Sleep disorders & cardiovascular risk in chronic spinal cord injury

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1 Sleep disorders & cardiovascular risk in chronic spinal cord injury PVA Summit Abdulghani Sankari, MD, PhD

2 Disclosures Presenter has Federal and private foundations research Funding. In addition he has pending Patent [Date 9/16/16 Serial number 62/395,634: "The Detection of Sleep Disordered Breathing Using Cardiac Autonomic Responses". Role: Inventor.] PESG and PVA staff have no interest to disclose. This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with PVA. PESG, PVA, and all accrediting organization do not support or endorse any product or service mentioned in this activity.

3 Learning Objectives At the conclusion of this activity, the participant will be able to: 1. To discuss the relationship between sleep disordered breathing and cardiovascular disease in SCI. 2. To discuss the heart rate responses in SCI compared to able bodied individuals and present preliminary data on cardiovascular outcome in patients with sleep disordered breathing. 3. To discuss the importance of early detection and management of sleep disordered breathing and cardiovascular disease in SCI

4 Sleep Disordered Breathing(SDB) Chronic condition characterized by repeated episodes of apnea and hypopnea during sleep. OSA Syndrome when associated with daytime symptoms (OSAHS) Estimated 30 million Americans (80% are undiagnosed). o DM: 50-80% Foster et.al. Diabetes Care 2009 Jun; 32(6): o Atrial Fibrillation: 30-60% Macdonald, et al J Clin Sleep Med 4.1: o CHF: 40-50% Bradley et al Circulation, 107(12), o Stroke: 50-70% Yaggi, et al NEJM 353(19), o CKD: 40-60% Sakaguchi, et al. CJASN, 6(5), o SCI: 60-80% Sankari, et al. JCSM A. Sankari 2017

5 National Heart, Lung, and Blood Institute NIH Polysomnography

6 A. Sankari 2016

7 94-89% A. Sankari 2016

8 A representative polygraph record of hypopneas with >3% desaturation and cortical arousals Sankari et al. SLEEP 2017

9 N=13 Hypopneas Sankari et al. SLEEP 2017

10 N=13 Hypopneas Sankari et al. SLEEP 2017

11 N=13 Hypopneas RE Sankari et al. SLEEP 2017

12 N=13 Hypopneas RE Upper Airway R Pulmonary R PTP~WOB ~10 20% Sankari et al. SLEEP 2017

13 Effect of CPAP on upper airway and lung resistance (a) 18 Pre-CPAP CPAP R UA (cmh 2 O.L -1.s -1 ) (b) Inspiratory Expiratory Pre-CPAP CPAP * R L (cmh 2 O.L -1.s -1 ) * 0 Inspiratory Expiratory Sankari et al. SLEEP 2017

14 Effect of CPAP on upper airway and lung resistance Effect of CPAP on heart rate (RRI) (a) 18 Pre-CPAP CPAP 16 R UA (cmh 2 O.L -1.s -1 ) * RRI (ms) 2 0 (b) Inspiratory Expiratory 50 Pre-CPAP CPAP 40 R L (cmh 2 O.L -1.s -1 ) * Mean ± SE; n = 6 (ECG of two subjects were not included due to poor signal), *p <.05 vs. baseline, +p <.05 vs. (3) nadir RRI. 0 Inspiratory Expiratory Sankari et al. SLEEP 2017

15 Effect of CPAP on upper airway and lung resistance Effect of CPAP on heart rate (RRI) (a) 18 Pre-CPAP CPAP R UA (cmh 2 O.L -1.s -1 ) * RRI (ms) Hypopnea Respiratory Event + * * (b) Inspiratory Expiratory Pre-CPAP CPAP 700 R L (cmh 2 O.L -1.s -1 ) * Baseline CPAP Mean ± SE; n = 6 (ECG of two subjects were not included due to poor signal), *p <.05 vs. baseline, +p <.05 vs. (3) nadir RRI. Can Heart Rate Responses during Sleep Predict Cardiovascular Disease? Inspiratory Expiratory Sankari et al. SLEEP 2017

16 Effect of nocturnal heart rate accelerations on long term CV outcome Study population: WSCS WSCS: 1546 adult employees of state agencies aged 30 to 60 years in started in Digital PSG recordings between 8/2000 to 12/2016 Inclusion: most recent full PSG with adequate ECG recording, not treated for SDB, no prior CVD event, No beta blockers used on the night of PSG or at any other point during follow up.

