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Original Research: Sleep Disorders |

Effect of Oxygen and Acetazolamide on Nocturnal Cardiac Conduction, Repolarization, and Arrhythmias in Precapillary Pulmonary Hypertension and Sleep-Disturbed BreathingRepolarization in Pulmonary Hypertension FREE TO VIEW

Deborah S. Schumacher, MD; Séverine Müller-Mottet, MD; Elisabeth D. Hasler, MD; Florian F. Hildenbrand, MD; Stephan Keusch, MD; Rudolf Speich, MD, FCCP; Konrad E. Bloch, MD, FCCP; Silvia Ulrich, MD
Author and Funding Information

From the Pulmonary Clinic, Department of Cardiovascular and Thoracic Medicine, University Hospital Zurich, Zurich, Switzerland.

CORRESPONDENCE TO: Silvia Ulrich, MD, Pulmonary Clinic, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland; e-mail: silvia.ulrich@usz.ch


FUNDING/SUPPORT: This study was funded by the Swiss National Science Foundation [Grant NF-32-130844 to Dr Ulrich] and the Zurich Lung League.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(5):1226-1236. doi:10.1378/chest.14-0495
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BACKGROUND:  Sleep-disturbed breathing (SDB) is common in patients with precapillary pulmonary hypertension (PH). Nocturnal oxygen therapy (NOT) and acetazolamide improve SDB in patients with PH, and NOT improves exercise capacity. We investigated the effect of NOT and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in patients with PH and SDB.

METHODS:  In a randomized, placebo-controlled, double-blind, crossover trial, 23 patients with arterial (n = 16) or chronic thromboembolic PH (n = 7) and SDB defined as a mean nocturnal oxygen saturation < 90% or dips (> 3%) > 10/h with daytime Pao2 ≥ 7.3 kPa were studied. Participants received NOT (3 L/min), acetazolamide tablets (2 × 250 mg), and sham-NOT/placebo each during 1 week separated by a 1-week washout period. Three-lead ECG was recorded during overnight polysomnography at the end of each treatment period. Repolarization indices were averaged over three cardiac cycles at late evening and at early morning, and nocturnal arrhythmias were counted.

RESULTS:  NOT was associated with a lower overnight (68 ± 10 beats/min vs 72 ± 9 beats/min, P = .010) and early morning heart rate compared with placebo. At late evening, the heart rate-adjusted PQ time was increased under acetazolamide compared with placebo (mean difference, 10 milliseconds; 95% CI, 0-20 milliseconds; P = .042). In the morning under NOT, the heart rate-adjusted QT (QTc) interval was decreased compared with placebo (mean difference, −25 milliseconds; 95% CI, −45 to −6 milliseconds; P = .007), and the interval between the peak and the end of the T wave on the ECG was shorter compared with acetazolamide (mean difference, −11 milliseconds; 95% CI, −21 to −1 milliseconds; P = .028). Arrhythmias were rare and similar with all treatments.

CONCLUSIONS:  In patients with PH with SDB, NOT reduces nocturnal heart rate and QTc in the morning, thus, favorably modifying prognostic markers.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NTC-01427192; URL: www.clinicaltrials.gov

Figures in this Article

Sleep-disturbed breathing (SDB) is highly prevalent in patients with pulmonary arterial and chronic thromboembolic pulmonary hypertension (CTEPH), with more than one-third suffering from periodic breathing and more than two-thirds from sustained nocturnal hypoxemia.13 SDB is relevant because it impairs quality of life.2 Oxygen deprivation in pulmonary vascular cells during SDB further triggers pulmonary vasoconstriction with increase in pulmonary vascular resistance maintaining a vicious cycle.3,4 Remodeling of the right ventricle (RV) in response to increased afterload together with hypoxemia and consecutive myocardial ischemia may affect myocardial autonomic activity, lead to conduction and repolarization abnormalities, and represent an arrhythmogenic substrate.57 Cardiac arrhythmias are important influencing factors to morbidity and mortality in patients with pulmonary hypertension (PH) and result in clinical deterioration and compromised cardiac function.6

We have shown that SDB in precapillary PH is significantly ameliorated with nocturnal oxygen therapy (NOT) or the ventilatory-stimulant drug acetazolamide and that NOT improves the 6-min walk distance (6MWD), symptoms, and hemodynamics during daytime.1,811 In the present study, we evaluated the hypothesis that NOT and acetazolamide would improve cardiac conduction, repolarization, and arrhythmias in patients with PH and SDB.

