Pacing From the Right Ventricular Septum and Development of New Atrial Fibrillation in Paced Patients With Atrioventricular Block and Preserved Left Ventricular Function

Abstract

Background: Whether pacing from the right ventricular (RV) septum improves prognosis is unclear. Furthermore, the clinical characteristics of patients who develop atrial fibrillation (AF) and cardiovascular events during long-term RV septal pacing have not been described.

Methods and Results: We retrospectively evaluated the incidence of AF and cardiovascular events, including cardiac death, heart failure requiring hospitalization, or stroke, for a median of 4.0 years in 123 recipients of dual-chamber pacemakers implanted for atrioventricular block with preserved left ventricular function, who were free from AF before device implantation. AF developed in 30 patients (24%), and multivariable analysis suggested that the cumulative percentage of RV pacing was the only independent predictor of newly developed AF (hazard ratio: 1.19 for each 10% increment; 95% confidence interval: 1.04–1.41; P=0.01). Furthermore, older age, newly developed AF and a paced QRS duration ≥155 ms at pacemaker implantation were significant predictors of cardiovascular events.

Conclusions: RV septum pacing may induce AF in up to one-quarter of patients paced for atrioventricular block, according to the frequency of pacing. More importantly, in such patients, AF induced by RV pacing and a paced QRS duration ≥155 ms at pacemaker implantation are significantly associated with poor prognosis. Therefore, we recommend pacing from sites producing a paced QRS duration <155 ms and avoiding unnecessary RV pacing. (Circ J 2016; 80: 2302–2309)

Long-term right ventricular (RV) apical pacing is known to increase the risk of left ventricular (LV) dysfunction, the incidence of atrial fibrillation (AF), and hospitalization for heart failure (HF) in patients with sinus node disease.^1,2 Pacing from the RV apex has been shown to cause mechanical dyssynchrony, limited myocardial blood flow, and depressed LV ejection fraction (LVEF).³ To minimize the risk of such side effects, it has been suggested that the RV septum may serve as a suitable alternative pacing site. Recent data demonstrated that, compared with RV apical pacing, RV septal pacing shows less dyssynchrony and abnormalities in the motion of the LV wall.^4,5 However, potential adverse effects of RV septal pacing on left atrial function may take longer to manifest. Zhang et al reported that cardiac events developed after 3 years of RV apical pacing.⁶ Meanwhile, to the best of our knowledge, the few clinical studies that have focused on the effects of RV septal pacing analyzed data from short follow-up periods.^7–9 Therefore, the long-term prognosis of patients with RV septal pacing remains unclear, especially with respect to the incidence of AF potentially induced by RV pacing.

Although RV septal pacing has been established as ventricular lead placement, no study has shown that septal pacing contributes to an improved prognosis.^7,10 Pacing itself may reduce cardiac function regardless of the pacing position. Furthermore, the clinical characteristics of patients who develop AF and cardiovascular events during RV septal pacing for atrioventricular (AV) block have not been described. It was previously reported that a wider-paced QRS duration (>165 ms) predicted new-onset HF after RV apical pacing.⁶ RV septal pacing is characterized by a shorter-paced QRS duration than that of the pacing at the RV apex.¹¹ These observations have raised interest in the relationship between paced QRS duration and clinical outcome in patients with RV septal pacing.

Therefore, we aimed to clarify the clinical characteristics of patients who developed AF and cardiovascular events during long-term RV septal pacing for AV block. We retrospectively analyzed data from patients paced for 2nd- or 3rd-degree AV block, with preserved LV function and free of AF prior to pacemaker implantation. The incidence and predictors of AF developing after pacemaker implantation, and the clinical predictors of cardiovascular events were evaluated in these patients.

Methods

Sample Population

Patients were eligible for inclusion in this study if they had undergone implantation of a dual-chamber pacemaker, were free from sinus node disease, had normal LV systolic function, no history of HF, had neither symptoms consistent with nor a suspicion of AF or other atrial tachyarrhythmias, and had not been previously treated with an antiarrhythmic drug. Patients were excluded from the study if ≥1 episode of AF was retrieved from the device’s memory at the follow-up visit 3 months after pacemaker implantation, ventriculoatrial conduction was observed during ventricular pacing, or the clinical data regarding that patient were incomplete.