17 Effect of nocturnal heart rate accelerations on long term CV outcome Study protocol: The ECG and SaO2 of every participant that meet the entry criteria will be examined to obtain beat to beat RRI dips and ODI. Primary outcome is incident CVD event: death related to CVD or self reported physician diagnosed heart attack, heart failure, a CVD procedure angioplasty, stent, pacemaker, bypass, or defibrillation.

18 Heart Rate Responses during Sleep in a Participant from the Wisconsin Sleep Cohort (who was not on beta blocker) RRDI(90%) is 54.5, average heart rate is 61.1 BPM, and ODI(4%) is 2.3 desats/hour Matlab program developed internally at WSU for automated heart rate changes (R R interval dips) [pending patent #62/395,634]. RRI 80, 70 and 60%

19 Heart Rate Responses during Sleep Predicts Cardiovascular Disease in a Community Based Cohort: Results from the Wisconsin Sleep Cohort Excluded: 141 used Beta Blockers during PSG 84 used CPAP on the night of the study Studies were scored N= scored PSG studies from 745 individuals CVD Events N (%) Adjusted for age, BMI, and gender Hazard Ratio (95% CI) p-value Adjusted for age, BMI, gender and AHI categories (<5, 5-15 >15) Adjusted for age, BMI, gender and AHI categories (<5, 5-15 >15), Diabetes, HTN, Stroke, and Smoking Adjusted for age, BMI, gende and AHI categories (< >15), Diabetes, HTN Stroke, Smoking, Average HR, %TST lt 90% SaO2 Excluded: 70 had no follow up 46 had an event before PSG Continuous RRDI (10-unit increment) 26/571 (5) 1.17 (1.07, 1.28) (1.09, 1.29) (1.10, 1.31) < (1.10, 1.32 < Individuals with PSG data N=629 CVD events: death related to CVD or self reported physician diagnosed heart attack, heart failure, a CVD procedure (angioplasty, stent, pacemaker, bypass, or defibrillation); RRDI: R R interval dips index. Excluded: Individuals who used beta blockers at any other time during the study (n=58) Sleep&Breathing 2017 Individuals with PSG data included in the analysis N= 571

20 Heart Rate Responses during Sleep Predicts Cardiovascular Disease in a Community Based Cohort: Results from the Wisconsin Sleep Cohort Excluded: 141 used Beta Blockers during PSG 84 used CPAP on the night of the study Studies were scored N= scored PSG studies from 745 individuals Excluded: 70 had no follow up 46 had an event before PSG Individuals with PSG data N=629 CVD events: death related to CVD or self reported physician diagnosed heart attack, heart failure, a CVD procedure (angioplasty, stent, pacemaker, bypass, or defibrillation); RRDI: R R interval dips index. Excluded: Individuals who used beta blockers at any other time during the study (n=58) For every 10 HR changes/h CVD/events ~ 20% Sleep&Breathing 2017 Individuals with PSG data included in the analysis N= 571

21 Heart Rate Responses during Sleep Predicts Cardiovascular Disease in a Community Based Cohort: Results from the Wisconsin Sleep Cohort 100% Risk of incident CVD event CVD Event Free Survival 98% 96% 94% 92% 90% RRDI < 20 RRDI % 86% RRDI > 40 Log Rank test p = Years of Follow Up

