Cipriani, C

Francini, S

Fumagalli, Stefano

Jelic, S

Makhanian, Y

Marchionni, Niccolo&apos

Padeletti, Luigi

Padeletti, M

Rinaldi, Mc

Tarantini, Francesca

English

Florence Research

0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ijcard.2010.04.091[2] Compton PA, Zankar AA, Adesanya AO, Banerjee S, Brilakis ES. Risk of noncardiacsurgery after coronary drug-eluting stent implantation. Am J Cardiol 2006;98:1212–3.[3] Schouten O, Bax JJ, Poldermans D. Management of patients with cardiac stentsundergoing noncardiac surgery. Curr Opin Anaesthesiol 2007;20:274–8.[4] Godet G, Le Manach Y, Lesache F, Perbet S, Coriat P. Drug-eluting stent thrombosis inpatients undergoing non-cardiac surgery: is it always a problem? Br J Anaes2008;100:472–7.[5] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.Obstructive sleep apnea after myocardial infarctionStefano Fumagalli a,⁎, Francesca Tarantini a, Chiara Cipriani a, Marta Casalone Rinaldi a, Sanja Jelic b,Sara Francini a, Yasmine Makhanian a, Margherita Padeletti a, Luigi Padeletti c, Niccolò Marchionni aa Department of Critical Care Medicine and Surgery, Gerontology and Geriatric Medicine, Intensive Care Unit, University of Florence and AOU Careggi, Florence, Italyb Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USAc Department of Critical Care Medicine and Surgery, Internal Medicine and Cardiology Unit, University of Florence and AOU Careggi, Florence, Italya r t i c l e i n f oArticle history:Received 27 March 2010Received in revised form 21 April 2010Accepted 29 April 2010Available online 1 June 2010Keywords:ECG Holter monitoringHeart rate variabilityMyocardial infarctionObstructive sleep apneaVentricular arrhythmiasObstructive sleep apnea (OSA) is a risk factor for hypertension,myocardial ischemia and stroke, and is associated with increasedmortality [1,2]. Hypoxia-induced activation of the sympatheticnervous system, inflammation and oxidative stress contribute toincrease cardiovascular risk in patients with sleep disturbances [2–4].The present study was aimed at evaluating the prevalence of OSA aftera recent myocardial infarction (MI) and defining its clinical predictors.All patients with recent MI (median time from symptoms onset:32 days), admitted to our cardiac rehabilitation center betweenMarch2007 and December 2008, were enrolled in the study. All subjectswere in stable clinical conditions.At baseline, patients underwent echocardiogram, ECG Holter,ergometric stress test, and blood tests. Ventricular arrhythmia riskprofile was quantified on ECG Holter analysis, using the Lown andWolf classification: frequent (N30/h) and complex (presence ofcouplets and tachycardia) arrhythmias [5]. Frequent supraventriculararrhythmia was defined as a number of ectopic beats N30/h. The peakCPK-MB and Troponin I values detected during acute MI wereregistered.The presence of OSA was assessed by ECG Holter recording usinga validated software (Lifescreen Apnea; SPACELABS Healthcare —Issaquah, Washington, USA and Hertford, UK) integrated in theImpresario Holter Analysis System (Symphony model; SPACELABSHealthcare). Briefly, the continuous change from airways obstructionto normal air flow determines a shift from sympathetic to para-sympathetic dominance, with related changes in heart rate. Thesoftware analyzes modifications in heart rate variability (HRV) and inQRS amplitude, returning the mean apnea-hypopnea index (AHI)[6,7]. Diagnostic sensitivity of this technique, compared to polysom-nography, is 90% [6,7]. ECG Holter recorders had a sampling rate of2048 Hz (EVO recorder; SPACELABS Healthcare). Patients werestratified on AHI values into three groups: normal (AHI≤5), mild(AHI 5–15) and moderate-severe apnea (AHIN15) [1,2]. Two para-meters of HRV in time domain analysis were evaluated, SDNN (thestandard deviation of RR intervals of the ECG Holter recording) andRMSSD (the square root of the mean squared differences of successiveRR intervals), corresponding to sympathetic and parasympatheticactivity— the former, and to parasympathetic activity only— the latter[8].Exclusion criteria for the study were: dominant non-sinus rhythm;presence of an implanted pacemaker; frequent artifacts in the ECGHolter recording; diabetes mellitus type 1 and other conditionsassociated with a severe