Implantation of ventricular leads in the RV septum was performed under fluoroscopic guidance in both the posteroanterior and left anterior oblique 40° views and was considered appropriate when a negative or isoelectric vector was produced in ECG lead I and QRS notching was absent in leads II, III, and aVf.^10,12–14 Further, the area with narrowest paced QRS duration was selected for RV lead placement. The site of the tip of the RV septal pacing leads was confirmed by chest X-ray in the posteroanterior and lateral views on postoperative day 1.

The protocol of the present study was approved by the Ethics Committee of the University of Occupational and Environmental Health in Kitakyushu, Japan. Because all data were collected retrospectively from the medical records of patients who had undergone standard medical care, the patients whose records were analyzed as part of the present study were not required to provide written informed consent.

Follow-up Data Analysis

The presence of an atrial high rate episode (AHRE) stored in the device’s memory was examined by an electrophysiologist at the 3-month visit, using the intracardiac electrograms (iEGM), to determine whether the AHRE was caused by AF or by another pacemaker-related atrial tachyarrhythmia, such as pacemaker-mediated tachycardia, repetitive non-reentrant ventriculoatrial synchrony, or far-field R wave oversensing.^15,16 Patients in whom AF was confirmed at the 3-month visit were removed from the study to exclude patients with AF unrelated to RV pacing.

At each follow-up visit and with each round of device programming, the pacemaker’s memory was examined to confirm the absence of both far-field R wave oversensing and ventriculoatrial conduction. This was tested via ventricular pacing at 15 beats/min faster than the spontaneous ventricular rate or the back-up pacing rate. If ventriculoatrial conduction was present, the patient was excluded from the study analysis. If far-field R wave oversensing was confirmed by iEGM, the post-ventricular atrial blanking was set at a longer or equal duration than the far-field R wave oversensing +25 ms to prevent double atrial counting.¹⁶

At 3 months after device implantation and at every 6-month interval thereafter, a 12-lead ECG and chest X-ray were obtained, and we reviewed the patient’s medication list and health status, including the interim development of palpitation or chest pain. At each visit, we recorded the cumulative percentage of atrial (cumul%AP) and ventricular (cumul%VP) paced events, the atrial and ventricular pacing and sensing thresholds, and the measurements of lead impedance. The pacemaker data were assessed for AHRE according to the AF criteria set out by the ASSERT trial;¹⁷ the device was thus set at >190 beats/min during >6 min for all patients. If episodes of AHRE were present in a patient, the iEGMs of the AHRE were also reviewed for that patient.

Quantitative data were retrieved from the device’s memory at each follow-up visit, including the number of detected AHREs, duration of the episodes, time of episode onset, and total time spent in AHRE since the last follow-up.

Records regarding cardiovascular events consisting of cardiovascular death, unexplained sudden death, lethal cardiac arrhythmias, myocardial infarction, HF requiring hospitalization, and stroke were examined to calculate the incidence of cardiovascular events.

Statistical Analysis

Continuous variables are expressed as mean ± standard deviation (SD) or median (25–75th percentile), depending on the distribution of the data, whereas categorical variables are expressed as counts and percentages. Student’s t-test or the Mann-Whitney U-test were used as appropriate for between-group comparisons of continuous variables. Categorical variables were compared using the χ² test. The Kaplan-Meier method and Cox proportional hazard regression analysis were used to identify the clinical predictors of newly developed AF and cardiovascular events. The receiver-operating characteristic (ROC) curve was constructed, and the area under the curve of the diagnostic test was obtained for independent variables that may be used for prediction of cardiovascular events. Variables with P values <0.1 after a single variable analysis were entered into a multiple-variable regression analysis in search of independent predictors of newly developed AF and cardiovascular events. The analyses were performed using the JMP^® 10.0.2 software (SAS Institute Inc, Cary, NC, USA).

Results

Patients Characteristics

We investigated 171 AV block patients with dual-chamber pacemakers. Of them, 16 patients were excluded for ventriculoatrial conduction at the time of implantation or at a follow-up visit, 13 patients for AF within 3 months of pacemaker implantation, 8 with a history of myocardial infarction or <50% LVEF, 5 with valvular heart disease, 5 undergoing hemodialysis, and 1 patient with hypertrophic cardiomyopathy. A total of 123 patients were analyzed in the present study.

