Fredrik Holmqvist

Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation—Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)

BACKGROUND Obstructive sleep apnea (OSA) is common in patients with atrial fibrillation (AF). Little is known about the impact of OSA on AF treatment and long-term outcomes. We studied whether patients with OSA have a greater likelihood of progressing to more persistent forms of AF or require more hospitalizations and/or worse outcomes compared with patients without OSA. METHODS A total of 10,132 patients were enrolled between June 2010 and August 2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) and followed for up to 2 years. The prevalence of OSA and continuous positive airway pressure (CPAP) treatment was captured at baseline. The association between OSA and major cardiovascular outcomes was analyzed using multivariable hierarchical logistic regression modeling and Cox frailty regression model. RESULTS Of the 10,132 patients with AF, 1,841 had OSA. Patients with OSA were more symptomatic (22% vs 16% severe/disabling symptoms; P < .0001) and more often on rhythm control therapy (35% vs 31%; P = .0037). In adjusted analyses, patients with OSA had higher risk of hospitalization (hazard ratio [HR], 1.12; 95% CI, 1.03-1.22; P = .0078), but no difference in the risks of death (HR, 0.94; 95% CI, 0.77-1.15; P = .54); the composite of CV death, myocardial infarction, and stroke/transient ischemic attack (HR, 1.07; 95% CI, 0.85-1.34; P = .57); major bleeding (HR, 1.18; 95% CI, 0.96-1.46; P = .11); or AF progression (HR, 1.06; 95% CI, 0.89-1.28; P = .51). Patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF compared with patients without CPAP (HR, 0.66; 95% CI, 0.46-0.94; P = .021). CONCLUSION Compared with those without, AF patients with OSA have worse symptoms and higher risks of hospitalization, but similar mortality, major adverse cardiovascular outcome, and AF progression rates. CLINICAL TRIAL REGISTRATION NCT01165710 (http://www.clinicaltrials.gov).

Interatrial conduction can be accurately determined using standard 12-lead electrocardiography: validation of P-wave morphology using electroanatomic mapping in man.

BACKGROUND Different P-wave morphologies during sinus rhythm as displayed on standard ECGs have been postulated to correspond to differences in interatrial conduction. OBJECTIVE The purpose of this study was to evaluate the hypothesis by comparing P-wave morphologies using left atrial activation maps. METHODS Twenty-eight patients (mean age 49 +/- 9 years) admitted for ablation of paroxysmal atrial fibrillation were studied. Electroanatomic mapping of left atrial activation was performed at baseline during sinus rhythm with simultaneous recording of standard 12-lead ECG. Unfiltered signal-averaged P waves were analyzed to determine orthogonal P-wave morphology. The morphology was subsequently classified into one of three predefined types. All analyses were blinded. RESULTS The primary left atrial breakthrough site was the fossa ovalis in 8 patients, Bachmann bundle in 18, and coronary sinus in 2. Type 1 P-wave morphology was observed in 9 patients, type 2 in 17, and type 3 in 2. Seven of eight patients with fossa ovalis breakthrough had type 1 P-wave morphology, 16 of 18 patients with Bachmann bundle breakthrough had type 2 morphology, and both patients with coronary sinus breakthrough had type 3 P-wave morphology. Overall, P-wave morphology criteria correctly identified the site of left atrial breakthrough in 25 (89%) of 28 patients. CONCLUSION In the vast majority of patients, P-wave morphology derived from standard 12-lead ECG can be used to correctly identify the left atrial breakthrough site and the corresponding route of interatrial conduction.

