CLINICAL RESEARCH

European Heart Journal (2014) 35, 192–199 doi:10.1093/eurheartj/eht450

Acute coronary syndromes

Impact of sleep-disordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction Stefan Buchner 1†*, Anna Satzl1†, Kurt Debl 1, Andrea Hetzenecker 1, Andreas Luchner 1, Oliver Husser 1, Okka W Hamer 3, Florian Poschenrieder 3, Claudia Fellner 3, Florian Zeman 4, Gu¨nter A.J. Riegger 1, Michael Pfeifer 1,2, and Michael Arzt 1

Received 13 March 2013; revised 9 August 2013; accepted 28 September 2013; online publish-ahead-of-print 27 October 2013

Aims

Sleep-disordered breathing (SDB) may be a risk factor for expansion of infarct size early after acute myocardial infarction (MI) by exposing the heart to repetitive oxygen desaturations and increased cardiac afterload. The objective of this study was to assess the impact of SDB on myocardial salvage and infarct size within 3 months after acute MI. ..................................................................................................................................................................................... Methods Patients with acute MI and percutaneous coronary intervention were enrolled in this prospective observational study. All patients underwent cardiovascular magnetic resonance (CMR) to define salvaged myocardium and infarct size within and Results three to five days and at 3 months after acute MI. Patients were stratified according to apnoea–hypopnoea index (AHI) assessed by polysomnography at baseline into those with (AHI ≥15/h) and without (AHI ,15/h) SDB. Of the 56 patients included, 29 (52%) had SDB. The area at risk between both groups was similar (40 + 12% vs. 40 + 14%, P ¼ 0.925). Patients with SDB had significantly less salvaged myocardium (myocardial salvage index 52% vs. 77%, P , 0.001), smaller reduction in infarct size (0.3% vs. 6.5%, P , 0.001) within 3 months after acute MI, a larger final infarct size (23% vs. 12%, P , 0.001), and a lower final left ventricular ejection fraction (48% vs. 54%, P ¼ 0.023). In a multivariate analysis, including established risk factors for large MI, AHI was independently associated with less myocardial salvage and a larger infarct size 3 months after acute MI. ..................................................................................................................................................................................... Conclusions Sleep-disordered breathing was associated with less myocardial salvage and a smaller reduction in infarct size. These findings suggest a contribution of SDB to impaired healing of MI.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Myocardial infarction † Sleep apnoea † Magnetic resonance imaging † Heart failure

Introduction In acute myocardial infarction (MI), immediate restoration of coronary perfusion to the ischaemic myocardium is the current standard treatment. This approach has been shown to limit infarct size expansion, to salvage ischaemic myocardium and have beneficial effects on post-infarction myocardial healing.1 Beyond successful recanalization of the infarct-related artery by percutaneous coronary intervention (PCI), transient and permanent myocardial damage is frequent in the infarct-related area at risk. Healing of the area at risk is a

complex and dynamic process2 including oxidative stress, haemodynamic changes, neurohumoral activation, and inflammation, which are involved in the infarct and ischaemic border zone.3 The ischaemic border zone might play the key role in ventricular remodelling after acute MI, since myocardial healing is mainly found in this zone which is potentially salvageable.4 Sleep-disordered breathing (SDB) has been shown to be associated with myocardial ischaemia5 and has frequently been noted in patients with acute MI.6 – 8 Sleep-disordered breathing induces acute and chronic stresses that could predispose to myocardial

* Corresponding author: Tel: +49 941 944 7211, Fax: +49 941 944 7213, Email: [email protected] †

Contributed equally.

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]

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1 Klinik und Poliklinik fu¨r Innere Medizin II, Universita¨tsklinikum Regensburg, Regensburg, Germany; 2Zentrum fu¨r Pneumologie, Klinik Donaustauf, Germany; 3Institut fu¨r Ro¨ntgendiagnostik, Universita¨tsklinikum Regensburg, Regensburg, Germany; and 4Zentrum fu¨r klinische Studien, Biostatistics, Universita¨tsklinikum Regensburg, Regensburg, Germany

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ischaemia. The haemodynamic, vascular, inflammatory, and myocardial oxidant stress mechanisms promoted by SDB may influence the infarcted and ischaemic myocardium and the myocardial healing from the acute to the chronic phase adversely.9,10 However, there are limited data on the complex relationship between infarct healing, left ventricular remodelling,7 and SDB in patients with acute MI. This study tested the hypothesis that SDB is associated with less salvaged myocardium and a smaller reduction in infarct size, assessed by cardiovascular magnetic resonance (CMR), within 3 months after acute MI.