Design and Setting

The data for this study were collected as part of a randomized, double-blind, sham/placebo-controlled three-period crossover trial in patients with PH and SDB.8 The study compared effects of (1) nocturnal supplemental oxygen by nasal cannula (3 L/min, NOT) and placebo tablets, (2) acetazolamide tablets (2 × 250 mg) and sham NOT (room air by nasal cannula with a flow rate of 3 L/min), with (3) sham NOT and placebo tablets (Fig 1). Subsequently, these treatment combinations are termed NOT, acetazolamide, and placebo. Each treatment was applied for 1 week in the patient’s home; the last night patients spent at hospital for sleep studies. During washout of 1 week, patients did not receive study treatment. The trial was performed from December 2010 to August 2012. This study was conducted in accordance with the amended Declaration of Helsinki. The study was approved by the cantonal ethical review board of Zurich (KEK-ZH-NR: 2010-0129) and registered at ClinicalTrials.gov: NTC-01427192.

Figure Jump LinkFigure 1 –  Patient flow. AZM = treatment with acetazolamide tablets 250 mg bid; NOT = nocturnal oxygen therapy via a nasal cannula at a flow of 3 L/min; placebo = tablets bid; sham-NOT = room air at a flow rate of 3 L/min.Grahic Jump Location
Patients, Randomization, and Blinding

Consecutive patients aged 20 to 80 years diagnosed with pulmonary arterial hypertension (PAH) (World Health Organization [WHO] group 1) or inoperable CTEPH (WHO group 4)12 were eligible for enrollment upon written informed consent. All patients were diagnosed according to current guidelines and had undergone right-sided heart catheterization at the time of initial evaluation.13 Patients were considered for inclusion if they were in a stable condition on the same medication for > 4 weeks. Eligible patients had SDB defined as either a mean nocturnal oxygen saturation (Spo2) < 90% or an oxygen desaturation index (> 3% dips) > 10/h during ambulatory nocturnal pulse oximetry. Patients with Pao2 < 7.3 kPa during daytime, predominantly OSA, more than mild lung disease (FEV1 ≤ 60%), or concomitant left ventricular disease were excluded.

NOT (or sham-NOT) was delivered via a nasal cannula at a flow rate of 3 L/min by an oxygen concentrator (Respironics EverFlo; Koninklijke Philips N.V.). The sham concentrators were prepared by modifying the similar concentrators to provide room air. Acetazolamide (Diamox; Vifor Pharma) was administered at a dose of 2 × 250 mg/d with breakfast and dinner. Identical-looking capsules containing acetazolamide or placebo were prepared by the cantonal pharmacy of Zurich and packed in containers labeled with a code that was broken only after data analysis. Allocation to one of the six study sequences was performed by an independent pharmacist, assuring a balanced block design. Patients and investigators participating in evaluation of outcomes were blinded to the treatment.

ECG Measurements and Potassium

Three-lead ECG recordings were obtained during the last night of each treatment period (Alice 5; Koninklijke Philips N.V.).2,14 ECG measurements were performed manually on a computer screen (Alice Sleepware; Koninklijke Philips N.V.) by a trained reviewer blinded to treatments. Supraventricular and ventricular arrhythmias were counted. Premature atrial contractions (PACs), paroxysmal tachycardia, flutter, and fibrillation were scored. Paroxysmal atrial fibrillation (AF) was specified as an event lasting > 30 s. AFs lasting < 30 s were defined as atrial bursts. Supraventricular disturbances included sinus bradycardia (< 40/min) and tachycardia (> 100/min). Ventricular disturbances included premature contractions, tachycardia, flutter, and fibrillation. In addition to computing ECG-derived variables over the entire night, we averaged conduction and repolarization parameters over three cardiac cycles 10 min after lights off (late evening) when the treatment (NOT, acetazolamide tablet evening dose) was after a short time on therapeutic dose, and 10 min before lights on (early morning) when the treatment was effective for several hours. These measurements included: RR interval corresponding to the distance between two consecutive R spikes, P-wave duration, PQ interval, and QRS duration. RR was used to calculate heart rate. A prolonged QRS complex was defined as ≥ 120 milliseconds.15 The indexes of cardiac repolarization were determined as follows: QT interval, defined as time from the earliest onset of the QRS complex to the end of T wave.16 The end of T wave was fixed as an intersection between a line tangent to the descending arm of T wave and the isoelectric line.17 The interval between the peak and the end of the T wave on ECG (TpTe) corresponds to the time from the point of largest amplitude of T-wave deflection to the end of T wave.17,18 For heart rate-adjusted PQ (PQc), the Soliman and Rautaharju method was used.19 Bazett’s formula was used to obtain heart rate-corrected values of QT (QTc) and TpTe (TpTec).20 TpTe/QT was calculated as a measure of dispersion of repolarization.18 Potassium analysis was retrieved from a radial artery blood sample taken in the morning (ABL90 Flex blood gas analyzer; Radiometer Medical ApS).

