A 4-Day Exposure to High Altitude Prolongs QTc in Healthy Human Subjects

Abstract

Introduction

Long QTc syndrome can predispose patients to fatal ventricular arrhythmias. We studied the effects of a rapid ascent and a multiday stay at high altitude on QTc interval.

Methods

We recorded electrocardiograms (ECGs) on study subjects at sea level and then again after a 1-d ascent to 3800 m. Two sea-level ECGs were recorded at the initial screening visit (SL1) and 14 days later (SL2). Altitude ECGs were recorded at approximately 16 and 86 h after arrival. SpO₂ was recorded prior to each ECG measurement. We defined prolonged QTc as a QTc interval >450 ms for men and >470 ms for women. We used multivariate analysis to analyze the QTc interval for the effect of drugs, altitude, and changes in electrolytes.

Results

We enrolled 107 subjects: 61 males and 46 females between the ages of 19 and 54 y, with a median age of 34 y. QTcF (QT interval for varying heart rates using Fridericia's formula) at SL1 was 405±17 ms; at SL2, 404±17 ms; at 16 h, 411±18 ms; and at 86 h, 427±24 ms. After 86 h at altitude, 12 participants met the criteria for prolonged QT syndrome, and 61% of subjects had QTc prolongation of >20 ms from sea-level values. This was independent of changes in serum electrolyte levels, (i.e., sodium, potassium, and calcium), bicarbonate levels, and SpO₂.

Conclusion

High altitude exposure can lengthen a healthy adult's QTc interval by more than 20 ms. It remains unknown whether this increase might raise the risk of torsades de pointes in people with long QT intervals at baseline.

Keywords

QT interval high altitude medicine QT prolongation electrocardiology hypobaric hypoxia torsades de pointes

Introduction

In 2019, mountain tourism accounted for between 9% and 16% of international tourism worldwide, which represents ∼375 million tourists traveling to altitude.¹ As the number of people traveling to the mountains increases, a deeper understanding of human physiology, especially the risks associated with traveling to high altitude, is necessary.

The QT interval is measured from the beginning of the QRS complex to the end of the T wave on the electrocardiogram (ECG), representing the completion of 1 cycle of ventricular depolarization and repolarization.² Heart rate affects the length of the QT interval, with higher heart hearts leading to shorter QT intervals. For this reason, the QT interval is corrected for heart rate, creating a QTc value that can be compared across variable heart rates and used to determine if the QT interval is prolonged. The normal upper limit of QTc is 450 ms in males and 470 ms in females. Long QTc can be proarrhythmic and lead to torsades de pointes (TdP), a type of ventricular arrhythmia associated with a prolonged QTc interval. TdP can self-terminate, and some patients with TdP are asymptomatic, but if TdP persists, symptoms can include palpitations, dizziness, and syncope.³ About 10% to 20% of TdP cases degenerate into ventricular fibrillation that is often lethal.^3,4 Although a QTc interval greater than the normal limits does not definitively mean that a ventricular arrhythmia will occur, QTc length is clinically significant because the risk of ventricular arrhythmia is believed to increase by ∼6% for each 10-ms increase from baseline.⁵ When QTc length is greater than 500 ms, it may increase the risk of TdP threefold.⁶ Genetic background, female sex, heart failure, myocardial ischemia, serum electrolyte levels, and certain drugs can prolong the QT interval and are associated with TdP.⁷ The effects of these factors on the QT interval can be additive.⁸ There is also evidence that acute hypoxia can prolong the QTc interval in healthy human subjects.^9,10

Few studies have investigated changes in the ECG during acute or prolonged altitude exposure (hypobaric hypoxia) or sea-level hypoxia (normobaric hypoxia). Most are limited by small sample sizes, short exposure durations, and elevation changes throughout the study period.^11–14 We performed a secondary analysis using data from a clinical trial titled, “A randomized phase 2 study to evaluate efficacy and safety of AR36 for prevention of acute mountain sickness” (NCT03552263), that aimed to investigate a novel therapy for acute mountain sickness.¹⁵ The primary trial identified no effect of the investigational drug on QTc interval. This study focused on how a 4-d exposure to high altitude affects QTc interval and its relationship to multiple electrolytes in healthy human subjects.