22 SDB prevalence in chronic SCI # patients Level SDB Short et al (1992) 22 (20 M) T10 above 25% (10% central) Flavell et al (1992) 10 (10 M) Cervical 30% O2sat>10% <90% McEvoy et al (1995) 40 (37 M) Cervical 22% OSA+ mixed Klefbeck et al (1998) 33 (28 M) Cervical 15% (ODI >4%)+ PB Burns et al (2000) 20 (20 M) L1 above 40% Stockhammer (2002) 50 (40 M) Cervical 48% Berlowitz et al (2005) 30 (25 M) Cervical 62% (RDI>10) HSAT Ludec et al (2007) 41 (41 M) Cervical 53% HSAT Sankari et al (2014) 26 (16 M) T6 above 77% (AHI >5) PSG Bauman et al (2015) 81 (75 M) T6 above 81% (AHI>5) HSAT

23 Top causes of death post SCI The prevalence rates of CVD in SCI is 30 50% (able bodied range is 5 10%) Myers J, et al. Am J Phys Med Rehabil 2007;86 Strong relationship between SDB and cardiac medication use Stockhammer et al. Spinal Cord 2002, CVD and respiratory disorders combined are #1 cause of mortality in SCI HL Frankel et al, Spinal Cord

24 Sleep Disturbances Characteristics in Chronic SCI Cohort SCI Cohort N=28 Sleep Health Questionnaires In Lab PSG SDB 79% (N=22*) No SDB 21% (N=6) Response to Followup 90% (N=20) Reported SDB to HCP 50% (N=10) Treated 30% (N=6) Untreated 70% (N=14) Using PAP 66% (N=4) Less than 20% of SCI with symptomatic SDB are on treatment *There are 4 patients previously diagnosed and 18 newly diagnosed with SDB SDB: sleep disordered breathing, HCP: health care provider, PAP: Positive airway pressure, ESS: Epworth sleepiness scale, PSQI: Pittsburgh sleep quality index; FSS: fatigue severity scale; BQ: Berlin questionnaire.

25 Evaluation of SDB in SCI/D & Cardiovascular Morbidities (N=221) % of patients % of patients SCI/D VA (n=168) SCI/D non VA (n=53) SCI trauma (n=84) 6 SCD MS (n=77) SDB PAP Therapy HTN CVD Only 11% were evaluated for SDB Less than 5% were treated by PAP More than 50% have HTN 6 20% have CVD (MI, CAD, or CHF)

26 Evaluation of SDB in SCI/D & Cardiovascular Morbidities (N=221) % of patients % of patients SCI/D VA (n=168) SCI/D non VA (n=53) SCI trauma (n=84) 6 SCD MS (n=77) SDB PAP Therapy HTN CVD Only 11% were evaluated for SDB Less than 5% were treated by PAP More than 50% have HTN 6 20% have CVD (MI, CAD, or CHF)

27 Cardiovascular Morbidity and Spinal Cord Injury (SCI) Cardiac and respiratory disorders are the two leading causes of morbidity and mortality (SDB affect 70 80% of SCI). SCI alterations in the autonomic nervous system, which may influence the magnitude of heart rate changes following respiratory events. Sankari et al. Spinal Cord Sankari et al. JCSM

28 Cardiac Autonomic Control in Patients with Chronic SCI & SDB A representative polygraph record of a hypopnea in a Cervical SCI ~20%

29 Cardiac Autonomic Control in Patients with Chronic SCI & SDB A representative polygraph record of a hypopnea in a Thoracic SCI ~20%

30 Cardiac Autonomic Control in Patients with Chronic SCI & SDB Cervical SCI Thoracic SCI Able Bodied N AGE (YEARS) 47.6± ± ±13.7 BMI (KG/M 2 ) 23.6± ± ±3.5 GENDER (M/W) 6/2 5/3 7/3 NC (CM) 38.9± ± ±4.0 SYSTOLIC BP (MMHG) 112.1± ± ±11.1 DIASTOLIC BP (MMHG) 72.1± ± ±6.7 ALL DATA MEAN±SD. Abbreviations; BMI: body mass index, Gender (M/W): Men/Women, NC: neck circumference, BP: Blood Pressure.