The characteristics of the 74 women and 49 men included in this study are shown in Table 1. Their mean age was 76±10 years. Hypertension and diabetes mellitus were present in approximately two-thirds and one-third of the patients, respectively. The mean echocardiographic LVEF and left atrium volume indices were within normal limits. The atrial pacing and sensing lead was placed in the right atrial appendage in more than 85% of the patients and in the low atrial septum for the remaining patients. The ventricular pacing and sensing lead was implanted in the RV septum in all patients. Typical 12-lead ECG and chest radiography in a patient with RV septal pacing are shown in Figure 1.

Table 1. Characteristics of Patients Undergoing RV Septal Pacing

Age, years	76±10
Men	49 (40)
History
Hypertension	82 (67)
Diabetes mellitus	37 (30)
Angina pectoris	5 (4)
Medication regimen
ACEI	5 (4)
ARB	68 (55)
β-adrenergic blocker	5 (4)
Statin	31 (25)
Roentgenographic cardiothoracic ratio, %	54±6
Echocardiographic measurements
LVEF, %	58±4
Left atrial diameter, mm	38±6
Volume index, ml/m2	33±13
Pacing site
Right atrial
Appendage	106 (86)
Low septum	17 (14)
Right ventricular septum	123 (100)

Values are mean ± standard deviation or total number (%) of observations. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; LVEF, left ventricular ejection fraction; RV, right ventricular.

Figure 1.

Typical 12-lead ECG and chest X-rays from a patient with RV septal pacing. (A) Negative-paced QRS complex vector can be seen in lead I and a positive QRS complex in leads II, III, and aVf. Note the lack of notching of the paced QRS complex in leads II, III, and aVf. (B) Chest X-rays in the posteroanterior (Left) and lateral (Right) views. In the lateral view, the tip of the ventricular pacing lead is forward posteriorly.

Pacemaker Programming and ECG Observations

The pacemaker programming scheme at the time of implantation is shown in Table 2. Nearly all devices were programmed in DDD mode. For 3 patients, who developed episodes of infrequent paroxysmal AV block, the pacemakers were set to DDI mode.

Table 2. Pacemaker Programming and ECG Observations in Patients Undergoing RV Septal Pacing

Pacing mode
DDD	120 (98)
DDI	3 (2)
Atrial sensitivity, mV	0.4±0.1
Pacing rate, ppm
Back-up	51±4
Maximum	121±9
Atrioventricular interval, ms
Sensed	188±58
Paced	208±48
ECG intervals, ms
P wave	99±16
Paced QRS	156±10

Values are mean ± standard deviation or total number (%) of observations. DDD, dual-chamber pacing; DDI, dual-chamber pacing and sensing, but inhibited mode.

Incidence of AF Developing After Pacemaker Implantation

Over a median follow-up of 4.0 years (2.3–6.3 years), 30 (24%) of the 123 patients developed episodes of AF, at a median of 1.9 years (1.1–3.3 years) after pacemaker implantation.

Relationship Between Newly Developed AF and cumul%VP

The median cumul%AP and cumul%VP over the entire follow-up period were 2% (1–15%) and 99% (46–100%), respectively. The 123 study patients were divided into 3 groups according to previous studies,^1,6 using 2 cut-off values (cumul%VP 40%, lower cut-off value; cumul%VP 90%. higher cut-off value): high cumul%VP (>90%), 74 patients (60%); medium cumul%VP (>40% and ≤90%), 19 patients (15%); and low cumul%VP (≤40%), 30 patients (24%). The clinical characteristics of these 3 study groups are shown in Table 3. The mean age, age distribution, presence of concomitant disorders, medications, cardiothoracic ratio on chest radiography, echocardiographic measurements (LVEF, left atrial diameter, left atrial volume index), and cumul%AP were similar among the 3 study groups. However, the proportion of male patients in the group with medium cumul%VP was lower than in the other groups.