Methods

The University of California, San Francisco, Institutional Review Board approved this research, which was registered with Clinicaltrials.gov (NCT03552263). We enrolled 168 healthy human subjects in a double-blind, randomized, placebo-controlled trial investigating the efficacy of the drug AR36 in preventing altitude sickness. All study staff and subjects remained blinded to the enrollment group until the study was completed for all subjects.

Enrollment criteria included healthy people between the ages 18 and 55 y with normal vital signs, normal physical exams, oxygen saturation greater than 95% at sea level, no history of chronic diseases such as hypertension or diabetes, no chronic headache, ability to pass a urine screen for illicit drugs, not ascending to an altitude greater than 3048 m (10,000 ft) within 4 mo of participating in the trial, a primary residence below 305 m (1000 ft), and normal baseline laboratory panel and normal baseline ECG. A complete list of enrollment criteria is provided in Table 1.

Table 1.

Inclusion and exclusion criteria used in the study.

Inclusion criteria	Exclusion criteria
1. Healthy volunteers: ages 18–55 y 2. Primary residence elevation of 1000 ft or lower 3. Not ascending to altitude >10,000 ft within 4 mo prior to screening 4. Females of childbearing potential must have a negative pregnancy test, not be breastfeeding, and established on a method of contraception that in the investigator's opinion is acceptable. ^a Females must agree to remain on their established method of contraception from the time of the screening visit and throughout the study period. 5. Willing to participate voluntarily and to sign a written informed consent	1. Subjects with medical history of cardiovascular disease, cerebrovascular diseases, or asthma 2. Subjects with clinically significant respiratory system disease, digestive disease, mental disease, metabolic disease, acute infection, or anemia 3. Total Lake Louise Scoring System self-assessment score and clinical assessment score >1 before ascending (Screening visit and Visit 1) 4. Blood oxygen saturation (SpO₂)<95% at sea level 5. Subjects with abnormal renal or liver function with clinical significance (alanine transaminase [ALT] or aspartate transaminase [AST] >2×upper limits of normal [ULN], creatinine >ULN) ^b 6. Subjects with C-reactive protein >ULN ^c 7. Subjects with primary headache ^d 8. Surgery or blood donation within 3 mo prior to screening 9. On treatment of any medications (including any dietary supplements) except for birth control within 14 d prior to screening and throughout the study period 10. Contraindication to treatment with Danshen (Radix Saliva Miltiorrhize Bge, RSM) products ^e 11. Women in pregnancy or lactation period 12. Substance abuse: Subjects with a recent history (within the last 2 y) of alcoholism or known drug dependence 13. Participation in any other clinical trial or on an investigational drug within 30 d prior to screening 14. A family member or relative of the study-site staff 15. Any other condition that, in the opinion of the investigator, is likely to prevent compliance with the study protocol, interfere with the assessment, or pose a safety concern if the subject participates in the study

Inclusion criteria

Exclusion criteria

1. Healthy volunteers: ages 18–55 y
2. Primary residence elevation of 1000 ft or lower
3. Not ascending to altitude >10,000 ft within 4 mo prior to screening
4. Females of childbearing potential must have a negative pregnancy test, not be breastfeeding, and established on a method of contraception that in the investigator's opinion is acceptable. ^a Females must agree to remain on their established method of contraception from the time of the screening visit and throughout the study period.
5. Willing to participate voluntarily and to sign a written informed consent

1. Subjects with medical history of cardiovascular disease, cerebrovascular diseases, or asthma
2. Subjects with clinically significant respiratory system disease, digestive disease, mental disease, metabolic disease, acute infection, or anemia
3. Total Lake Louise Scoring System self-assessment score and clinical assessment score >1 before ascending (Screening visit and Visit 1)
4. Blood oxygen saturation (SpO₂)<95% at sea level
5. Subjects with abnormal renal or liver function with clinical significance (alanine transaminase [ALT] or aspartate transaminase [AST] >2×upper limits of normal [ULN], creatinine >ULN) ^b
6. Subjects with C-reactive protein >ULN ^c
7. Subjects with primary headache ^d
8. Surgery or blood donation within 3 mo prior to screening
9. On treatment of any medications (including any dietary supplements) except for birth control within 14 d prior to screening and throughout the study period
10. Contraindication to treatment with Danshen (Radix Saliva Miltiorrhize Bge, RSM) products ^e
11. Women in pregnancy or lactation period
12. Substance abuse: Subjects with a recent history (within the last 2 y) of alcoholism or known drug dependence
13. Participation in any other clinical trial or on an investigational drug within 30 d prior to screening
14. A family member or relative of the study-site staff
15. Any other condition that, in the opinion of the investigator, is likely to prevent compliance with the study protocol, interfere with the assessment, or pose a safety concern if the subject participates in the study

^a Acceptable contraception methods included, hormonal birth control or abstinence. The ULN was based on University of California, San Francisco, lab reporting guidelines.