Data Analysis and Statistics

Comparisons between treatments (NOT, acetazolamide, and placebo) were calculated using Wilcoxon matched-pairs test and Fisher exact test. Data are presented as number (%), medians (quartiles), and mean difference (95% CI). A P value < .05 was considered statistically significant. All statistical analyses were performed using SPSS (IBM).

Patient Characteristics

Characteristics of the 23 patients (15 women) with idiopathic PAH or inoperable CTEPH in the study are shown in Table 1. All participants completed the study. The ECG data could not be analyzed from one patient under acetazolamide because of technical failure in ECG recordings. With the exception of one patient with established diagnosis of persistent AF, all patients were in sinus rhythm at the time of inclusion.

Table Graphic Jump Location
TABLE 1 ]  Baseline Patient Characteristics

Data obtained during screening. NYHA = New York Heart Association; PDE = phosphodiesterase; PH = pulmonary hypertension.

a 

Data obtained during last right-sided heart catheterization.

b 

Mean (SD).

Overnight Assessments and Potassium

NOT was associated with a reduced mean nocturnal heart rate compared with placebo (mean difference, −3 beats/min [bpm]; 95% CI, −5 to −1 bpm; P = .010) (Fig 2, Table 2). Supraventricular and ventricular dysrhythmias, such as episodes of sinus tachycardia and atrial bursts, were rarely observed and equally found under placebo and therapies. Under acetazolamide, PACs/h were reduced compared with NOT. In addition to the single case with preexisting AF, neither a new-onset AF nor episodes of ventricular bradyarrhythmia or tachyarrhythmia were observed (Fig 3). Acetazolamide significantly reduced blood potassium levels compared with placebo/NOT.

Figure Jump LinkFigure 2 –  Effect of nocturnal oxygen and acetazolamide on mean nocturnal heart rate. Data are presented as mean and 95% CI. *There was a significant decrease in heart rate under NOT compared with placebo (P = .010). bpm = beats/min. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Table Graphic Jump Location
TABLE 2 ]  Overnight Mean Nocturnal Heart Rate, Cardiac Arrhythmias, and Potassium and Effect of Nocturnal Oxygen or Acetazolamide

Data given as No. of patients affected (%) and medians (quartiles) with the exception of heart rate, which is mean (SD). P by Wilcoxon matched-pairs test for comparisons between treatments with sufficient patient data. bpm = beats/min; Δ = difference NOT respective to acetazolamide with sham-NOT/placebo; NOT = nocturnal oxygen therapy.

a 

P by Fisher exact test for comparisons between treatments with sufficient patient data.

Figure Jump LinkFigure 3 –  Examples of arrhythmias in nocturnal ECG recordings. A, Atrial fibrillation. B, Atrial burst. C, Premature atrial contraction. D, Premature unifocal ventricular complexes.Grahic Jump Location
Cardiac Conduction and Repolarization

At late evening, P duration on acetazolamide was longer than on placebo (mean difference, 5 milliseconds; P = .038) (Table 3). PQc was prolonged under acetazolamide (mean difference, 10 milliseconds; 95% CI, 0-20 milliseconds; P = .042), whereas the PQc interval under NOT was similar. The QRS complex was shorter on NOT compared with acetazolamide (mean difference, −6 milliseconds; 95% CI, −10 to −1 milliseconds; P = .044).

Table Graphic Jump Location
TABLE 3 ]  Late Evening: Effect of Nocturnal Oxygen or Acetazolamide on ECG Interval Times

Values are medians (quartiles) and between-treatment differences are means (95% CIs). P value by Wilcoxon matched-pairs test for comparisons between treatments. PQc = heart rate-adjusted value of PQ; QTc = heart rate-corrected value of QT; TpTe = interval between the peak and the end of the T wave on ECG; TpTec = heart rate-corrected value of the interval between the peak and the end of the T wave on ECG. See Table 2 legend for expansion of other abbreviations.

a 

Heart rate-adjusted.