Methods

Polysomnography Polysomnography was performed in all subjects using standard polysomnographic techniques (Alice System, Respironics, Pittsburgh, USA). Respiratory efforts were measured with the use of respiratory inductance plethysmography, and airflow by a nasal pressure cannula. Sleep stages, arousals, and apnoeas and hypopnoeas were determined according to the American Academy of Sleep Medicine criteria by one experienced sleep technician blinded to the clinical data.14 Apnoea was defined as a cessation of inspiratory airflow for ≥10 s. Hypopnoea definition A was used.14 The apnoea– hypopnoea index (AHI) was defined as the number of apnoeas and hypopnoeas per hour of sleep. An AHI of ≥15 events per hour indicates at least a moderate degree of SDB. Patients were stratified into those with (AHI ≥15/h) and without (AHI ,15/h) SDB.15

Patients

Study design This prospective observational study was performed at the Universita¨tsklinikum Regensburg, Germany. The study protocol was reviewed and approved by the local institutional ethics committee. The study was performed according to the Helsinki Declaration of Good Clinical Practice. A written informed consent was obtained from all patients prior to enrolment. Eligible patients underwent an overnight in-laboratory sleep study (polysomnography) within 3 – 5 days after PCI. Cardiovascular magnetic resonance studies were performed on Day 3 – 5 after PCI and 3 months later. To assess subjective limitations of physical and daily activities by symptoms of coronary artery disease, the Seattle Angina Questionnaire was used in its German validated form.11,12 Clinical management and medication was at the discretion of the responsible physician according to contemporary practice and guidelines. During follow-up, all patients received aspirin, adenosine diphosphate (ADP) receptor inhibitors, lipid-lowering treatment, ACE inhibitors or angiotensin receptor blockers (ARBs), and b-receptor blockers, unless contraindicated. The primary endpoint of the study was myocardial salvage index defined as the area at risk minus infarct size as a percentage of the area at risk, as measured by CMR. The myocardial salvage index was chosen as the primary endpoint because a low myocardial salvage index is associated with significantly impaired survival.13 The area at risk was measured 3 – 5 days after PCI and the final myocardial infarct size was measured 3 months later. Secondary endpoints were change in infarct size, final infarct size, left ventricular ejection fraction (LVEF), and left ventricular volumes.

Percutaneous coronary intervention Percutaneous coronary intervention was performed according to the standard clinical practice. Thrombectomy and glycoprotein IIb/IIIa inhibitors were used by the decision of the operator, usually in the presence of high thrombus burden. All patients received aspirin, intravenous heparin, and ADP receptor inhibitors.

Cardiovascular magnetic resonance acquisition protocol Cardiovascular magnetic resonance studies were performed on a clinical 1.5-Tesla scanner (Avanto, Siemens Healthcare Sector, Erlangen, Germany) using a 32-channel phased-array receiver coil. All CMR images were acquired during breath hold and with ECG triggering. Examination of ventricular function was performed by acquisition of steady-state free precession cine images in standard short-axis planes (SSFP, trueFISP; slice thickness 8 mm; inter-slice gap 2 mm; repetition time 60.06 s; echo time 1.16 s; flip angle 608; FOV 300 × 300 mm, matrix size 134 × 192; readout pixel bandwidth 930 Hz/pixel). Based on the retrospective triggering, 25 cardiac phases covering systole and diastole within a cardiac cycle were reconstructed. For short-axis T2w-STIR imaging, a breath-hold black-blood turbo spin echo technique was adopted by the use of a triple inversion recovery preparation module (slice thickness 8.0 mm; inter-slice gap 4 mm; repetition time 2 RR intervals; echo time 61 ms; FOV 276 × 340 mm, matrix size 119 × 256). Finally, short-axis delayed enhancement images were obtained by use of a segmented inversion recovery SSFP technique (slice thickness 8.0 mm; inter-slice gap 2 mm; repetition time 1 RR interval; echo time 1.48 ms; flip angle 608; FOV 360 × 360 mm, matrix size 128 × 256) and acquired 10 –15 min after injection (Gadovist; 0.2 mol/kg body weight).