autonomic dysfunction.Each patient gave written informed consent to the study; theprotocol conforms to the ethical guidelines of the 1975 Declaration ofHelsinki.Continuous and categorical variables were expressed as mean±standard deviation (SD) and percentages, respectively. For continuousvariables, Student's t test or analysis of variance were employed tocompare two or more groups of subjects. When the variables were notnormally distributed, non parametric tests were employed. Theassociation between two continuous variables was assessed withlinear regression analysis. Differences in categorical variables dis-tribution were evaluated with χ2 test.To identify the clinical predictors of OSA, those factors correlated tothis condition in univariate analysis, were entered into a multivariatelinear regression model.We enrolled 191 patients (Table 1), 73% after a ST-elevation MI(STEMI). Primary percutaneous coronary intervention was performedin 84% of cases. Mean peak values of CPK-MB and troponin I were113 UI/L (25th–75th percentile: 38–145 UI/L) and 106 ng/mL (25th–75th percentile: 16–141 ng/mL), respectively (Table 2).The maximum workload attained at the baseline ergometricstress test was 118±40 Watt. The test was suggestive of myocardialischemia only in 18 patients (9.4%).ECG Holter recordings had a mean length of 22:09±1:27 h. Meanheart rate was 66±9 b/min. SDNN and RMSSD were within lowernormal limits (Table 2). Second or third degree atrioventricular blockswere absent, cardiac pauses longer than 2 s were present only in 7⁎ Corresponding author. Department of Critical Care Medicine and Surgery, IntensiveCare Unit, Gerontology and Geriatric Medicine, University of Florence and AOU Careggi,Via delle Oblate, 4-50141-Florence, Italy. Tel.: +39 055 4271471; fax: +39 0554271469.E-mail address: fumadue@tin.it (S. Fumagalli).550 Letters to the Editorpatients (3.7%). ST segment depression was observed in 6 patients(3.1%).Mean sleep time was 7:56±1:13 h; 143 subjects (74.9%) had AHIscores N5, with a mean value of 17.7±10.8 (mild: N=67, 35.3%;moderate-severe apnea: N=76, 40.1%).Body weight correlated directly with AHI (Table 3), with thehighest value observed in moderate-severe apnea patients (normal:75±13 kg, mild: 74±11 kg, moderate-severe apnea: 80±12 kg;p=0.029).Uncontrolled hypertension (i.e. blood pressure N130/80 mmHg atthe time of enrollment), was positively associated with AHI. AHIlinearly increased with uric acid and CPK-MB plasma concentrations,and RBC count (Table 3). While patients with STEMI displayed highervalues of AHI (Table 3), no relation was found with residual LVEF(p=0.536) (Table 3). Complex ventricular arrhythmias directly cor-related with AHI (Table 3), with the highest prevalence of frequentventricular arrhythmias in themoderate-severe group (normal: 12.5%,mild: 18.8%, moderate-severe apnea: 68.8%; p=0.033).The multivariate linear regression analysis confirmed the directcorrelation of AHI with body weight, RBC count, use of K+ sparingagents, presence of uncontrolled hypertension and complex ventri-cular arrhythmias (Table 4).This study suggests that OSA is highly prevalent in patients with arecent MI. The study was conducted 4 weeks after MI to excludepossible confounders, such as acute inflammation and overt left ven-tricular failure. CPK-MB peak plasma concentration and STEMI, twoindicators of MI extension, correlated with the severity of OSA. Fur-thermore, K+ sparing agents, more frequently prescribed in patientswith moderate-severe left ventricular dysfunction (pb0.001), wereassociated with greater AHI. A strong relationwas found between OSAand RBC count, corroborating previous reports of a predictive value ofhemoglobin and hematocrit for the presence of sleep disturbances [9].The correlation between AHI and plasma levels of uric acid, possiblyrelated to enhanced ATP transformation, may suggest tissue distress[10].Table 1Clinical characteristics of patients.RangeAge (years) 62±13 28–94Men (%) 81.7Weight (kg) 77±13 47–115BMI (kg/m2) 26.6±3.5 16.3–40.2SmokersCurrent (%) 21.6Past (%) 51.1ComorbiditiesCOPD (%) 7.9Diabetes (%) 15.3Dyslipidemia (%) 45.0Hypertension (%) 56.3Previous MI (%) 8.7Stroke/TIA (%) 3.6Valvular heart diseasesAortic insufficiency (%) 3.2Aortic stenosis (%) 10.2Mitral insufficiency (%) 9.7Blood