In the early morning, the RR interval on NOT was increased compared with placebo, corresponding to a lower heart rate (mean difference, −5 bpm; 95% CI, −9 to −1 bpm; P = .031) (Table 4). NOT was associated with a reduced QTc compared with placebo (mean difference, −25 milliseconds; 95% CI, −45 to −6 milliseconds; P = .007) (Fig 4) and a significantly shortened TpTec interval compared with acetazolamide (mean difference, −11 milliseconds; 95% CI, −21 to −1 milliseconds; P = .028) (Fig 5).

Table Graphic Jump Location
TABLE 4 ]  Early Morning: Effect of Nocturnal Oxygen or Acetazolamide on ECG Interval Times

Values are medians (quartiles) and between-treatment differences are means (95% CIs). P value by Wilcoxon matched-pairs test for comparisons between treatments. See Table 2 and 3 legends for expansion of abbreviations.

a 

Heart rate-adjusted.

Figure Jump LinkFigure 4 –  Effect of nocturnal oxygen and acetazolamide on QTc interval at late evening. *There was a significant decrease in QTc duration under NOT compared with placebo (P = .007). QTc = heart rate-corrected value of QT. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5 –  Effect of nocturnal oxygen and acetazolamide on TpTec interval at late evening. #There was a significant decrease in TpTec duration under NOT compared with acetazolamide (P = .028). TpTec = heart rate-corrected value of interval between the peak and the end of the T wave on ECG. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

This randomized, sham/placebo-controlled, double-blind trial in patients with PAH or CTEPH suffering from SDB demonstrates that NOT given for 1 week improves several prognostic electrographic markers (ie, it reduces heart rate and QTc). Since it not only favorably modifies heart rate and repolarization but also improves exercise performance, NOT is a promising treatment of patients with PH with SDB.

A higher resting heart rate is associated with worse prognosis in PAH and CTEPH, even if corrected for age, sex, hemodynamics, and functional status.21 Increased RV afterload is associated with a decreased stroke volume. A compensatory heart rate increase due to sympathetic activation allows preserving the cardiac output and systemic oxygen delivery. However, long-term sympathetic overdrive may impair RV function.22 Supplemental oxygen therapy, as pulmonary vasodilator, could break this vicious circle and, thus, prevent or even reverse an inauspicious increase in heart rate.23 In this study, we found that NOT has a favorable effect on mean nocturnal heart rate and that this effect is most pronounced in the early morning after use of NOT. Notably, NOT reduced the heart rate even in patients on optimized double or triple medical PH-target therapy and already after 1 week, along with an improvement in 6MWD.8 According to the inclusion criteria, the participants in the current study had no severe daytime hypoxemia, with a mean Spo2 of 93% and Pao2 of 8.05 kPa (61 mm Hg) during screening; however, nocturnal Spo2 was reduced because of SDB. In accordance, other investigators found that supplemental oxygen ameliorates pulmonary vascular resistance even at Pao2 values > 8 kPa.23

Patients with structural heart disease have an increased prevalence of PAC and also of premature ventricular complexes.2426 In patients with PH, PACs are frequently recorded ECG abnormalities. PACs are independent and strong predictors of development of new AF and associated complications in patients with PH.2426 Concordantly, patients with frequent PACs (> 100 PAC/d) had higher incidence of AF than those without frequent PACs, with a hazard ratio of 3.9 (95% CI, 3.2-11.1; P < .001).26 In our trial, PACs were reduced under acetazolamide, potentially because of a diuretic-induced reduced wall stress.27

In patients with PH, supraventricular tachycardia is prevalent, with an annual risk of 2.8% per patient,6,28,29 with atrial flutter/AF followed by atrioventricular nodal reentry tachycardia being the most common. In previous studies, restoration of normal sinus rhythm was correlated with clinical improvement as well as recovery from RV failure.29 These observations appear to be related to improved atrial transport and a longer diastolic filling time by restoration of sinus rhythm. According to Olsson et al,28 permanent AF but not transient episodes are associated with increased mortality. However, it may well be that short atrial bursts (< 30 s) antecede AF6,28,30 and may be relevant in certain clinical settings (eg, in the presence of brain infarcts)31 or herald longer periods of AF occurring outside the monitoring period.32 In our cohort, only one patient suffered from persistent AF, and no events of paroxysmal AF has been identified, but we registered episodes of atrial bursts.