Table 3. Patients Characteristics Stratified by Cumulative Percentage of RV Pacing (cumul%VP)

	Patient group
	cumul%VP ≤40 (n=30)	40<cumul%VP≤90 (n=19)	cumul%VP >90 (n=74)	P value
Age, years	74±9	74±9	77±11	0.29
Men	12 (40)	3 (16)	34 (46)	0.04
History
Hypertension	24 (80)	13 (68)	46 (62)	0.20
Diabetes mellitus	10 (33)	3 (16)	24 (32)	0.30
Angina pectoris	2 (7)	0 (0)	2 (3)	0.33
Medications
ARB/ACEI	21 (70)	8 (42)	42 (57)	0.15
Statin	10 (33)	6 (32)	15 (20)	0.30
Roentgenographic cardiothoracic ratio, %	52±6	53±6	55±6	0.09
Echocardiographic measurements
LVEF, %	58±4	59±5	57±4	0.17
Left atrial diameter, mm	39±6	37±8	38±6	0.45
Volume index, ml/m2	33±16	28±9	34±11	0.24
Cumulative percentage
Atrial pacing, %	2 (1–11)	3 (1–16)	3 (1–18)	0.35
Ventricular pacing, %	10 (1–21)	73 (57–82)	99 (99–100)	<0.0001
ECG intervals, ms
P wave	103±16	100±16	100±16	0.20
Paced QRS	156±7	152±8	156±11	0.21

Values are mean ± standard deviation, median (25–75th percentile), or total number (%) of observations. Abbreviations as in Table 1.

Figure 2 shows the significantly higher incidence of newly developed AF, using Kaplan-Meier analysis, in the group of patients with high cumul%VP when compared with the other 2 groups. Using single- and multiple-variable Cox proportional hazard regression analyses, cumul%VP was identified as an independent predictor of the development of new AF, with a hazard ratio (HR) of 1.19 for each 10% increment, and 95% confidence interval (CI) of 1.04–1.41 (P=0.01, Table 4).

Figure 2.

Kaplan-Meier curves of survival free from atrial fibrillation induced by right ventricular pacing in patients stratified by cumulative percentage of ventricular pacing (cumul%VP).

Table 4. Cox Proportional Hazard Regression Analysis of Potential Clinical Predictors of New Occurrence of AF in Patients Undergoing RV Septal Pacing

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age (per year)	1.02 (0.98–1.07)	0.29
Male sex	1.45 (0.63–3.34)	0.38
History
Hypertension	0.78 (0.33–1.90)	0.58
Diabetes mellitus	0.99 (0.39–2.39)	0.99
Angina pectoris	5.06 (0.80–39.89)	0.08	6.97 (0.98–65.63)	0.05
Medications
ARB/ACEI	0.79 (0.34–1.82)	0.58
Statin	0.68 (0.23–1.77)	0.44
Roentgenographic cardiothoracic ratio (per 10% increment)	1.32 (0.68–2.51)	0.41
Echocardiographic measurements
LVEF (per 10% increment)	0.91 (0.31–2.56)	0.85
Left atrial diameter (per 10-mm increment)	0.85 (0.44–1.67)	0.64
Volume index (per 10-ml/m2 increment)	1.25 (0.86–1.81)	0.23
Cumulative percentage
Atrial pacing (per 10% increment)	1.14 (0.93–1.38)	0.21
Ventricular pacing (per 10% increment)	1.18 (1.03–1.38)	0.02	1.19 (1.04–1.41)	0.01
ECG intervals, per 10-ms increment
P wave duration	0.86 (0.64–1.13)	0.27
Paced QRS duration	0.89 (0.55–1.39)	0.61

AF, atrial fibrillation; CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Cardiovascular Events

Over a median follow-up of 4.0 years (2.3–6.3 years), a total of 10 patients (8%) had cardiovascular events: 2 patients (2%) with cardiovascular death, 4 patients (3%) with HF requiring hospitalization, and 4 patients (3%) with stroke after pacemaker implantation. Single- and multiple-variable Cox proportional hazard regression analyses showed that older age (HR, 1.22; 95% CI, 1.07–1.47; P=0.001), wider-paced QRS duration (HR, 3.37; 95% CI, 1.40–10.48; P=0.005) and newly developed AF (HR, 16.47; 95% CI, 2.36–224.60; P=0.003) were significant predictors of cardiovascular events (Table 5).