PR Interval Identifies Clinical Response in Patients With Non–Left Bundle Branch Block A Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy Substudy

Background —In MADIT-CRT, patients with non-LBBB (including RBBB, IVCD) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR-interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results —Non-LBBB patients (n=537, 30%) were divided in two groups based on their baseline PR-interval as normal (including minimally prolonged) PR (PR < 230 ms), and prolonged PR (PR ≥ 230 ms). The primary end point was heart failure (HF) or death. Separate secondary end points included HF events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to ICD therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR-interval, CRT-D treatment was associated with a 73% reduction in the risk of HF/Death (HR=0.27, 95% CI: 0.13-0.57, p<0.001) and 81% decrease in the risk of all-cause mortality (HR=0.19, 95% CI: 0.13-0.57, p<0.001) compared to ICD therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend towards an increased risk of HF/Death (HR=1.45, 95% CI: 0.96-2.19, p=0.078, interaction p-value<0.001) and more than a 2-fold higher mortality (HR=2.14, 95% CI: 1.12-4.09, p=0.022, interaction p-value<0.001) compared to ICD therapy. Conclusions —The data support the use of CRT-D in MADIT-CRT, non-LBBB patients with a prolonged PR-interval. In non-LBBB patients with a normal PR-interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration —http://clinicaltrials.gov; Unique Identifier: [NCT00180271][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Fcircae%2Fearly%2F2014%2F06%2F24%2FCIRCEP.113.001299.atomBackground—In Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT), patients with non–left bundle branch block (LBBB; including right bundle branch block, intraventricular conduction delay) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results—Non-LBBB patients (n=537; 30%) were divided into 2 groups based on their baseline PR interval as normal (including minimally prolonged) PR (PR <230 ms) and prolonged PR (PR ≥230 ms). The primary end point was heart failure or death. Separate secondary end points included heart failure events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to implantable cardioverter defibrillator therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR interval, CRT-D treatment was associated with a 73% reduction in the risk of heart failure/death (hazard ratio, 0.27; 95% confidence interval, 0.13–0.57; P<0.001) and 81% decrease in the risk of all-cause mortality (hazard ratio, 0.19; 95% confidence interval, 0.13–0.57; P<0.001) compared with implantable cardioverter defibrillator therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend toward an increased risk of heart failure/death (hazard ratio, 1.45; 95% confidence interval, 0.96–2.19; P=0.078; interaction P<0.001) and a more than 2-fold higher mortality (hazard ratio, 2.14; 95% confidence interval, 1.12–4.09; P=0.022; interaction P<0.001) compared with implantable cardioverter defibrillator therapy. Conclusions—The data support the use of CRT-D in MADIT-CRT non-LBBB patients with a prolonged PR interval. In non-LBBB patients with a normal PR interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration—http://clinicaltrials.gov; Unique Identifier: NCT00180271.

PR-Interval Identifies Clinical Response in Patients with Non-LBBB: A MADIT-CRT Sub-Study

Background —In MADIT-CRT, patients with non-LBBB (including RBBB, IVCD) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR-interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results —Non-LBBB patients (n=537, 30%) were divided in two groups based on their baseline PR-interval as normal (including minimally prolonged) PR (PR < 230 ms), and prolonged PR (PR ≥ 230 ms). The primary end point was heart failure (HF) or death. Separate secondary end points included HF events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to ICD therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR-interval, CRT-D treatment was associated with a 73% reduction in the risk of HF/Death (HR=0.27, 95% CI: 0.13-0.57, p<0.001) and 81% decrease in the risk of all-cause mortality (HR=0.19, 95% CI: 0.13-0.57, p<0.001) compared to ICD therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend towards an increased risk of HF/Death (HR=1.45, 95% CI: 0.96-2.19, p=0.078, interaction p-value<0.001) and more than a 2-fold higher mortality (HR=2.14, 95% CI: 1.12-4.09, p=0.022, interaction p-value<0.001) compared to ICD therapy. Conclusions —The data support the use of CRT-D in MADIT-CRT, non-LBBB patients with a prolonged PR-interval. In non-LBBB patients with a normal PR-interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration —http://clinicaltrials.gov; Unique Identifier: [NCT00180271][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Fcircae%2Fearly%2F2014%2F06%2F24%2FCIRCEP.113.001299.atomBackground—In Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT), patients with non–left bundle branch block (LBBB; including right bundle branch block, intraventricular conduction delay) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results—Non-LBBB patients (n=537; 30%) were divided into 2 groups based on their baseline PR interval as normal (including minimally prolonged) PR (PR <230 ms) and prolonged PR (PR ≥230 ms). The primary end point was heart failure or death. Separate secondary end points included heart failure events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to implantable cardioverter defibrillator therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR interval, CRT-D treatment was associated with a 73% reduction in the risk of heart failure/death (hazard ratio, 0.27; 95% confidence interval, 0.13–0.57; P<0.001) and 81% decrease in the risk of all-cause mortality (hazard ratio, 0.19; 95% confidence interval, 0.13–0.57; P<0.001) compared with implantable cardioverter defibrillator therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend toward an increased risk of heart failure/death (hazard ratio, 1.45; 95% confidence interval, 0.96–2.19; P=0.078; interaction P<0.001) and a more than 2-fold higher mortality (hazard ratio, 2.14; 95% confidence interval, 1.12–4.09; P=0.022; interaction P<0.001) compared with implantable cardioverter defibrillator therapy. Conclusions—The data support the use of CRT-D in MADIT-CRT non-LBBB patients with a prolonged PR interval. In non-LBBB patients with a normal PR interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration—http://clinicaltrials.gov; Unique Identifier: NCT00180271.