31 Cardiac Autonomic Control in Patients with Chronic SCI & SDB Cervical SCI Thoracic SCI Able Bodied N AHI (>5 EVENTS/HR) AHI (EVENTS/HR) 37.9± ± ±15.5 HYPOPNEA INDEX 17.3± ± ±11.2 (EVENTS/HR) ODI (DESATURATION/HR) 19.7± ± ±15.3 HR (BPM) 63.6± ± ±9.9 T (EVENT TO NADIR 8.3± ±3.0 RRI) (S) 7.2±3.0 RRDI (DIPS/HOUR) 50.0± ± ±26.2 ALL DATA MEAN±SD. Abbreviations; BMI: body mass index, Gender (M/W): Men/Women, NC: neck circumference, BP: Blood Pressure.

32 Maresh et al Abstract Sleep&Breathing 2017 WSU-MS-YR3 The following time points were used for comparison to baseline sleep: 1.) RRI at beginning of event (BE) 4.) RRI at nadir SaO 2 (NS) 2.) RRI at end of event (EE) 5.) Maximum RRI following nadir (MR) 3.) Nadir RRI following event (NR)

33 Maresh et al Abstract Sleep&Breathing 2017 WSU-MS-YR3

34 Cardiac Autonomic Control in Patients with Chronic Spinal Cord Injury and Sleep-Disordered Breathing Cervical and high thoracic SCI have preserved heart-rate responses to respiratory events during sleep indicating that SDB may contribute to recurrent cardiac sympathetic modulation in response to apneas/hypopneas. Autonomic control may play an important role in the pathogenesis of SDB and sleep fragmentation in individuals with SCI.

35 Mechanism HR Shear Stress Theory HR and plaque development Tardif et al. MEDICOGRAPHIA, Vol 36, No. 1, 2014 HR and atherosclerotic plaque rupture: evidence and clinical perspectives

36 Sankari et al JAP 2014

37

38 Baseline PSG Screening Study Awake Studies SS Spirometry & Sleep Q Cervical SCI C4 7 Thoracic SCI T1 6 Able Bodied EH Sham EH Sham EH Sham EH Baseline RA H1 1min Isocapnic Hypoxia x15 H2 H3 H4 H5 H6 H7 H8 H9H10 H11 H12 H13 H14 H15 Recovery RA 20 minutes 40 minutes 60 minutes Sham Baseline RA Isocapnic RA Recovery RA

39 A representative polygraph recording of intermittent hypoxia protocol in a subject with cervical spinal cord injury (SCI) that illustrates respiratory changes (A) and heart rate changes (B) using R-R interval before, during, and 40 min after AIH during reco... Abdulghani Sankari et al. J Appl Physiol 2015;119:

40 A Representative Example of Episodic Hypoxia during Wakefulness Baseline Sankari et al. JAP H1 H2 H3 H4 H5 H6 H7 H8 H9 H10H11 H12 H13 H14 H15 Recovery 40 min (A) (B) Baseline HR Beat Beat HR responses for EH HR variability(hrv) Spectral Analysis

41 Cardiac Responses: Heart Rate Variability

42 Cardiac Responses: Heart Rate Variability LF power HF power

43 Cardiac Responses: Heart Rate Variability LF/HF= Sympathovagal response LF power (Sympathetic) HF power (Para )

44 Effect of EH on Heart Rate & Autonomic Response Immediate HR response to acute hypoxia in SCI is similar to able bodied Baseline RA Hypoxia Recovery 25 % RRI or HR (A) Sankari et al. J Appl Physiol RRI (ms) * * * Episodic hypoxia 80 88% (B) SaO2 (%) * * * Cervical Thoracic Able