Table 5. Cox Proportional Hazard Regression Analysis of Potential Clinical Predictors of Cardiovascular Events in Patients Undergoing RV Septal Pacing

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age (per year)	1.13 (1.03–1.25)	0.005	1.22 (1.07–1.47)	0.001
Male sex	1.57 (0.41–5.94)	0.50
History
Hypertension	1.14 (0.30–5.50)	0.86
Diabetes mellitus	0.24 (0.01–1.34)	0.11
Angina pectoris	3.03 (0.15–23.39)	0.39
Medications
ARB/ACEI	0.71 (0.19–2.69)	0.61
Statin	0.72 (0.11–3.10)	0.69
Roentgenographic cardiothoracic ratio (per 10% increment)	1.84 (0.68–4.82)	0.22
Echocardiographic measurements
LVEF (per 10% increment)	3.43 (0.73–16.43)	0.12
Left atrial volume index (per 10-ml/m2 increment)	1.25 (0.65–2.17)	0.47
Cumulative percentage of ventricular pacing (per 1% increment)	1.24 (0.98–1.90)	0.08	1.17 (0.97–20.69)	0.29
ECG intervals
Paced QRS duration (per 10-ms increment)	2.19 (1.13–4.48)	0.02	3.37 (1.40–10.48)	0.005
Incidence of new AF	9.13 (2.35–44.96)	0.001	16.47 (2.36–224.60)	0.003

Abbreviations as in Tables 1,3,4.

A total of 7 of 30 (23%) patients who had newly developed AF suffered from cardiovascular events, in detail, 3 patients had a stroke, 3 patients had HF requiring hospitalization, and 1 patient died of cardiovascular cause. Also, as determined by the ROC curve analysis, the area under the curve for age at implantation and paced QRS duration was 0.78 and 0.73, respectively. Using a cut-off value of 155 ms for paced QRS duration yielded a sensitivity of 80% and a specificity of 53% to predict cardiovascular events. Kaplan-Meier analysis revealed that patients with paced QRS ≥155 ms had a significantly higher incidence of cardiovascular events than did patients with paced QRS <155 ms (Figure 3).

Figure 3.

Kaplan-Meier curves of survival free from major cardiovascular events, including cardiovascular death and stroke, in patients stratified by the paced QRS duration (≥155 or <155 ms).

Discussion

The main findings of our study can be summarized in a few key points. First, over a median follow-up of 4.0 years (2.3–6.3 years) after pacemaker implantation at the level of the RV septum, AF developed in almost one-quarter of patients with AV block and normal LV function, who had no history of AF before implantation, and no AF within 3 months of device implantation. Second, an increase in cumul%VP was significantly associated with the occurrence of pacing-induced AF. Third, newly developed AF and a paced QRS duration ≥155 ms at pacemaker implantation were significantly associated with the incidence of cardiovascular events.

To the best of our knowledge, the present study involving patients paced for AV block is an analysis with the longest follow-up after implantation of a pacing system at the level of the RV septum.

Correlation Between cumul%VP and Post-Implantation AF in Patients Paced for AV Block

We found that almost one-quarter of patients with AV block but normal LV function and no history of AF developed AF after several years of RV pacing. The ASSERT trial included recipients of dual-chamber pacemakers or implantable defibrillators; they were patients with sinus node disease or AV block who had no history of AF; over a median follow-up of 2.5 years, the incidence of AF lasting >6 min at an atrial rate >190 beats/min was 34.7%.¹⁷ The overall incidence of post-implantation AF noted in the present study was lower than that observed in previous studies.^17,18 This is likely the result of stricter inclusion criteria for our sample population. Specifically, only patients with preserved LV function and who did not present with AF within 3 months after pacemaker implantation were included; moreover, patients with ventriculoatrial conduction were excluded, as this condition is known to increase the risk of RV pacing-induced AF.¹⁹

In previous studies of sinus node disease, high cumul%VP was found to be associated with an increased incidence of AF,^1,2,20 but the relationship between cumul%VP and the incidence of RV pacing-induced AF had not been confirmed in patients presenting with AV block. To the best of our knowledge, the present study is the longest follow-up analysis in patients who received RV septal pacing for AV block.