Cardiovascular magnetic resonance image analysis Calculation of left ventricular volumes and ejection fraction was performed in the serial short-axis slices using commercially available software (Syngo Argus, version B15; Siemens Healthcare Sector, Erlangen, Germany). The extent of edematous myocardium and delayed enhancement in each image was quantified with custom analysis software (VPT, Siemens Corporate Research, Princeton, NJ, USA).16 After manual tracing of pericardial and endocardial contours, a region of interest was drawn within a remote non-infarcted myocardium segment. On delayed enhancement imaging, MI was considered to be present if the signal intensity of hyper enhanced myocardium was greater than five standard deviations (SDs) above the mean signal intensity of the remote region.17 On T2-weighted images, the infarct-related area at risk (oedema) was considered present if the signal intensity of the myocardium was greater than two SDs above the mean signal intensity of the remote non-infarcted myocardium region.18 All measurements were expressed as a percentage of the total left ventricular myocardial volume; the absolute infarct size also was quantified in grams.

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Patients aged 18 – 80 years with a first acute MI (ST elevation on ECG, or complete occlusion of coronary artery in non-ST elevation MI) and PCI treated at the Universita¨tsklinikum Regensburg within 24 h after symptom onset were eligible for inclusion. The exclusion criteria were previous MI or previous myocardial revascularization (PCI or surgical), indication for surgical myocardial revascularization, cardiogenic shock, implanted cardiac device or other contraindications for CMR, known treated SDB, other severe diseases (e.g. lung disease, stroke), and followup not feasible (e.g. long distance to place of residence, language).

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Quality of life Disease-specific quality of life was assessed using the validated Seattle Angina Questionnaire.11,12 Patients completed the questionnaire at the 3-month follow-up. Higher scores indicate better quality of life.

Statistical analysis

time, left ventricular mass, and AHI/h. All models were additionally controlled for the baseline characteristics such as age, body mass index (BMI), gender, and diabetes. The linearity assumption of each multiple linear regression model was checked by component-plus-residual plots for each independent variable. In case of non-linearity, the respective variable was centred (values—mean) and an additional variable (e.g. x 2) was calculated. The new variable was added to a second model if there was a significant improvement according to the F value. For graphical illustrations, bar charts with standard error of the mean and scatter plots with regression lines were used. All reported P values were twosided, and a P value of 0.05 was considered the threshold for statistical significance. Data entry and calculations were made with the software package SPSS 19.0 (Chicago, EUA) and R (version 2.14.2).

Results Between March 2009 and June 2011, a total of 220 consecutive patients with acute MI were admitted to the catheterization laboratory at the Universita¨tsklinikum Regensburg and screened for eligibility, of whom 68 fulfilled the inclusion and exclusion criteria and were enrolled in the study (Figure 1). Twelve patients withdrew their consent for either CMR or Polysomnography. Fifty-six patients were included in the analysis. There was no significant difference in the timing of CMR in both groups (mean 4.0 + 0.3 vs. 4.3 + 0.2 days after acute MI, P ¼ 0.222).

Figure 1 Flow of patients through the study. AMI, acute myocardial infarction; CMR, cardiovascular magnetic resonance; PCI, percutaneous coronary intervention; PSG, polysomnography; SDB, sleep-disordered breathing.

