Metoprolol to Reduce Perioperative Myocardial Injury

All patients will be beta-blocker naïve for at least 30 days prior to surgery and be
randomized 1:1 to receive metoprolol tartrate or placebo. Patients will receive up to 3 IV
doses of study drug (placebo or IV metoprolol tartrate 5mg) prior to extubation, and
subsequently an oral dose (placebo or 25mg metoprolol tartrate) in the PACU, and then oral
dosing at approx. every 8 hours thereafter through postop day 3 (72 hrs). From arrival in the
preop holding area through up to 72 hours postop or end of study treatment (whichever occurs
first), patients will be continuously monitored with Holter ECG, a mobile hemodynamic monitor
(VisiMobile), daily follow-up visits to include 12-lead ECG, and blood collections for serial
cardiac biomarkers for high-sensitivity troponin.

In addition to the previously-mentioned suite of wireless monitors, we propose to apply two
physiologic monitors that focus on the patient's autonomic state. These two measurements are
non-invasive and potentially will enable us to better characterize the patient's autonomic
response at critical timepoints. Additional benefits of these monitors include their possible
correlation with pain and stress, and their potential as key elements in future Mobile Health
(mHealth)-based studies and therapies.

The first of the enhanced monitors uses an off-the-shelf wristband fitness tracker (e.g.,
Fitbit) for collection of heart rate, and from these data, derives the patient's heart rate
variability (HRV). HRV is a dynamic measure of the number and type of distinct frequencies
that exist within the subject's overall heart beat pattern, and can be related to both
cardiovagal tone and numerous affective states. There is some evidence that the acute
response to pain correlates with HRV. Additionally, HRV has been found to have decreased
high-frequency components in patients with chronic pain. Our HRV collection and analysis
would use the technology underlying the Mindset app, (but not the app itself) to stream the
heart rate data to a secured tablet and perform the heart rate variability analysis., The
Mindset app, which itself will not be used by the patient is being utilized in a current
IRB-approved study as a potential sensor-assisted e-therapy for PTSD (P.I. Dr. Rumi Price,
Ph.D.). This app also allows for the real-time, tablet-based collection of subjective data
(e.g., pain and anxiety scores).

The second of the monitors uses an ultra-thin, ultra-compliant non-invasive sensor to
intermittently measure changes in temperature and blood flow on skin's surface. This highly
sensitive device can detect subtle changes in skin blood flow, including those that occur as
part of the autonomic response to stressful conditions. The thermal sensors, referred to as
epidermal transient plane source (ETPS) sensors, utilize the well-established transient plane
source method toward the identification of the thermal characteristics of skin. The ETPS
sensor capabilities have been thoroughly studied, and the device concepts have been employed
successfully in clinical studies related to blood flow[8], dermatological health[9], thermal
transport properties of skin, and wounds. The measures that the ETPS sensors-—cutaneous blood
flow and temperature—will be analyzed along with HRV responses to identify potential
correlations between autonomic tone and the subject's responses to different phases of
post-operative recovery.

In conjunction with the additional history questions asked of the subject, the subject may
also be asked about the presence or absence of previous chronic pain and/or anxiety. At
several time points along the course of recovery, the subject may be asked to provide
subjective information on his/her pain and anxiety. Data on medication administration (type
of medication, dose amount, and time of administration) may also be collected.

Follow-up at approximately 30 days and 1 year after surgery.

Inclusion Criteria

1. Age >= 50 years

2. Beta-blocker naïve [30 days prior to surgery]

3. Previously diagnosed CAD, or

1. History of PVD, or

2. CKD [eGFR ≤60ml/min], or

3. History of positive stress test or

4. At high risk for CAD (must meet at least 2 criteria):

i. Age >= 70 years ii. Hypertension iii. Diabetes requiring oral medication or insulin
iv. Current smoker or some days smoker within the past 2 years

4. Major non-cardiac, elective surgery under general anesthesia

Exclusion Criteria

Subjects will not be enrolled if any of the following criteria exist:

1. History of stroke, or TIA

2. Previously diagnosed carotid disease, i.e., either 70% unilateral or 50% bilateral
carotid occlusion.

3. Heart rate <=55bpm

4. Congestive heart failure with New York Heart Association(NYHA) Functional
Classification of III-IV or left ventricular heart failure with ejection fraction ≤50%

5. Severe valvular regurgitation

6. Second or third degree AV block without pacemaker

7. Active asthma or COPD with symptoms or resolving symptoms on day of surgery

8. Anemia [HB<=9g/dL]

9. Allergy to beta-blockade drugs

10. Unwilling or unable to give consent for participation

11. Undergoing any carotid endarterectomy, endovascular, endoscopic, superficial, or
ambulatory procedures

12. Pregnancy or lactating women

13. Prisoners