testsCreatinine (mg/dL) 0.95±0.24 0.50–2.00ESR (mm/h) 27.2±20.1 2.0–111.0Hemoglobin (g/dL) 13.5±1.4 10.0–16.4RBC count (106/mm3) 4.6±0.5 3.4–7.0Uric acid (mg/dL) 5.9±1.3 2.0–9.7BMI: body mass index; CABG: coronary artery bypass graft; COPD: chronic obstructivepulmonary disease; ESR: erythrocyte sedimentation rate.Table 2Cardiological characteristics of patients and drug therapy.RangeType of myocardial infarctionAnterior STEMI (%) 36.6Inferior STEMI (%) 36.6NSTEMI (%) 26.8Primary PCI siteLeft main (%) 0.5Left anterior descending (%) 41.7Circumflex (%) 12.3Right CA (%) 29.4No PCI (%) 16.0LVEF (%) 52±11 20–74Preserved (%) 62.4Mild reduction (%) 19.4Moderate/severe reduction (%) 18.2ECG Holter monitoringFrequent SV arrhythmias (%) 4.7Frequent V arrhythmias (%) 8.4Complex V arrhythmias (%) 36.6SDNN (ms) 116±34 37–222RMSSD (ms) 33±20 10–128Drug therapyASA (%) 96.9Clopidogrel (%) 95.3ACE inhibitors/ATII antagonists (%) 94.8β-blocking agents (%) 89.5Statins (%) 93.2K+ sparing agents (%) 14.7Diuretics (%) 22.5AT: angiotensin; CA: coronary artery; LVEF: left ventricular ejection fraction —categorized as normal (N50%), mildly (41–49%), moderately (26–40%), and severely(b25%) depressed; MI: myocardial infarction; PCI: percutaneous coronary intervention;RMSSD: root mean square of the squared difference between consecutive RR intervals;SDNN: standard deviation of all RR intervals of the ECG Holter recording; STEMI/NSTEMI: ST-/non-ST-elevation MI; SV/V: supraventricular/ventricular.Table 3Univariate analysis of apnea-hypopnea index by clinical variables.Condition p− +Men 8.0±6.9 15.2±11.8 b0.001Present smokers 13.7±11.4 14.8±11.8 0.584COPD 14.0±11.6 13.6±10.0 0.893Diabetes 13.7±11.6 15.3±11.7 0.907History of hypertension 13.4±10.8 14.4±12.0 0.551Uncontrolled hypertension 12.5±10.2 16.1±13.1 0.039Stroke/TIA 14.1±11.6 9.1±8.4 0.293Aortic insufficiency 13.6±11.6 22.8±8.3 0.055Aortic stenosis 14.1±11.5 13.6±12.1 0.868Mitral insufficiency 14.2±11.6 13.3±11.4 0.515Frequent SV arrhythmias (%) 14.4±11.5 5.5±6.1 0.023Complex V arrhythmias (%) 12.5±10.2 16.2±13.0 0.029STEMI 11.6±10.6 15.0±11.8 0.049ACE inhibitors/AT II antagonists 19.9±11.9 13.6±11.4 0.092β-blocking agents 15.1±15.8 13.8±10.9 0.623Statins 12.5±15.1 14.1±11.2 0.645K+ sparing agents 13.3±11.0 18.1±13.6 0.048Diuretics 14.5±12.0 12.0±9.4 0.206β±se R pAge (Δ·year) / 0.035 0.633Weight (Δ·kg) 0.23±0.07 0.243 0.001BMI (Δ·kg/m2) / 0.138 0.059CPK MB (Δ·UI/L) 0.04±0.01 0.364 0.001Creatinine (Δ·mg/dL) / 0.108 0.148ESR (Δ·mm/h) / 0.077 0.299Hemoglobin (Δ·g/dL) / 0.138 0.062RBC count (Δ·106/mm3) 3.8±1.5 0.179 0.015Uricemia (Δ·mg/dL) 1.5±0.7 0.159 0.032HR (Δ·b/min) / 0.032 0.661SDNN (Δ·ms) / 0.117 0.111RMSSD (Δ·ms) / 0.133 0.071`Uncontrolled hypertension: blood pressure N130/80 mmHg at baseline evaluation;SV/V: supraventricular/ventricular; Δ: AHI changes per unitary change of theindependent variable. Variables represented in less than 5% of the studypopulation were excluded from the analysis.551Letters to the EditorTable 4Clinical predictors of apnea–hypopnea index by multivariate linear regression analysis(R=0.435, pb0.001).β±se 95%CI pBody weight (Δ·Kg) 0.2±0.1 0.1–0.3 0.001RBC count (Δ·106/mm3) 3.0±1.5 0.1–5.8 0.043Complex V arrhythmias (yes vs. no) 3.5±1.6 0.3–6.8 0.030Frequent SV arrhythmias (yes vs. no) −9.5±3.7 −(16.7–2.3) 0.010Uncontrolled hypertension (yes vs. no) 4.2±1.6 1.0–7.4 0.011K+ sparing agents (yes vs. no) 5.2±2.3 0.7–9.8 0.024Constant −20.1±8.0 −(35.9–4.4) 0.013Δ: AHI changes per unitary change of the independent variable; RBC: red blood cell; SV/V: supraventricular/ventricular.The association between AHI and complex ventricular arrhythmiasis an important novel finding. In the Sleep Heart Health Study, thepresence of a sleep disturbance, increased about three times the risk todevelop a not sustained ventricular tachycardia, and at least two timesthe risk to experience complex ventricular arrhythmias [11]. Thecorrelation between OSA and ventricular arrhythmias might beexplained by several factors, including increased left ventricularafterload with consequent reduction in preload, increased sympa-thetic outflow, and the possible presence of diastolic dysfunction [12].Few limitations of the study need to be acknowledged. Only 2patients reported the use of a CPAP previous to the