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All quantitative data are expressed as mean + SD or median and interquartile range on the basis of whether or not they had a normal distribution. Categorical data are expressed as frequencies with percentages. Comparison between quantitative variables was performed by an independent-sample parametric (unpaired Student’s t-test) or nonparametric (Mann – Whitney) statistical test as appropriate, whereas a paired t-test was used for comparing results from initial and repeated measurements. For the comparison of changes in CMR variables between groups, analysis of covariance was used including group as the main factor and the baseline value of the outcome variable as a covariate to adjust for baseline differences. Comparison between categorical variables was performed by use of the exact unconditional Pearson chi-squared statistic (zpooled). Associations between infarct characteristics and SDB were described using linear regression analysis. Multivariable linear regression analyses were performed to identify predictors of infarct size (at baseline and 3 months) and myocardial salvage index. Known potential confounders and riskfactors,13 which can affect infarct size and myocardial salvage, were entered in the fully adjusted models: Categorical variables included infarct location, TIMI flow before and after PCI. Continuous variables included symptom onset to reperfusion

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Impact of SDB on MI size

Patient characteristics Baseline characteristics are presented in Table 1. There was no significant difference between the SDB and no SDB groups with respect to age, gender, coronary risk factors, and haemodynamic findings. Table 1

Baseline characteristics No SDB (n 5 27)

SDB (n 5 29)

P value

Patients with SDB had a significantly higher BMI and higher left ventricular mass compared with those with no SDB. There were no significant differences between the patient groups for time from symptom onset to revascularization, infarct-related artery, TIMI flow pre- or post-PCI, thrombus aspiration, or use of glycoprotein IIb/IIIa inhibitors during PCI. All patients were on optimal medical therapy. During the 3 months follow-up, one patient without SDB had clinical evidence of recurrent MI. Sleep characteristics are shown in Table 2.

................................................................................ Age, years Body mass index, kg/m2 Male gender, n (%)

54 + 10 26.8 + 2.7 21 (78)

56 + 10 29.7 + 3.8 25 (86)

0.015 0.500

0.371

73 + 17

77 + 18

0.396

Systolic blood pressure, mmHg

129 + 24

131 + 19

0.627

Diastolic blood pressure, mmHg

80 + 13

79 + 12

0.777

Hypertension, n (%)

16 (59)

17 (59)

1.000

Current smoker, n (%) Diabetes mellitus, n (%)

18 (67) 3 (11)

12 (41) 6 (21)

0.069 0.368

9 (33)

12 (41)

0.573

282 (307)

363 (793)

0.380

5 (19)

5 (17)

0.941

Hypercholesterolemia, n (%) Symptom-to-balloon time, min Non-ST-elevation, n (%)

Table 2

Sleep characteristics No SDB (n 5 27)

SDB (n 5 29)

P value

,0.001

................................................................................

................................................................................ Territory of infarction, n (%) LAD artery Circumflex artery

11 (41) 4 (15)

12 (41) 7 (24)

0.615

Right coronary artery

12 (44)

10 (34)

Non-LAD-infarction, n (%)

16 (59)

17 (59)

1.000

TIMI-flow before PCI, n (%) Grade 0

22 (81)

26 (90)

0.460

5 (19)

3 (10)

................................................................................

Grade 1

At baseline, the area at risk was similar in patients with SDB and without SDB (40 + 12% vs. 40 + 14%, P ¼ 0.925; Figure 2). Baseline and final infarct sizes were significantly larger in patients with SDB than in those with no SDB (24 + 11% vs. 18 + 10%, P ¼ 0.032; and 23 + 10% vs. 12 + 10%, P , 0.001, respectively; Figure 2). The myocardial salvage index, the primary study endpoint, was significantly

Apnoea– hypopnoea index, /h

5+3

34 + 19

Mean oxygen saturation, % Minimum oxygen saturation, %

93 + 2 87 + 4

93 + 2 83 + 7

0.993 0.003

306 + 82

338 + 67

0.109

Total sleep time, min

Data are expressed as mean + SD. SDB, sleep-disordered breathing.