^b For this study, ALT ULN was 61 U·L^–1; AST ULN was 44 U·L^–1; creatinine ULN was 1.24 mg·dL^–1 for males and 1.02 mg·dL^–1 for females.

^c The ULN for c-reative protein was >5 mg·L^–1.

^d Primary headache includes the diagnosis of migraines or other persistent headaches.

^e Danshen is the active ingredient in AR36, the study drug used in the trial.

Table 2.

QTc values at sea-level and altitude.

Visit	QTcF (ms)	QTcF males (ms)	QTcF females (ms)
SL1	405±17	401±17	409±15
SL2	404±17	399±15	410±17
16 h	411±18	409±19	413±17
86 h	427±24	427±24	426±24

Study team members recorded 2 baseline ECG measurements at sea level for each subject, 1 at the initial screening visit and 1 the day before ascent to altitude about 2 wk later (SL1 and SL2). The first ECG was taken to determine whether the subject met the eligibility criteria for the study. The second ECG was recorded after a 14-d run-in period where the subject may have been taking the investigation medication depending on their randomization group. A metabolic panel and complete blood count were collected, and we measured SpO₂ by pulse oximetry using a Rainbow 7 oximeter (Masimo, Irvine, CA) or an Onyx pulse oximeter (Nonin, Minneapolis MN).

On Day 15 of the study, all subjects were transported from sea level to the White Mountain Research Center, Barcroft Station, at 3800 m (12,470 ft) over ∼10 h of driving. On arrival and each day at altitude, subjects completed an exercise test on a bicycle ergometer. We also performed a physical exam and measured basic vital signs. ECG measurements were again performed approximately 16 h after reaching the target altitude and on Day 4, after 86 h at altitude. Study physicians drew a complete blood count and comprehensive metabolic panel from each subject in parallel to ECGs at altitude. We used pulse oximetry to determine blood oxygen saturation (SpO₂) values when each subject woke up, prior to ECG recording. The timing for the first ECG taken at altitude was based on the logistics of transporting subjects and collecting other data after arrival at the station. The final ECG was taken in conjunction with the final blood draw prior to leaving the station.

We used an ELI 10 ECG machine to record and store the ECGs (Mortara, Milwaukee WI). We corrected the QT interval for differences in heart rate using Fridericia's method, or QTcF, which was automatically calculated using the machine's algorithm. Every ECG was reviewed by a physician blinded to the study, and we performed random audits using direct measurement, which showed no difference in values by calculation or measurement from those reported by the ECG machine. QTcF was used in the primary drug study for calculating QTc length. Similarly, we used QTcF for primary analysis for this study because it has been shown to better correct over a wider range of heart rates such as tachycardia likely encountered during an ascent to altitude.¹⁶

Statistics

We analyzed QTcF and blood oxygen saturation by 2-way analysis of variance for effect of drug and altitude as well as post-hoc Sidak's correction to adjust the significance level for multiple comparisons at each time point. We calculated the correlation coefficient between heart rate and QTc interval to determine whether Fridericia's method was effective at correcting QT interval in our subject population. There should be no correlation between heart rate and QT interval if the correction is effective.¹⁶ We performed linear regression to determine the relationship between SpO₂ and QTc length. Because electrolyte values were normal in most subjects, we analyzed changes in serum potassium, calcium, and sodium levels in our participants between sea level and altitude to look for a relationship to QTc length. We performed multivariate linear regression to identify the influence of changes in serum potassium, calcium, sodium, and bicarbonate on QTc length. We reported all values as mean±SD (with range). We considered P values of 0.05 or less significant, and we adjusted for multiple comparisons when they occurred. All statistical tests were completed using Prism 9.2 Software (GraphPad, San Diego CA).