A disturbance in conduction from right to left atrium results in a broad P.33 P wave has been shown to be significantly longer in patients with chronic lung diseases who subsequently developed AF compared with those remaining in sinus rhythm.34 The PQ interval represents the conduction through the atria and atrioventricular node.33 Increased atrial conduction time or intra-atrial block may manifest as prolonged PQ and may directly increase the risk of AF.34 However, PQ and P duration can change with heart rate, and PQ can, thus, be adjusted (PQc).19 We found a longer P wave and PQc under acetazolamide in the evening. Acetazolamide is a mild diuretic and a respiratory stimulant and is used to treat SDB at high altitude.27,35 A single dose of acetazolamide given before bedtime improves SDB in heart failure and results in better oxygenation.9 This may be reflected in an improvement in cardiac function. However, metabolic acidosis and chemoreceptor stimulation by acetazolamide increase sympathetic activity,9 whereas improved SDB may reduce it. This may explain why the PQc was only prolonged in the evening, when acetazolamide tablets had been taken shortly before, but not in the morning, when favorable effects on SDB predominate.

Sun et al15 retrospectively analyzed the QRS duration in 212 patients with idiopathic PAH. A prolonged QRS complex, defined as a QRS duration ≥ 120 milliseconds, was present in 35 patients (16.5%) and, hence, higher than in the general population, confirmed by others as well.36 Patients with increased QRS duration had a more advanced WHO functional class and larger diameter of the right side of the heart, suggesting a possible pathogenetic role of RV overload.15 In these patients, the prevalence of a prolonged QRS complex was also common, with a significantly shorter QRS duration under NOT compared with acetazolamide in the evening. In a previous study, the prolonged QRS was not shortened by PAH target therapy, and the authors concluded that unfavorable conduction changes may be difficult to reverse by therapy.37

Compared with placebo, NOT was associated with a significantly shorter QTc interval, whereas the QTc interval under acetazolamide was unchanged. The QT corresponds to the total duration of ventricular myocardial depolarization and repolarization, which includes the vulnerable period for reentry tachycardia38 and might be responsible for arrhythmia and impaired RV function.38,39 Patients with PAH or CTEPH have longer QTc compared with control subjects.38 A prolonged QTc (≥ 480 milliseconds) in patients with PAH is a predictor of worse outcome and mortality39 and correlates with RV size and function.39 Although in our study 17%, 9%, and 23% under placebo, NOT, and acetazolamide had a QTc ≥ 480 milliseconds, the median QTc was shorter with active treatments than with placebo and significantly shorter after a night with NOT compared with sham/placebo and acetazolamide.

TpTe represents the maximal transmural dispersion of repolarization of the ventricle.40 It is a useful index in the assessment of arrhythmic risk, as an amplification of the transmural dispersion of repolarization may facilitate propagation of early afterdepolarizations (R-on-T phenomenon) and lead to functional transmural reentry and development of polymorphic ventricular tachycardia and fibrillation.41 Further, an increase of the transmural dispersion of repolarization under conditions of QT prolongation serves as a functional reentrant substrate for the maintenance of torsade de pointes.40 In our study, we found that in the morning after NOT, the TpTec was significantly shorter compared with acetazolamide and tended to be shorter compared with placebo. Whether these differences would translate in a true improvement on arrhythmogenic risk under NOT has to be assessed in future, longer-term studies. It could be that the increase in TpTec under acetazolamide is attributed to a lower serum potassium, a condition with known proarrhythmic potential.42,43 However, although serum potassium was lower in patients treated with acetazolamide, the mean values were still above the lower limit of normal given by our laboratory, and arrhythmias were, with the exception of PAC, similarly found under all treatments. It is important to consider that the consequence of an increased arrhythmogenic risk due to an altered repolarization or conduction have not been studied in PH and it is not known whether patients with PH die because of ventricular arrhythmias.