Signal-averaged P wave analysis for delineation of interatrial conduction – Further validation of the method

BackgroundThe study was designed to investigate the effect of different measuring methodologies on the estimation of P wave duration. The recording length required to ensure reproducibility in unfiltered, signal-averaged P wave analysis was also investigated. An algorithm for automated classification was designed and its reproducibility of manual P wave morphology classification investigated.MethodsTwelve-lead ECG recordings (1 kHz sampling frequency, 0.625 μV resolution) from 131 healthy subjects were used. Orthogonal leads were derived using the inverse Dower transform. Magnification (100 times), baseline filtering (0.5 Hz high-pass and 50 Hz bandstop filters), signal averaging (10 seconds) and bandpass filtering (40–250 Hz) were used to investigate the effect of methodology on the estimated P wave duration. Unfiltered, signal averaged P wave analysis was performed to determine the required recording length (6 minutes to 10 s) and the reproducibility of the P wave morphology classification procedure. Manual classification was carried out by two experts on two separate occasions each. The performance of the automated classification algorithm was evaluated using the joint decision of the two experts (i.e., the consensus of the two experts).ResultsThe estimate of the P wave duration increased in each step as a result of magnification, baseline filtering and averaging (100 ± 18 vs. 131 ± 12 ms; P < 0.0001). The estimate of the duration of the bandpass-filtered P wave was dependent on the noise cut-off value: 119 ± 15 ms (0.2 μV), 138 ± 13 ms (0.1 μV) and 143 ± 18 ms (0.05 μV). (P = 0.01 for all comparisons).The mean errors associated with the P wave morphology parameters were comparable in all segments analysed regardless of recording length (95% limits of agreement within 0 ± 20% (mean ± SD)). The results of the 6-min analyses were comparable to those obtained at the other recording lengths (6 min to 10 s).The intra-rater classification reproducibility was 96%, while the interrater reproducibility was 94%. The automated classification algorithm agreed with the manual classification in 90% of the cases.ConclusionThe methodology used has profound effects on the estimation of P wave duration, and the method used must therefore be validated before any inferences can be made about P wave duration. This has implications in the interpretation of multiple studies where P wave duration is assessed, and conclusions with respect to normal values are drawn.P wave morphology and duration assessed using unfiltered, signal-averaged P wave analysis have high reproducibility, which is unaffected by the length of the recording. In the present study, the performance of the proposed automated classification algorithm, providing total reproducibility, showed excellent agreement with manually defined P wave morphologies.