Results

Of the 168 subjects who met inclusion criteria and consented, 107 had full compliance with all ECG procedures and were included in this study. Sixty-one males and fourty-six females between the ages of 19 and 54 y with a median age of 34 y participated. QTc values at all time points are shown in Figure 1. At the 86-h time point, 11% of participants met clinical criteria for prolonged QTc interval, and 61% of subjects had an increase of >20 ms over baseline. Table 2 shows the mean QTc values observed at each visit. There was no difference between male and female QTc values at altitude visits. Two-way analysis of variance identified time at altitude as a significant factor in QTc duration. There was no effect of drug treatment, and post-hoc analysis identified significant differences in QTc interval between SL1 and 16 h (P<0.0001) and SL1 and 86 h (P<0.0001), with a 7-ms increase from SL1 to 16 h and a 22-ms increase from SL1 to 86 h. There also was a significant increase between SL2 and 16 h (P<0.0001) and SL2 and 86 h (P<0.0001), with a 7-ms increase between SL2 and 16 h and a 23-ms increase between SL2 and 86 h. QTc interval also increased significantly at altitude between 16 h and 86 h (16 ms; P<0.0001; Figure 2).

Figure 1.

QTcF for subjects separated by day. Asterisks indicate significant differences (P<0.05).

Figure 2.

Intrasubject variability between sea-level and altitude measurements. The top figure shows the intrasubject difference between 16 and86 h. The bottom figure shows the intrasubject difference between SL1 and 86 h.

Heart rate increased modestly at altitude compared with sea level (SL1=63±12 beats/min; SL2=67±11 beats/min; 16 h=78±13 beats/min; 86 h=78±143 beats/min). Correlation coefficients between heart rate and QTc interval were not significant.

Sea-level blood oxygen saturation at SL1 was 98%±1%, and at SL2, it was 98%±1%. Blood oxygen saturation values at altitude were not different at 16 h (88%±5%) and 86 h (88%±4%). We found no correlation between blood oxygen saturation and QTc interval at these time points.

Table 3 shows the changes in electrolytes throughout the study. There were significant changes from sea level to altitude, but electrolyte levels did not change between altitude measurements. Using multivariate linear regression to analyze the relationship between serum electrolyte changes and the increase in QTc interval, we found no relationship between potassium, bicarbonate, calcium, and sodium with QTc changes.

Table 3.

Changes in electrolyte values between sea-level and altitude measurements.

Timepoint	K⁺	Ca²⁺	Na⁺	HCO₃^–
16 h, SL1	−0.2±0.6 mmol/L ^a	0.1±0.4 mg/dL ^a	0.5±2.5 mmol/L ^a	−3.9±2.5 mmol/L ^a
86 h, SL1	0.2±0.4 mmol/L ^a	0.2±0.4 mg/dL ^a	0.3±3.5 mmol/L	−4.4±2.7 mmol/L ^a
16 h, SL2	0.1±0.7 mmol/L ^a	0.2±0.4 mg/dL ^a	0.2±2.3 mmol/L	−3.1±2.5 mmol/L ^a
86 h, SL2	0.1±0.4 mmol/L ^a	0.3±0.4 mg/dL ^a	−0.0±3.3 mmol/L	−3.6±3.0 mmol/L ^a
86–16 h	0.0±0.6 mmol/L	0.1±0.4 mg/dL	−0.2±3.3 mmol/L	−0.5±2.4 mmol/L

^a Changes that were significantly different.

Discussion

The novel finding of this study is that the QTc interval is prolonged after acute ascent to 3800 m of altitude, including a 22-ms increase 86 h after arrival. Other authors have reported that a >20-ms increase in QTc interval creates an “almost definite” risk for TdP,⁵ and when reviewing drugs for regulatory control, the US Food and Drug Administration stated that a 20-ms increase from baseline is of definite concern due to the risk of TdP.¹⁷

A correlation between QTc interval and blood oxygen saturation has been reported in a small study of healthy subjects exposed to normobaric hypoxia for less than 20 min.⁹ We found no relationship between blood oxygen saturation and QTc interval after 16 or 86 h at altitude. Because blood oxygen saturation did not change significantly between 16 and 86 h at altitude, but an increase in QTc interval was observed, we concluded that hypoxia is unlikely the only driving force behind the increase in QTc interval.

