Electrocardiographic changes during sustained normobaric hypoxia in patients after myocardial infarction

The safety of prolonged high-altitude stays and exercise for physically fit post-myocardial infarction (MI) patients is unclear. Myocardial tissue hypoxia and pulmonary hypertension can affect cardiac function and electrophysiology, possibly contributing to arrhythmias. We included four non-professional male athletes, clinically stable after left ventricular MI (three with ST-segment elevation MI and one with non-ST-segment elevation MI) treated with drug-eluting stents for single-vessel coronary artery disease. Oxygen levels were reduced to a minimum of 11.8%, then restored to 20.9%. We conducted electrocardiography (ECG), ergometry, and echocardiography assessments in normoxic and hypoxic conditions. With an average age of 57.8 ± 3.3 years and MI history 37 to 104 months prior, participants experienced a significant increase in QTc intervals during hypoxia using Bazett’s (from 402 ± 13 to 417 ± 25 ms), Fridericia’s (from 409 ± 12 to 419 ± 19 ms), and Holzmann's formulas (from 103 ± 4 to 107 ± 6%) compared to normoxia. This effect partially reversed during recovery. Echocardiographic signs of pulmonary hypertension during normobaric hypoxia correlated significantly with altered QTc intervals (p < 0.001). Despite good health and complete revascularization following MI, susceptibility to hypoxia-induced QTc prolongation and ventricular ectopic beats persists, especially during physical activity. MI survivors planning high-altitude activities should consult cardiovascular specialists with high-altitude medicine expertise.

Inclusion criteria encompassed patients with a history of prior myocardial infarction, fully revascularized left anterior descending (LAD) lesions, overall good health, physical fitness, and prior altitude tolerance exceeding 2000 m.Patients were clinically stable in the preceding 12 months and had previously tolerated altitudes of > 2000 m.
Exclusion criteria covered myocardial infarction within the last 12 months, non-LAD culprit lesion, incomplete revascularization during percutaneous coronary intervention (PCI), multivessel coronary artery disease, significant pre-existing lung disease, left ventricular ejection fraction (LVEF) < 35%, regular angina pectoris, cardiac decompensation within the past year, absence of heart failure medication, and blood parameter abnormalities, particularly thrombocytosis.
In the DLR:envihab hypoxia module (https:// www.dlr.de/ envih ab/ en/ deskt opdef ault.aspx/), we gradually decreased atmospheric oxygen (FIO2) to a minimum of 11.8% (hypoxia), which equals the oxygen content at ≈ 4500 m, over a period of 14 days.FIO2 of 11.8% was maintained for 4.5 days followed by return to normoxia within two days.Subjects received a standard normocaloric diet with four meals per day.Following a structured daily schedule, subjects woke up at 7 a.m., spent 15 h awake performing light activities, and went to bed at 10 p.m.Each subject completed 60 min of aerobic exercise daily on a treadmill or bicycle.We obtained 12-lead resting ECG daily.Transthoracic echocardiography was performed on the second day of acclimatization and daily at 11.8% FIO 2 , and during the first two days of recovery at 20.9% FIO 2 to assess echocardiographic signs of PH (TR dPmax tricuspid regurgitation jet maximal pressure gradient, PVAT pulmonary velocity acceleration time, RA right atrium area, TR Vmax maximal tricuspid regurgitation velocity).We submitted participants to exercise ECG with 25 W increments until exhaustion on a bicycle ergometer under normoxia, and under 17.5% FIO 2 (~ 1500 m) but for safety reasons not during more intense hypoxia.
The study, including all experimental protocols, was registered (DRKS00013772), approved by the local ethics committee of the North Rhine Medical Association in Düsseldorf, Germany ("Ärztekammer Nordrhein") and conducted in accordance with the Declaration of Helsinki after obtaining informed consent from all subjects.All methods were carried out in accordance with relevant guidelines and regulations.