Our study is relatively small, with only 23 patients included. However, PAH and CTEPH are rare diseases, and patients affected are heterogeneous. The crossover design has the advantage that patients are their own control subjects; thus, the design addresses heterogeneity and allows reducing sample size. The randomization of treatment sequences and statistical analysis for carryover effects are mandatory; the latter was not found in our study. The relatively complex design with double crossover was chosen as we wanted to study the effect of not only NOT but also acetazolamide, a promising drug from a theoretical standpoint since it reduced periodic breathing at high altitude, in idiopathic central sleep apnea, and in periodic breathing secondary to left-sided heart failure. We used the 6MWD as primary end point according to its widespread acceptance in PH for disease monitoring, as trial end point, and for drug registration. However, we are aware that the 6MWD has many drawbacks as trial end point. In this article, we focus on the effects of NOT and acetazolamide on cardiac arrhythmias, conduction, and repolarization. The value of these measures to predict longer-term outcome has to be assessed in future studies.

In summary, our study shows that NOT given for a week reduces heart rate and QTc in patients with PH and SDB compared with placebo. The fact that NOT favorably modifies markers of prognosis and disease severity in PH already after a few days is promising. It supports the use of NOT in long-term studies that might corroborate the beneficial effect of NOT on exercise performance and on prognosis.

Author contributions: S. U. is the guarantor and takes responsibility for the content of the manuscript, including the data and analysis. D. S. S. contributed to acquiring, analyzing, and interpreting the data, writing and revising the article critically for important intellectual content and providing final approval of the version to be published; S. M.-M., E. D. H., F. F. H., S. K., and R. S. contributed to data collection and analysis and revising the article critically for important intellectual content; and K. E. B. and S. U. conceived the project and contributed to data collection, analysis, and interpretation, writing the manuscript, revising the article critically for important intellectual content, and providing final approval of the version to be published.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

6MWD

6-min walk distance

AF

atrial fibrillation

bpm

beats/min

CTEPH

chronic thromboembolic pulmonary hypertension

NOT

nocturnal oxygen therapy

PAC

premature atrial contraction

PAH

pulmonary arterial hypertension

PH

pulmonary hypertension

PQc

heart rate-adjusted value of PQ

QTc

heart rate-corrected value of QT

RV

right ventricle

SDB

sleep-disturbed breathing

Spo2

oxygen saturation

TpTe

interval between the peak and the end of the T wave on ECG

TpTec

heart rate-corrected value of the interval between the peak and the end of the T wave on ECG

WHO

World Health Organization

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Latshang TD, Nussbaumer-Ochsner Y, Henn RM, et al. Effect of acetazolamide and autoCPAP therapy on breathing disturbances among patients with obstructive sleep apnea syndrome who travel to altitude: a randomized controlled trial. JAMA. 2012;308(22):2390-2398. [CrossRef] [PubMed]
 
Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation in patients with pulmonary hypertension. Int J Cardiol. 2013;167(5):2300-2305. [CrossRef] [PubMed]
 
Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J. 2007;153(1):127-132. [CrossRef] [PubMed]
 
Ruiz-Cano MJ, Gonzalez-Mansilla A, Escribano P, et al. Clinical implications of supraventricular arrhythmias in patients with severe pulmonary arterial hypertension. Int J Cardiol. 2011;146(1):105-106. [CrossRef] [PubMed]
 
Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-e198. [CrossRef] [PubMed]
 
Alhadramy O, Jeerakathil TJ, Majumdar SR, Najjar E, Choy J, Saqqur M. Prevalence and predictors of paroxysmal atrial fibrillation on Holter monitor in patients with stroke or transient ischemic attack. Stroke. 2010;41(11):2596-2600. [CrossRef] [PubMed]
 
Snyder ML, Soliman EZ, Whitsel EA, Gellert KS, Heiss G. Short-term repeatability of electrocardiographic P wave indices and PR interval. J Electrocardiol. 2014;47(2):257-263. [CrossRef] [PubMed]
 
Hayashi H, Miyamoto A, Kawaguchi T, et al. P-pulmonale and the development of atrial fibrillation. Circ J. 2014;78(2):329-337. [CrossRef] [PubMed]
 
Nussbaumer-Ochsner Y, Latshang TD, Ulrich S, Kohler M, Thurnheer R, Bloch KE. Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. Chest. 2012;141(1):131-138. [CrossRef] [PubMed]
 
Kalogeropoulos AP, Georgiopoulou VV, Howell S, et al. Evaluation of right intraventricular dyssynchrony by two-dimensional strain echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2008;21(9):1028-1034. [CrossRef] [PubMed]
 
Snipelisky D, Burger C, Shapiro B, Kusumoto F. Electrocardiographic changes in patients responding to treatment with group I pulmonary arterial hypertension. South Med J. 2013;106(11):618-623. [CrossRef] [PubMed]
 