................................................................................ TIMI-flow post-PCI, n (%) Grade 2

1 (4)

3 (10)

Grade 3

26 (96)

26 (90)

0.474

................................................................................ Thrombus aspiration, n (%)

11 (41)

14 (48)

0.625

Glycoprotein IIb/IIIa inhibitor, n (%)

21 (78)

23 (79)

0.915

CK at admission, U/L Peak CK median, U/L

236 (416) 292 (553) 1073 + 1490 1843 + 1268

0.470 0.126

133 + 31

166 + 34

Aspirin (%) ADP receptor inhibitors (%)

27 (100) 27 (100)

29 (100) 29 (100)

1.0 1.0

b-blocker (%) ACE inhibitor/ARB (%)

27 (100) 26 (96)

27 (93) 29 (100)

0.277 0.370

Statins (%)

27 (100)

27 (93)

0.277

Left ventricular mass, g

,0.001

................................................................................ Medication at discharge

Data are expressed as n (%), or mean + SD, or median (interquartile range). ACE, angiotensin-converting enzyme; ADP, adenosine diphosphate; ARB, angiotensin receptor blocker; CK, creatinine kinase; LAD, left anterior descending; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.

Figure 2 Area at risk, infarct size at baseline and after 3 months in percentage of the left ventricle. Values are expressed as mean + standard error; SDB, sleep-disordered breathing.

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Heart rate, beats/minute

Salvage index and infarct size

196 smaller in patients with SDB compared with those without SDB (52 + 12% vs. 77 + 16%; P , 0.001; Figure 3). Figure 4 shows individual patient data and documents the significant relationship between myocardial salvage index and AHI. Sleep-disordered breathing type, obstructive or central, had no influence on myocardial salvage. In the entire group of MI patients, infarct size decreased between baseline and 3 months (21 + 11%–17 + 11%; P , 0.001). Infarct size was unchanged from baseline to 3 months in patients with SDB (difference of 20.2% [95%CI, 21.6–1.2]; P ¼ 0.609 within group), but decreased in those without SDB [difference 26.9% (95%CI, 28.3 to 25.4); P , 0.001 within group] (Figure 5). The decrease in

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infarct size was significantly greater in the no SDB group compared with the SDB group after accounting for infarct size at baseline (between-group difference, 26.7 95% CI, 28.7 to 24.7; P ≤ 0.001). At 3 months, infarct mass decreased significantly in both patients with SDB [by 25.7 g (95%CI, 27.6 to 23.8); P , 0.001 within group] and without SDB [by 213.9 g (95%CI, 215.9 to 212.0); P , 0.001 within group]. However, between-group comparison showed a significantly greater decrease in infarct mass from baseline to 3 months in patients who did not have SDB compared with those who did (difference, 28 g; 95% CI, 211.0 to 25.4; P , 0.001). Correspondingly, the relative reduction of infarct size was significantly smaller in the SDB compared with the no SDB group (16 + 18% vs. 50 + 19%, P , 0.001).

Left ventricular function and volumes

Predictors of infarct size Figure 3 Degree of myocardial salvage according to the presence of sleep-disordered breathing.

Figure 4 Scatterplot of the correlation between myocardial salvage index and apnoea– hypopnoea index, by type of sleepdisordered breathing.

Multiple logistic regression analysis was used to identify independent predictors of myocardial injury and impaired healing defined by infarct size at baseline and 3 months, and myocardial salvaged index (Table 4). Anterior infarction, pre-TIMI flow, and LVM were independent predictors of infarct size at baseline. While AHI was not a predictor

Figure 5 Changes in infarct size and mass. Differences in infarct size in percentage of the left ventricle from baseline to 3 months according to sleep-disordered breathing. Values are expressed as mean + standard error.

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At baseline, there was no significant difference in LVEF between the two groups (Table 3). Both patients with and without SDB had a significant improvement in LVEF from baseline within 3 months after MI. At 3 months, patients with SDB had significantly lower left ventricular ejection fraction (48% vs. 54%, P ¼ 0.023). The change in LVEF from baseline to 3 months was similar in those with and without SDB (between-group difference 21.7%; 95% CI, 21.0 –4.4; P ¼ 0.217). End-systolic and end-diastolic left ventricular volumes were significantly greater in patients with SDB compared with those without SDB at baseline and 3 months. The mean change in end-systolic and end-diastolic volumes from baseline to 3 months was not significantly different between patient groups (Table 3).