Results are presented as mean ± standard deviation.Pearson correlation between any two variables were calculated and accompanied by a "Wald-type" p-value based on bootstrap standard errors.Differences in mean values over conditions were evaluated by linear mixed models with fixed effect condition and random effect subject.Differences between paired measurements were tested by the (exact) Wilcoxon signed-rank test.Additionally, Friedman test was applied to assess significant differences among multiple related groups with non-normally distributed dependent variables.www.nature.com/scientificreports/Of the initially screened 11 patients, we included four male recreational athletes (age, 54-63 years; body mass index, 21-25 kg/m 2 ; VO 2 max, 32-43 mL/kg per minute) who were in clinically stable conditions 37 to 104 months following left ventricular myocardial infarction.Three participants had experienced ST-segmentelevation myocardial infarction (STEMI), while one had a history of non-ST-segment-elevation myocardial infarction (NSTEMI).In each participant, effective revascularization was achieved by subsequent drug-eluting stent intervention, targeting an isolated stenosis within the mid-to-ostial segment of the LAD artery.Two women were excluded, one due to thrombocytosis and the other due to right ventricular involvement 5 .An additional male participant (aged 60 years), who was athletically active and had no previous history of myocardial infarction, was included as a control.Transthoracic echocardiography revealed distinct left ventricular wall motion abnormalities and corresponding LVEF for each patient: Patient 1 presented with apical, anteroseptal, and anterolateral akinesis (LVEF = 50%); Patient 2 showed apical, septal, anterior, and apical inferior akinesis (LVEF = 36%); Patient 3 exhibited apical and apical septal hypokinesis (LVEF > 50%); and Patient 4 had no abnormalities (EF = 58%).Following myocardial infarction, all participants received standard medical treatment, including aspirin for two out of four, marcumar for one out of four, anti-Xa-antagonist for one out of four, statins for all four, ACE inhibitors/AT1 antagonist for all four, azetidinone for one out of four, β-blockers for one out of four, and dihydropiyridine for one out of four 5 .
The datasets that support the findings of this study are available from the corresponding author upon reasonable request.
The key finding of our study is that clinically stable and physically fit post-myocardial infarction patients exhibit QTc interval prolongation in response to hypoxia-induced PH.Additionally, VES occur more frequently during and after exercise, even at altitudes equivalent to approximately 1500 m, likely due to hypoxia-induced PH and sympathetic activation 1 .QTc interval prolongation is also common in chronic PH with impaired right ventricular function 6 .While cardiac output and hematocrit adjustments usually maintain systemic oxygen delivery 1 , microcirculatory dysfunction-induced tissue hypoxia may affect cardiac electrophysiology.There is no evidence of a significant risk of fatal arrhythmias from hypoxia in healthy individuals 1 .However, in patients with heart diseases, QTc interval prolongation and VES should be taken seriously 7 .
Limitations include the small sample size consisting of only four participants and the exclusive inclusion of male participants, which restrict the generalizability of our findings to a broader post-myocardial infarction population.Additionally, asymptomatic electrocardiographic changes may not directly predict clinical outcomes.Moreover, variability in patients' ejection fractions has the potential to introduce heterogeneity in the study population.Furthermore, the inclusion of a patient with NSTEMI, characterized by distinct pathogenesis and myocardial scar mass compared to STEMI, could confound result interpretation.Given the pilot nature of this study, our preliminary findings require careful consideration.
Despite these limitations, our study indicates that even exceptionally healthy, fully revascularized post-myocardial infarction patients may be susceptible to hypoxia-induced QTc interval prolongation and VES, particularly during physical exertion.Albeit the clinical implications of these findings may warrant further investigation, we recommend cardiovascular evaluation by a high-altitude medicine specialist for post-myocardial infarction patients planning high-altitude physical activities.Future research should investigate the efficacy of hypoxiainduced cardiovascular stress testing in guiding such decisions.