Hong-liang Z, Qin L, Zhi-hong L, et al. Heart rate-corrected QT interval and QT dispersion in patients with pulmonary hypertension. Wien Klin Wochenschr. 2009;121(9-10):330-333. [CrossRef] [PubMed]
 
Rich JD, Thenappan T, Freed B, et al. QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension. Int J Cardiol. 2013;167(3):669-676. [CrossRef] [PubMed]
 
Hlaing T, Guo D, Zhao X, et al. The QT and Tp-e intervals in left and right chest leads: comparison between patients with systemic and pulmonary hypertension. J Electrocardiol. 2005;38(4 suppl):154-158. [CrossRef] [PubMed]
 
Hlaing T, DiMino T, Kowey PR, Yan GX. ECG repolarization waves: their genesis and clinical implications. Ann Noninvasive Electrocardiol. 2005;10(2):211-223. [CrossRef] [PubMed]
 
Richalet JP, Rivera-Ch M, Maignan M, et al. Acetazolamide for Monge’s disease: efficiency and tolerance of 6-month treatment. Am J Respir Crit Care Med. 2008;177(12):1370-1376. [CrossRef] [PubMed]
 
Slovis C, Jenkins R. ABC of clinical electrocardiography: conditions not primarily affecting the heart. BMJ. 2002;324(7349):1320-1323. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Patient flow. AZM = treatment with acetazolamide tablets 250 mg bid; NOT = nocturnal oxygen therapy via a nasal cannula at a flow of 3 L/min; placebo = tablets bid; sham-NOT = room air at a flow rate of 3 L/min.Grahic Jump Location
Figure Jump LinkFigure 2 –  Effect of nocturnal oxygen and acetazolamide on mean nocturnal heart rate. Data are presented as mean and 95% CI. *There was a significant decrease in heart rate under NOT compared with placebo (P = .010). bpm = beats/min. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3 –  Examples of arrhythmias in nocturnal ECG recordings. A, Atrial fibrillation. B, Atrial burst. C, Premature atrial contraction. D, Premature unifocal ventricular complexes.Grahic Jump Location
Figure Jump LinkFigure 4 –  Effect of nocturnal oxygen and acetazolamide on QTc interval at late evening. *There was a significant decrease in QTc duration under NOT compared with placebo (P = .007). QTc = heart rate-corrected value of QT. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5 –  Effect of nocturnal oxygen and acetazolamide on TpTec interval at late evening. #There was a significant decrease in TpTec duration under NOT compared with acetazolamide (P = .028). TpTec = heart rate-corrected value of interval between the peak and the end of the T wave on ECG. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Patient Characteristics

Data obtained during screening. NYHA = New York Heart Association; PDE = phosphodiesterase; PH = pulmonary hypertension.

a 

Data obtained during last right-sided heart catheterization.

b 

Mean (SD).

Table Graphic Jump Location
TABLE 2 ]  Overnight Mean Nocturnal Heart Rate, Cardiac Arrhythmias, and Potassium and Effect of Nocturnal Oxygen or Acetazolamide

Data given as No. of patients affected (%) and medians (quartiles) with the exception of heart rate, which is mean (SD). P by Wilcoxon matched-pairs test for comparisons between treatments with sufficient patient data. bpm = beats/min; Δ = difference NOT respective to acetazolamide with sham-NOT/placebo; NOT = nocturnal oxygen therapy.

a 

P by Fisher exact test for comparisons between treatments with sufficient patient data.

Table Graphic Jump Location
TABLE 3 ]  Late Evening: Effect of Nocturnal Oxygen or Acetazolamide on ECG Interval Times

Values are medians (quartiles) and between-treatment differences are means (95% CIs). P value by Wilcoxon matched-pairs test for comparisons between treatments. PQc = heart rate-adjusted value of PQ; QTc = heart rate-corrected value of QT; TpTe = interval between the peak and the end of the T wave on ECG; TpTec = heart rate-corrected value of the interval between the peak and the end of the T wave on ECG. See Table 2 legend for expansion of other abbreviations.

a 

Heart rate-adjusted.

Table Graphic Jump Location
TABLE 4 ]  Early Morning: Effect of Nocturnal Oxygen or Acetazolamide on ECG Interval Times

Values are medians (quartiles) and between-treatment differences are means (95% CIs). P value by Wilcoxon matched-pairs test for comparisons between treatments. See Table 2 and 3 legends for expansion of abbreviations.

a 

Heart rate-adjusted.