197

Impact of SDB on MI size

of infarct size at baseline, AHI was a significant independent predictor for larger infarct size at 3 months, and lower myocardial salvage index. Since AHI did not comply with the linearity assumption, we added AHI-squared to a second model for each, infarct size at 3 months and myocardial salvage index. In both models, a significant increase of the F value and thus of R 2 could be shown (infarct size at 3 months: R21 = 0.52 to R22 = 0.57, P ¼ 0.039; myocardial salvage index: R21 = 0.51 to R22 = 0.55, P ¼ 0.057), while the regression coefficients and P values of the remaining predictors remained similar. To explore the relation of different types of SDB with infarct size and myocardial salvage index, obstructive and central AHI were

Table 3 Changes in left ventricular morphological and functional parameters SDB (n 5 29)

P value

................................................................................ LVEDV (mL) Baseline

151 + 34

171 + 38

0.049

3 months

151 + 36

174 + 44

0.040

0 + 21

3 + 32

0.401

D

................................................................................ P value (baseline vs. 3 months) LVESV (mL)

0.971

0.594

Baseline

78 + 24

96 + 31

0.017

3 months D

72 + 26 26 + 12

93 + 34 23 + 21

0.014 0.429

P value (baseline vs. 3 months)

0.027

0.431

................................................................................ LVEF (%) Baseline

49 + 8

45 + 9

0.060

3 months D

54 + 8 5+5

48 + 11 3+5

0.023 0.217

P value (baseline vs. 3 months)

,0.001

0.007

Data are mean + SD. LVEDV, left ventricular end-diastolic volume; LVEF, Left ventricular ejection fraction; LVESV, left ventricular end-systolic volume.

Table 4

Quality of life Quality of life, as assessed by the Seattle Angina Questionnaire mean score, showed no significant differences in physical limitations, diseasespecific quality of life, and scores for frequency of angina between patients with and without SDB at 3 months after acute MI (81 + 17 vs. 76 + 23, P ¼ 0.424, 65 + 23 vs. 65 + 24, P ¼ 0.994, 90 + 11 vs. 88 + 16, P ¼ 0.475, respectively). Scores for angina stability (77 + 26 vs. 91 + 18, P ¼ 0.037) and satisfaction with treatment (81 + 23 vs. 94 + 11, P ¼ 0.016) were significantly lower in patients with compared with those without SDB at 3 months after acute MI.

Discussion This study of the association between SDB and myocardial damage in patients with acute MI after PCI reports several novel observations: (i) Between 3 and 5 days after acute MI, the area at risk was similar in patients with and without SDB, whereas infarct size was greater in those with SDB. (ii) At 3 months, there was less myocardial salvage and infarct size was greater in those with SDB. (iii) Regardless of the type of SDB (central or obstructive), SDB was an independent predictor of lower myocardial salvage index and larger infarct size 3 months after acute MI. (iv) In addition, patients with SDB had increased angina burden and reduced satisfaction with treatment at 3 months after acute MI.

Predictors of myocardial damage (multiple linear regression)

Predictors of endpoint

Infarct size (baseline)

......................................

B (95% CI)

Infarct size (3 months)

..........................................

P

B (95% CI)

0.93 0.027

20.001 (20.37, 0.37) 5.20 (20.47, 10.86)

P

Myocardial salvage index

..........................................

B (95% CI)

P

............................................................................................................................................................................... Symptom to balloon time (h) Anterior infarction TIMI-flow pre PCIa TIMI-flow post PCIb Left ventricular mass AHI/h Model summaryc

0.02 (20.38, 0.41) 6.77 (0.79, 12.74) 11.35 (3.23, 19.47)

0.007

9.27 (1.58, 16.96)

25.71 (216.76, 5.34) 0.17 (0.06, 0.27)

0.30 0.004

23.73 (214.20, 6.74) 0.19 (0.09, 0.30)

0.07 (20.07, 0.22)

0.31

R 2 ¼ 0.41; F ¼ 3.14

0.22 (0.08, 0.36)

0.99 0.071 0.019 0.48 ,0.001 0.002

R 2 ¼ 0.52; F ¼ 4.90

AHI, apnoea–hypopnoea index; B, regression coefficient; CI, confidence interval; TIMI, thrombolysis in myocardial infarction. a TIMI Grade 0 vs. TIMI Grade 1. b TIMI Grade 2 vs. TIMI Grade 3; PCI, percutaneous coronary intervention. c All models are controlled for age, BMI, gender, and diabetes mellitus.