A history of symptomatic or asymptomatic AF is a strong predictor of AF recurrence.^21–23 Nevertheless, the patients included in most previous studies presented with AF before pacemaker implantation.^1,20,24–26 Therefore, the true incidence of AF induced by RV pacing remains unknown. In our study, cumul%VP was an independent predictor of post-implantation AF in patients with no history of AF. These observations strongly suggest that, in the long-term, the percentage of RV pacing contributes significantly to the development of AF in patients with AV block and preserved LV function.

Clinical Predictors of Cardiovascular Events After Long-Term RV Septal Pacing

Limited data are available regarding the long-term prognosis for patients with AV block after implantation of an RV-septum pacing device. A recent study⁷ involving patients with high-grade AV block analyzed data from 2 years of follow-up and reported that RV pacing affects LV function. Other studies have suggested that a change in LV function might occur after 12–18 months.^4,27 It is possible that the 2-year study period, typical for previous investigations regarding the effects of RV septal pacing, is insufficient to allow for observation of major clinical outcomes. Indeed, in the present study, cardiovascular events occurred after 3 years of RV pacing in the majority of patients.

The clinical characteristics of patients who have a poor outcome after RV septal pacing for AV block have not been described to date. With respect to RV apical pacing, Zhang et al reported that a paced QRS duration >165 ms predicted new-onset HF.⁶ However, RV septal pacing is characterized by shorter-paced QRS duration than with RV apex pacing,¹¹ and the relationship between paced QRS duration and clinical outcome remained unclear for RV septal pacing. In our study, a paced QRS duration ≥155 ms was associated with an increased risk of cardiovascular events after RV septal pacing. This observation is a very useful clinical indicator: to avoid detrimental effects associated with long-term pacing from the RV septum, the implantation site should be chosen from among those that produce a paced QRS duration <155 ms at pacemaker implantation.

In addition, we found that newly developed AF detected by pacemaker was associated with cardiovascular events. It is noteworthy that in the majority of patients, cardiovascular events occurred after 3 years of RV pacing, whereas AF developed after a median of 1.9 years. These results indicate that early detection of pacing-induced AF has significant clinical relevance. Patients paced for AV block who present with signs of post-implantation AF, especially elderly patients or those with wider-paced QRS duration, might need early treatment or interventions for prevention and management of future cardiovascular events; upgrading to an implantable cardiodefibrillator, cardiac resynchronization therapy, or anticoagulant therapy may be suitable strategies in such patients.

Finally, the advantage of RV septalm pacing for improving clinical outcome has not been established in patients with AV block. Therefore, further investigation is warranted to establish whether cardiac resynchronization therapy can prevent the development of AF and subsequent cardiovascular events in patients with AV block requiring long-term pacing, especially in paced patients with high cumul%VP.

Study Limitations

First, this was a retrospective, single-center study. However, the sample population was sufficiently large to enable meaningful analysis of the data and detection of significant between-group differences. Second, the conclusions of the present study refer only to RV septal pacing. Therefore, it is not possible to compare the long-term effects of septal pacing with those of apical pacing in terms of the incidence of pacing-induced AF. It is expected that the incidence of post-implantation AF and subsequent clinical outcomes may differ when pacing from different RV sites. Finally, further studies of long-term follow-up data, such as correlation between cumul%VP and changes in LVEF or LV dysfunction, are needed.

Conclusions

We found that over a median follow-up of 4.0 years after implantation of an RV-septum pacing device, AF developed in almost one-quarter of patients with AV block and normal LV function, who had no history of AF before pacemaker implantation or within 3 months of implantation. The increase in cumul%VP (>90%) was significantly associated with the occurrence of AF. More importantly, in patients with RV septal pacing, AF induced by RV pacing and a paced QRS duration ≥155 ms at pacemaker implantation were associated with poor prognosis. Therefore, regarding the management of patients with RV septal pacing, physicians should attempt to implant at sites producing a paced QRS duration <155 ms and avoid unnecessary RV pacing as much as possible.

Funding

This study was supported by Grant-in-Aid No. 25461081 from the Ministry of Education, Culture, Sports, Science and Technology in Japan (H.A.).

Conflict of Interest Statement

The authors have no conflict of interest to declare in relationship to the work presented in this manuscript. The funders had no role in data collection, interpretation of results, and preparation of the manuscript. The results were presented in the form of an abstract at the 2015 Congress of the European Society of Cardiology, in London, United Kingdom.

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