Age-related changes in P wave morphology in healthy subjects

BackgroundWe have previously documented significant differences in orthogonal P wave morphology between patients with and without paroxysmal atrial fibrillation (PAF). However, there exists little data concerning normal P wave morphology. This study was aimed at exploring orthogonal P wave morphology and its variations in healthy subjects.Methods120 healthy volunteers were included, evenly distributed in decades from 20–80 years of age; 60 men (age 50+/-17) and 60 women (50+/-16). Six-minute long 12-lead ECG registrations were acquired and transformed into orthogonal leads. Using a previously described P wave triggered P wave signal averaging method we were able to compare similarities and differences in P wave morphologies.ResultsOrthogonal P wave morphology in healthy individuals was predominately positive in Leads X and Y. In Lead Z, one third had negative morphology and two-thirds a biphasic one with a transition from negative to positive. The latter P wave morphology type was significantly more common after the age of 50 (P < 0.01). P wave duration (PWD) increased with age being slightly longer in subjects older than 50 (121+/-13 ms vs. 128+/-12 ms, P < 0.005). Minimal intraindividual variation of P wave morphology was observed.ConclusionChanges of signal averaged orthogonal P wave morphology (biphasic signal in Lead Z), earlier reported in PAF patients, are common in healthy subjects and appear predominantly after the age of 50. Subtle age-related prolongation of PWD is unlikely to be sufficient as a sole explanation of this finding that is thought to represent interatrial conduction disturbances. To serve as future reference, P wave morphology parameters of the healthy subjects are provided.

Abnormal P-Wave Morphology Is a Predictor of Atrial Fibrillation Development and Cardiac Death in MADIT II Patients

Background: Several ECG‐based approaches have been shown to add value when risk‐stratifying patients with congestive heart failure, but little attention has been paid to the prognostic value of abnormal atrial depolarization in this context. The aim of this study was to noninvasively analyze the atrial depolarization phase to identify markers associated with increased risk of mortality, deterioration of heart failure, and development of atrial fibrillation (AF) in a high‐risk population with advanced congestive heart failure and a history of acute myocardial infarction.

Variable interatrial conduction illustrated in a hypertrophic cardiomyopathy population.

Background: Patients with hypertrophic cardiomyopathy (HCM) have a high incidence of atrial fibrillation. They also have a longer P‐wave duration than healthy controls, indicating conduction alterations. Previous studies have demonstrated orthogonal P‐wave morphology alterations in patients with paroxysmal atrial fibrillation. In the present study, the P‐wave morphology of patients with HCM was compared with that of matched controls in order to explore the nature of the atrial conduction alterations.

Interatrial right-to-left conduction in patients with paroxysmal atrial fibrillation

PurposeWe wanted to illustrate the right-to-left impulse propagation routes during sinus in patients with paroxysmal atrial fibrillation (PAF), as alterations in conduction patterns have been linked to the pathogenesis of PAF, and as no large patient materials have been published.MethodsPatients underwent 3-D electroanatomical contact mapping prior to catheter ablation. The site of the earliest left atrial (LA) activation was determined.ResultsThree different interatrial routes were identified, either as solitary pathways (36/50 patients, 72%) or in their combinations (14/50). Bachmann’s bundle (BB) was involved in the majority of the cases with solitary routes (25/36). More seldom, impulse propagation occurred near the oval fossa (FO) (7/36) or the coronary sinus ostium (4/36). In patients with combined routes, both the BB (10/14) and FO routes (11/14) were included in most cases.ConclusionsIn PAF patients, LA can be activated during sinus rhythm through three distinct connections, either encompassing a single route or via any combination of these connections. In one third, the earliest LA activation occurs outside BB. The knowledge of the propagation patterns may give insight into the pathophysiology of PAF and into refining ablation therapy.

Altered Interatrial Conduction Detected in MADIT II Patients Bound to Develop Atrial Fibrillation

Background: Changes in P‐wave morphology have recently been shown to be associated with interatrial conduction route used, without noticeable changes of P‐wave duration. This study aimed at exploring the association between P‐wave morphology and future atrial fibrillation (AF) development in the Multicenter Automatic Defibrillator Trial II (MADIT II) population.