20.04 (20.63,0.56) 0.79 (28.26, 9.84)

0.89 0.86

25.63 (217.92, 6.66)

0.36

26.10 (222.82, 10.62) 20.21 (20.37, 20.04)

0.47 0.014

20.50 (20.72, 20.28)

,0.001

R 2 ¼ 0.51; F ¼ 4.63

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No SDB (n 5 27)

entered separately in the fully adjusted regression model. Both obstructive and central AHI were significantly associated with larger infarct size at 3 months (obstructive AHI, B 0.63, 95%%CI, 0.29, 20.96; P , 0.001 and central AHI, B 0.18, 95%CI, 0.01, 0.34 P ¼ 0.035) and with lower myocardial salvage index independent of potential confounders (obstructive AHI, B 20.70, 95% CI, 21.21, 20.19; P ¼ 0.008 and central AHI, B 20.49, 95% CI, 20.7, 20.25; P , 0.001). We analyzed the results for STEMI vs. NSTEMI in the multiple linear regression model and found no significant association with infarct size at baseline (B ¼ 20.08, 95%CI: 29.53–9.70, P ¼ 0.99), infarct size at 3 months (B ¼ 1.43, 95%CI: 27.67–10.53, P ¼ 0.75), and myocardial salvage index (B ¼ 3.53, 95%CI: 210.70–18.03, P ¼ 0.63).

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The role of sleep-disordered breathing in myocardial ischaemia

Pathophysiological considerations Impaired myocardial healing after PCI is a dynamic process characterized by multiple pathogenic components, including ischaemia-related injury, reperfusion-related injury, and distal embolization.25 Prolonged ischaemia triggers an inflammatory response in the myocardium at risk.26 Furthermore, proteomic analysis showed that, even on the first day after MI, tissue cells within the ischaemic border zone which were exposed to hypoxia and oxidative damage showed apoptotic or necrotic characteristics with differential expression of proteins considered to be involved in oxidative stress and inflammation-related cell processes.4 The larger infarct size, smaller reduction in infarct size, and smaller area of salvaged myocardium in patients with SDB documented in this study might be related to mechanisms of SDB. In particular, oxidative stress, inflammation, and vascular remodelling can be directly triggered by SDB.27 Furthermore, SDB-related factors such as autonomic and mechanical stresses on the myocardium may also increase myocardial oxygen demand.5,28 Although the extent of area at risk was comparable between the groups, infarct size at baseline was larger in patients with SDB. This suggests that, after acute MI and reperfusion, the border zone myocardium might be even more sensitive to alterations caused by SDB than healthy myocardium. This is in line with experimental studies showing that SDB induces persistent changes in microvascular integrity and can also alter myocardial ischaemia-reperfusion tolerance.20,29 – 31 In addition, SDB results in transient uncoupling of coronary blood flow and

myocardial work in humans,32 and can impair myocardial tissue perfusion in patients with acute MI.33 As a consequence, SDB may contribute to the inflammatory response triggered by prolonged ischaemia. Such mechanisms support the concept that SDB may adversely affect the dynamic myocardial healing process and lead to a larger infarct size in patients with acute MI.

Clinical impact The size of healed infarction is an important prognostic factor, predictive of increased left ventricular remodelling, heart failure, and worse clinical outcome.34 Therefore, reducing infarct size is an important goal in the management of patients with acute MI. The observed strong association between SDB and impaired myocardial healing raises the question as to whether SDB should be diagnosed and treated early after acute MI.

