dimension at the upper limits of normal or only slightly elevated.
In patients with persistent or permanent AF, PV disconnection alone resulted in a significantly lower rates of success (40%) [13, 14]. In these cases, the complexities of the anatomofunctional substrate required the cre- ation of other lesion lines to reduce the critical electrical mass. Additional lines between the lateral mitral ring and the left inferior PV or between the right superior and the left superior PVs, in concomitance with RF delivery inside the coronary sinus to obtain a conduction block at the level of the lat- eral mitral isthmus, can increase the rate of success to 60–80% depending on the study and the use of anti-arrhythmic drugs.
The Mayo Clinic group analysed the clinical-instrumental factors capable of predicting the efficacy of the PV electrical disconnection [19]. Paroxysmal
Table 3.Outcomes of ablation of paroxysmal atrial fibrillation
Author N. of No AA drugs AA drugs Follow-up
patients N° % N° % (months)
Haïssaguerre [10] 45 28 62 NA NA 8 ± 6
Chen [11] 79 68 86 10 13 6 ± 2
Pappone [14] 179/251 148 83 4 2 10 ± 5
Gerstenfeld 41 29 70 6 15 9 ± 2
Macle/Haïssaguerre 136 90 66 20 15 9 ± 5
Marrouche 102/190 96 94 4 4 9 ± 3
Oral/Morady 58/70 41 70 NA NA 5 ± 3
Magrum/Haines 64 42 66 NA NA 13 ± 7
Deisenhofer 75 38 51 NA NA 230 ± 133
Packer [19] 203 104 70 15 10 15 ± 5
AA Anti-arrhythmic
AF, AF duration, the adjunctive creation of the conduction block at the cavotricuspid isthmus level, the use of intracardiac echography and, to a lesser degree, the normal size of the left ventricle were all associated, in a univariate analysis, with significant control of AF recurrences.
The success of the electrical disconnection, however, must take into account the risk of complications related to the procedure [10–20]. These include PV stenosis, with an incidence of between 2 and 40% depending on the various experiences and the severity of the disease, cardiac tamponade (1–3%), damage to the phrenic nerve (1.2%), cerebral emboli (1–3%), and severe bradycardia (1%). The rate strictly dependent on the experience of each centre, and on the techniques used (cooled-tip catheters, RF delivery outside the PV ostium, nonfluoroscopic mapping systems, intracardiac echography). Intracardiac echography allows real-time monitoring of the position of the ablating and mapping catheters, and of the formation of microbubbles indicating parietal damage.
Intermediate-Term Results
A clear evaluation of the clinical efficacy of PV electrical disconnection as a definite treatment requires studies that compare this approach to the best pharmacological, electrical, and traditional ablative (AP) therapies. At pre- sent, only few studies have done so. Pappone et al. [20] compared the clinical outcomes of 589 patients undergoing circumferential PV ablation with elec- tro-anatomic mapping to those of 582 patients treated with drugs. The sub- jects in the first group showed a higher survival rate, a decrease in co-mor- bidities such as cardiac insufficiency and cerebrovascular accidents, and a reduction in recurring AF. An improvement in QOL was also observed in a subgroup treated with ablation, a finding also confirmed by a recent experi- ence at the Mayo Clinic.
Most authors, however, still feel the need for a large-scale validation of the ablation therapy and an evaluation of its economic impact.
Conclusions
At present, AP therapy in patients with paroxysmal or permanent drug refractory AF constitutes a valid alternative in the presence of major heart disease, advanced age (> 70 years), significant left atrial dilatation, impor- tant co-morbidities, and patient’s preference. The high short-term success rates (95–100%), low complication rates, low incidence of sudden death (<
2%/year), the favourable comparison with a matching population, and the positive data regarding improvement in QOL suggest the validity of this therapeutic strategy in specific subgroups of patients [21].
Therapy based on PV electrical disconnection and RF suppression of extravenous arrythmogenic foci is undoubtedly a fascinating solution from the physiopathologic viewpoint. The short-term result obtained in selected patients with idiopathic AF or minor heart disease look promising, even if limited to high-level laboratories dedicated to such therapy. There is a need for randomised studies to rigorously evaluate the long-term effects of this therapy.
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