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Roberts DH, Lepore JJ, Maroo A, Semigran MJ, Ginns LC. Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension. Chest. 2001;120(5):1547-1555. [CrossRef] [PubMed]
 
Conen D, Adam M, Roche F, et al. Premature atrial contractions in the general population: frequency and risk factors. Circulation. 2012;126(19):2302-2308. [CrossRef] [PubMed]
 
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Chong BH, Pong V, Lam KF, et al. Frequent premature atrial complexes predict new occurrence of atrial fibrillation and adverse cardiovascular events. Europace. 2012;14(7):942-947. [CrossRef] [PubMed]
 
Latshang TD, Nussbaumer-Ochsner Y, Henn RM, et al. Effect of acetazolamide and autoCPAP therapy on breathing disturbances among patients with obstructive sleep apnea syndrome who travel to altitude: a randomized controlled trial. JAMA. 2012;308(22):2390-2398. [CrossRef] [PubMed]
 
Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation in patients with pulmonary hypertension. Int J Cardiol. 2013;167(5):2300-2305. [CrossRef] [PubMed]
 
Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension. Am Heart J. 2007;153(1):127-132. [CrossRef] [PubMed]
 
Ruiz-Cano MJ, Gonzalez-Mansilla A, Escribano P, et al. Clinical implications of supraventricular arrhythmias in patients with severe pulmonary arterial hypertension. Int J Cardiol. 2011;146(1):105-106. [CrossRef] [PubMed]
 
Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-e198. [CrossRef] [PubMed]
 
Alhadramy O, Jeerakathil TJ, Majumdar SR, Najjar E, Choy J, Saqqur M. Prevalence and predictors of paroxysmal atrial fibrillation on Holter monitor in patients with stroke or transient ischemic attack. Stroke. 2010;41(11):2596-2600. [CrossRef] [PubMed]
 
Snyder ML, Soliman EZ, Whitsel EA, Gellert KS, Heiss G. Short-term repeatability of electrocardiographic P wave indices and PR interval. J Electrocardiol. 2014;47(2):257-263. [CrossRef] [PubMed]
 
Hayashi H, Miyamoto A, Kawaguchi T, et al. P-pulmonale and the development of atrial fibrillation. Circ J. 2014;78(2):329-337. [CrossRef] [PubMed]
 
Nussbaumer-Ochsner Y, Latshang TD, Ulrich S, Kohler M, Thurnheer R, Bloch KE. Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. Chest. 2012;141(1):131-138. [CrossRef] [PubMed]
 
Kalogeropoulos AP, Georgiopoulou VV, Howell S, et al. Evaluation of right intraventricular dyssynchrony by two-dimensional strain echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2008;21(9):1028-1034. [CrossRef] [PubMed]
 
Snipelisky D, Burger C, Shapiro B, Kusumoto F. Electrocardiographic changes in patients responding to treatment with group I pulmonary arterial hypertension. South Med J. 2013;106(11):618-623. [CrossRef] [PubMed]
 
Hong-liang Z, Qin L, Zhi-hong L, et al. Heart rate-corrected QT interval and QT dispersion in patients with pulmonary hypertension. Wien Klin Wochenschr. 2009;121(9-10):330-333. [CrossRef] [PubMed]
 
Rich JD, Thenappan T, Freed B, et al. QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension. Int J Cardiol. 2013;167(3):669-676. [CrossRef] [PubMed]
 
Hlaing T, Guo D, Zhao X, et al. The QT and Tp-e intervals in left and right chest leads: comparison between patients with systemic and pulmonary hypertension. J Electrocardiol. 2005;38(4 suppl):154-158. [CrossRef] [PubMed]
 
Hlaing T, DiMino T, Kowey PR, Yan GX. ECG repolarization waves: their genesis and clinical implications. Ann Noninvasive Electrocardiol. 2005;10(2):211-223. [CrossRef] [PubMed]
 
Richalet JP, Rivera-Ch M, Maignan M, et al. Acetazolamide for Monge’s disease: efficiency and tolerance of 6-month treatment. Am J Respir Crit Care Med. 2008;177(12):1370-1376. [CrossRef] [PubMed]
 
Slovis C, Jenkins R. ABC of clinical electrocardiography: conditions not primarily affecting the heart. BMJ. 2002;324(7349):1320-1323. [CrossRef] [PubMed]
 
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