Limitations The reduction in salvaged myocardium and increase of infarct size in patients with SDB compared with those without SDB were striking, but these findings have to be interpreted in the light of some limitations. The major limitation of this observational study is that we can only report an association between SDB and reduced myocardial salvage rather than a ‘causal relationship’ by design, although several pathophysiologic mechanisms suggest that SDB may contribute to myocardial damage. In addition, despite differences in infarct healing, this was not accompanied by clear changes in LVEF within the 3 months follow-up period. Importantly, there is evidence from previous CMR studies that both infarct size and LVEF are strong prognostic factors.35,36 Furthermore, the sample size was small and a power calculation was not performed in the current pilot study. Thus, we cannot rule out whether a larger sample size would have affected the findings. However, the present results generate a clinically important hypothesis and indicate a need for designing future interventional trials to assess the effect of SDB treatment on myocardial healing in acute MI.

Conclusion The finding of less salvaged myocardium, a smaller reduction in infarct size, and a greater final infarct size in patients with vs. without SDB suggests that SDB contributes to infarct expansion and impaired healing after PCI in patients with acute MI. Further research on SDB in the early phase after MI including interventional studies to improve understanding of the underlying pathophysiology of SDB as a potential treatment target is warranted.

Authors’ contributions S.B. and M.A. were responsible for the conception, hypotheses delineation, and design of the study, acquisition of funding, data acquisition, the analysis, and interpretation of such information, writing the article and in its revision prior to submission. A.S., A.H., O. H., K.D., A.L., O.W.H., and C,F. were involved in acquisition of the data, the analysis, and interpretation of such information and critical revision of the article prior to submission. G. A.R. and M.P. were involved in the interpretation of the data and critical revision of the article prior to submission. F.Z. performed the statistical analyses.

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Sleep-disordered breathing has been shown to be associated with myocardial ischaemia and is an independent predictor of MI.5,6 The current study provides the first data on the extent of MI and healing from the acute to the chronic phase in patients with SDB. Recent experiments in animal models support these findings: exposure to chronic intermittent hypoxia has been shown to result in larger infarct size after ischaemia/reperfusion, and left ventricular remodelling was more extensive due to excessive oxidative stress.10,19,20 In previous CMR studies, the reduction of infarct size within the first 3 months after acute MI is 5%;21,22 however, the individual change of infarct size can be quite variable.23,24 The overall decrease of infarct size in our study was similar compared with previous studies. In addition, we observed that the presence of SDB is associated with less reduction of infarct size compared with the absence of SDB. In parallel, patients with SDB had a lower LVEF. These results are consistent with the findings of a previous study that suggested that obstructive sleep apnoea might contribute to the development of left ventricular dysfunction in patients with acute MI.7 However, in that study, left ventriculograms were used to determine recovery of left ventricular function compared with CMR in the present study. Thus, comparability of the results between the two studies is limited. Our findings extend previous observations by documenting an association between SDB and impaired myocardial healing in patients with acute MI and the full spectrum of SDB. In addition, assessment of CMR provides quantitative morphological and functional information on the myocardium, e.g. size of oedema, infarct area, and myocardial salvage.

S. Buchner et al.

Impact of SDB on MI size

Acknowledgements The authors thank Astrid Brandl-Novak, Astrid Braune, Ruth Luigart, and Katja Ziczinski for excellent assistance. English language editing assistance was provided by Nicola Ryan.

Funding The study was funded by Resmed (Martinsried, Germany), Philips Home Healthcare Solutions (Murrysville, PA, USA), and the Faculty of Medicine University of Regensburg, Germany

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Conflict of interest: M.A. receives grant support from Resmed (Martinsried, Germany), Philips Home Healthcare Solutions (Murrysville, PA, USA), and the German Foundation for Cardiac Research (Deutsche Stiftung fu¨r Herzforschung). M.A. is the holder of an endowed professorship from the Free State of Bavaria at the University of Regensburg that was donated by Resmed (Martinsried, Germany) and Philips Home Healthcare Solutions (Murrysville, PA, USA). M.A. has previously received lecture fees from AstraZeneca, Philips Home Healthcare Solutions (Murrysville, PA, USA), and Resmed (Martinsried, Germany). S.B.; A.S.; K.D.; A.H.; A.L.; O.H.; O.W.H.; F.P.; C.F.; F. Z.; G.A.J.R.; M.P. have no conflicts of interest to disclose.

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