45 Effect of EH on Heart Rate & Autonomic Response Immediate HR response to acute hypoxia in SCI is similar to able bodied Baseline RA Hypoxia Recovery 25 % RRI or HR (A) Cardiac sympathetic activity in cervical SCI is similar to able bodied Baseline RA Recovery Post-EH * p<0.05 Baseline vs. Recovery * * (C) RRI (ms) * * * nlf (nu) Episodic hypoxia 80 88% (B) * (D) SaO2 (%) * * * LF/HF * Cervical Thoracic Able 0.0 Cervical Thoracic Able

46 Effect of EH on Heart Rate & Autonomic Response Immediate HR response to acute hypoxia in SCI is similar to able bodied Baseline RA Hypoxia Recovery 25 % RRI or HR (A) Cardiac sympathetic activity in cervical SCI is similar to able bodied Baseline RA Recovery Post-EH * p<0.05 Baseline vs. Recovery * * (C) RRI (ms) * * * nlf (nu) Episodic hypoxia 80 88% (B) * (D) SaO2 (%) * * * LF/HF * Cervical Thoracic Able 0.0 Cervical Thoracic Able

47 Intermittent hypoxia elicits spinal respiratory plasticity Autonomic innervation of the heart in cervical vs. thoracic SCI Cervical ganglion Stellate ganglion Thoracic ganglion Dale E A et al. Physiology 2014;29:39-48 Shen, M. J. et al. Nat. Rev. Cardiol. 2011

48 Heart Rate & Autonomic Response to Hypoxia in SCI Acute hypoxia HR responses in SCI w/o sympathetic tone. HR responses to hypoxia in SCI, may be associated with CVD as has been hypothesized in other populations with SDB. Need for further studies to determine cardiovascular risk in SCI.

49 Diurnal blood pressure in acute SCI compared with controls Day and night SBP (a) and DBP (b) for tetraplegics (n=33), high paraplegics (n=9), low paraplegics (n=17), immobilised controls (n=15) and mobilising controls (n=43) at baseline. Error bars represent s.e.m. Percentages above each set of bars represent night:day SBP and night:day DBP in respective graphs. Goh et al. Spinal Cord (2016)

50 Diurnal blood pressure in acute SCI compared with controls Majority of tetraplegics had night >day pressures, and ¼ had nocturnal hypertension. In the general population, abnormal diurnal variation (night:day SBP >90%) and elevated nocturnal BPs a/w poorer cardiovascular prognosis. Paraplegics had higher pulse rates increased sympathetic activity and autonomic balance. The results of this study emphasizes the need for ABPM in SCI to determine cardiovascular risk.

51 Conclusion The majority of SCI patients have symptomatic SDB and poor sleep quality. Many SCI patients are untreated for SDB and have increased cardiovascular morbidities. The cardiac autonomic changes are common in acute and chronic SCI and may play a role in the CVD risk. The lack of awareness and treatment of SDB among SCI patients may represent a form of health care disparity.

52 Future Goals Mechanism and test new therapeutic targets using pre clinical animal models and clinical studies. Early identification and treatment of both CVD and SDB in SCI. Role of heart rate and blood pressure monitoring in predicting clinical outcome.

53 Acknowledgments Co investigators: Wayne State University Safwan Badr, MD Harry Goshgarian, PhD University of Wisconsin Paul Peppard, PhD Erika Hagen, PhD Epidemiology Lab (Madison) Laurel Finn, MS Amanda Rasmuson Basic Science Lab Pershang Farshi, PhD Zeljka Minic, PhD Clinical Science Lab (Detroit) Sarah Vaughan, PhD Geoffery Ginter, BS Elizabeth Kruppe, MS Students & volunteers: Scott Maresh, MS (MD, 2019) Mulham Hamdon, MD Nawar Aljundi, BS Ghazwan Alkabisi, DDS Medea Shanizde, BS (premed) Aliza Rizwan, MD Current Funding Department of Veterans Affairs CDA # 1IK2CX (PI) DMC Foundation (PI) Cardiovascular Research Institute (PI) National Institute of Health, RO1 (Co I) Merit # 1I01CX (Co I) DoD #SC (Co I)

54 Special Thanks to All Veterans & Research Participants THANK YOU

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