occurrence of MI,but we cannot rule out the possibility that subclinical sleep dis-turbances might have been present before the acute event in a portionof our population. The technique we used to detect OSA, even ifvalidated, employs only the electrocardiographic dimension of thepolysomnography study. It is known that a recent MI may reduce HRVinfluencing the ability of ECG analysis to detect sleep apnea. However,HRV recorded in our study population was still within normal limits[8]; moreover, a reduction of HRV should determine an under-estimation of the prevalence of sleep disturbances. Furthermore, arecent Scientific Statement on sleep apnea and cardiovascular disease,recommended to adopt new non-invasive tools of screening, lessexpensive and more widely applicable than standard polysomnogra-phy [1].In conclusion, previously unrecognized OSA is highly prevalentamong patients with recent MI and associates with increased bodyweight, uncontrolled hypertension and complex ventricular arrhyth-mias. Clinicians should seek and treat sleep disturbances whenoccurring in patients with recent MI.Conflict of interestNone to disclose.We thank Aldo Europei, Luigi Garuglieri, and Alberto Nincheri(ESAOTE SpA, Florence, Italy) and SPACELABS Healthcare — Issaquah,Washington, USA and Hertford, UK, for technical support.The authors of this manuscript have certified that they complywith the Principles of Ethical Publishing in the International Journal ofCardiology [13].References[1] Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease. AnAmerican Heart Association/American College of Cardiology Foundation ScientificStatement From the American Heart Association Council for High Blood PressureResearch Professional Education Committee, Council on Clinical Cardiology, StrokeCouncil, and Council on Cardiovascular Nursing. Circulation 2008;118:1080–111.[2] Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular conse-quences. Lancet 2009;373:82–93.[3] Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms inobstructive sleep apnea. J Clin Invest 1995;96:1897–904.[4] Quan SF, Gersh BJ. Cardiovascular consequences of sleep-disordered breathing:past, present and future: report of a workshop from the national center on sleepdisorders research and the national heart, lung, and blood institute. Circulation2004;109:951–7.[5] Lown B, Wolf M. Approaches to sudden death from coronary heart disease.Circulation 1971;44:130–42.[6] Penzel T, McNames J, Murray A, de Chazal P, Moody G, Raymond B. Systematiccomparison of different algorithms for apnoea detection based on electrocardio-gram recordings. Med Biol Eng Comput 2002;40:402–7.[7] de Chazal P, Heneghan C, Sheridan E, Reilly R, Nolan P, O'Malley M. Automatedprocessing of the single-lead electrocardiogram for the detection of obstructivesleep apnoea. IEEE Trans Biomed Eng 2003;50:686–96.[8] Task Force of the European Society of Cardiology and the North American Societyof Pacing and Electrophysiology. Heart rate variability: standards of measurement,physiological interpretation, and clinical use. Circulation 1996;93:1043–65.[9] Zilberman M, Silverberg DS, Bits I, et al. Improvement of anemia witherythropoietin and intravenous iron reduces sleep-related breathing disordersand improves daytime sleepiness in anemic patients with congestive heart failure.Am Heart J 2007;154:870–6.[10] Braghiroli A, Sacco C, Erbetta M, Ruga V, Donner CF. Overnight urinary uric acid:creatinine ratio for detection of sleep hypoxemia. Validation study in chronicobstructive pulmonary disease and obstructive sleep apnea before and aftertreatment with nasal continuous positive airway pressure. Am Rev Respir Dis1993;148:173–8.[11] Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias withsleep-disordered breathing: the sleep heart health study. Am J Respir Crit CareMed2006;173:910–6.[12] Arias MA, Sanchez AM. Obstructive sleep apnea and its relationship to cardiacarrhythmias. J Cardiovasc Electrophysiol 2007;18:1006–14.[13] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ijcard.2010.04.096552 Letters to the Editor

Obstructive sleep apnea after myocardial infarction.

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Obstructive sleep apnea after myocardial infarction.

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