Hypokalemia, hypocalcemia, and hypomagnesemia can lead to QTc prolongation.¹⁸ However, our multivariate analysis found no relationship between electrolytes and QTc prolongation. Electrolyte levels did not explain the significant increase in QTc prolongation between the 2 altitude measurements because electrolyte levels did not change between 16 and 18 h.

When sojourners arrive at high altitude, they begin to hyperventilate to compensate for the low partial pressure of oxygen. This leads to respiratory alkalosis. With extended respiratory alkalosis, bicarbonate is excreted by the kidneys to return blood pH toward normal physiologic levels.¹⁹ The QTc interval is affected by pH. The initial lengthening of the QTc interval on ascent to high altitude could be caused by increased blood pH due to respiratory alkalosis. However, if the QTc interval changes were exclusively dependent on pH, then the renal compensation that drives the normalization of pH with extended time at altitude would decrease the QTc interval toward baseline. Instead, we observed an increase in the QTc interval, suggesting that other mechanisms affect QTc prolongation at high altitude.

One potential mechanism for the prolongation of the QTc interval at altitude is changes in pulmonary artery pressure. With the lower partial pressure of oxygen at high altitudes, pulmonary artery pressure increases due to vasoconstriction in the pulmonary vasculature.²⁰ Chronic pulmonary hypertension has been reported to increase the QTc interval.²¹ We suspect that pulmonary hypertension is a factor in the QTc interval increase we observed, although many other changes in addition to the pressure increase occur in chronic clinical pulmonary hypertension that would not have occurred in the 86 h our subjects were at altitude.^21,22 Further studies that directly or indirectly measure pulmonary artery pressures using ultrasound or other techniques may be able to identify whether a relationship between pulmonary pressure and QTc interval exists and shed more light on a potential mechanism.

The >20-ms increase in QTc interval seen in 61% of our subjects likely poses little risk to normal healthy people but might increase the risk of TdP and ventricular arrhythmias in people with inherent long QT syndrome or those taking medications that prolong the QT interval.

Limitations

Our data were not collected solely to analyze QTc interval at altitude. Because ECGs were not collected on arrival at altitude but 16 h later, it is unknown whether the change occurred on arrival or was gradual. We did not perform 12-lead ECGs on return to sea level, so we cannot determine how long it takes for the QTc interval to return to baseline. Although physicians reviewed all ECGs and random checks were performed on many ECGs, we relied on an algorithm to determine the QTc interval, which could result in errors in calculating QTc interval. We did not directly measure blood pH that might have accounted for changes in the QTc interval. Because this study was part of a larger trial, we only enrolled people who were healthy and not taking medications, which limits the generalizability of the results to the greater population. We also did not have a nonexercise control group for comparison. It is possible that daily maximum-intensity exercise could alter the QT length over several days. Although we initially analyzed both QTcB (QT correction with the Bazett formula) and QTcF, there are other corrections methods to correct the QT interval that we could have used.

Conclusion

Under the conditions in our study, QTc prolongation increases from baseline after ascent to high altitude and continues to increase over 4 d, unrelated to electrolyte levels or blood oxygen saturation. The lengthening of the QTc interval may cause an increase in the risk of TdP in persons with a prolonged QT interval whether the etiology be drug induced or genetic. Patients with these conditions may wish to discuss the risk of travel to high altitude with their medical providers. Further studies, controlling for level of exercise and medication use, are needed to determine the mechanism of an increasing QTc interval at altitude.

Footnotes

Acknowledgments

We thank the additional members of the UCSF T89 working group (Helge Eilers, Philip Bickler, John Feiner, and Andrea Olmos), the White Mountain Research Center, the Barcroft Station staff, and subjects who helped and participated in this work.

Author Contribution(s)

Koa Gudelunas: Investigation; Project administration; Writing – original draft.

Gregory A. Chinn: Formal analysis; Methodology; Writing – review & editing.

Barreto-Chang: Methodology; Writing – review & editing.

Leah Campbell: Investigation; Writing – review & editing.

Jeffrey W. Sall: Conceptualization; Formal analysis; Investigation; Methodology; Project administration; Supervision; Validation; Writing – review & editing.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The primary study was supported by funding from Tasly Pharmaceuticals, which facilitated the data collection for this project.

ORCID iDs

Odmara Barreto-Chang

Jeffrey W. Sall

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