An investigation of peri-operative heart rate phenotypes in patients with post-operative myocardial injury.

Each year around 20,000 patients die after surgery in the UK, although the exact total is unclear. The most common causes of death involve the heart, including heart attack or heart failure. New data, from research using a sensitive blood test, suggest that ~10% of surgical patients suffer damage to the heart muscle (myocardial injury) and are more likely to die. This phenomenon is poorly understood. Urgent research is needed to find out how these complications arise and to develop new treatments to make surgery safer.

Until recently some opinion leaders supported giving surgical patients beta-blockers (drugs which primarily lower heart rate). This reduced heart attacks after surgery, but was later found to increase the risk of stroke and death. The reason for this is unknown. One explanation is that elevated heart rate puts strain on the heart, increasing the demand for oxygen, which leads to damage. However, our understanding of how heart rate around the time of surgery relates to myocardial injury is incomplete. Heart rate during surgery has only been examined in a few studies. These looked at general cardiac complications, such as heart attacks, but did not use blood tests to look for myocardial injury. Heart rate before surgery has been linked to outcomes after cardiac operations, but this has not been fully investigated in non-cardiac surgery. Heart rate change during exercise may also be associated with surgical outcomes. However, the evidence is inconsistent.

It is assumed that a fast heart rate before or during surgery is associated with myocardial injury. However, little evidence supports this assertion. In order to reduce cardiac complications after surgery, we must have a clear idea of the mechanism of myocardial injury. Understanding the role of heart rate before and during surgery is a crucial step in this process. This work will address an important unanswered question: are changes in heart rate associated with myocardial injury after surgery?

Aim:
To determine if patients with myocardial injury after surgery share common heart rate characteristics.

Objectives:
1. Determine whether patterns of heart rate before or during surgery are associated with subsequent myocardial injury, and to define 'safe' heart rate ranges.

2. Investigate associations between exercise-induced changes in heart rate before surgery and subsequent myocardial injury.

3. Repeat analyses using major cardiac complications as an alternative endpoint to make this work comparable to other studies in the field.

4. Consider possible associations between myocardial injury and long-term outcomes.


Methods:
These objectives can only be addressed using large multi-centre datasets. Our group has unique access to four studies of surgical patients, making me ideally placed to answer these questions. Much of my work so far has involved collecting additional data for these studies, and adapting the datasets for use as part of my PhD. I will analyse these data using sophisticated statistical modelling. I will develop data management skills, learn complex statistical techniques and continue to conduct exercise tests for the METS study. I will be supported by a full-time statistician.

Applications and benefits:
1. Develop a new model for identifying patients at risk of myocardial injury after surgery using pre-operative heart rate at rest and during exercise. This could enhance pre-operative assessment and improve clinical outcomes.

2. Improve clinical care by defining 'safe' heart rate ranges. Clinicians would be better able to identify patients at risk of myocardial injury and target therapy to control heart rate.

3. Develop new treatments to reduce myocardial injury. Heart rate targets could be used in two ways. (a) To improve drug dosing in clinical trials of heart rate treatments during surgery. (b) To improve recruitment to clinical trials by selecting the patients most at risk of myocardial injury.

1 in 10 patients suffer myocardial injury after surgery. Beta-blockers can protect the heart, but increase the risk of stroke and death. The reason for this is unclear. Heart rate control may reduce myocardial injury by decreasing rate-related cardiac ischaemia. However, the relationship between heart rate and cardiac complications is poorly understood. Few studies have examined intra-operative heart rate and these did not use objective measures of myocardial injury. Pre-operative heart rate may predict outcomes after cardiac surgery and heart rate during exercise may be linked to post-operative outcomes. However, evidence in these areas is inconsistent. Understanding whether heart rate plays a role in the genesis of myocardial injury is a key step in making surgery safer.

Aim:
To determine if patients with post-operative myocardial injury share common heart rate phenotypes.

Objectives:
1. Determine whether patterns of heart rate before or during surgery are associated with subsequent myocardial injury, and to define 'safe' heart rate ranges.

2. Investigate associations between exercise-induced changes in heart rate before surgery and subsequent myocardial injury.

3. Repeat analyses using major cardiac complications as an alternative endpoint to make this work comparable to other studies in the field.

4. Consider possible associations between myocardial injury and long-term outcomes.

Methods:
Answers to these questions requires data from a large number of patients. I am ideally placed to conduct this work since our group has unique access to data from four big peri-operative studies. I will create three databases, which will be analysed using sophisticated statistics. I will be supported by a full-time statistician.

Impact :
1. Improve pre-operative assessment and reduce cardiac complications of surgery

2. Improve clinical care by defining 'safe' heart rate ranges

3. Improve drug dosing for heart rate control in clinical trials

If this work identifies common peri-operative heart rate phenotypes shared by patients with post-operative myocardial injury, the following groups could benefit:

- Patients undergoing non-cardiac surgery

- Clinicians (anaesthetists and surgeons)

- Secondary care providers (including NHS hospitals)

- Pharmaceutical companies

- Researchers


How will they benefit?

1. Defined 'safe' peri-operative heart rate ranges

Beneficiaries: surgical patients, clinicians (surgeons and anaesthetists), secondary care providers, researchers

Output: It is assumed that heart rate is associated with complications following surgery. Clinicians often make interventions to reduce heart rate, but there is little evidence to support specific heart rate targets. This work aims to define a 'safe' intra-operative heart rate range, which will allow clinicians to respond to changes in intra-operative heart rate in a more evidence-based way.

Impact: Clinicians and patients will benefit from an evidence-based heart rate target because it will be easier to identify patients at risk of cardiac complications. Clinicians could use the heart rate target to guide therapy to lower heart rate. However, the efficacy of heart rate lowering therapy needs further evaluation.

2. Developing new treatments to reduce peri-operative cardiac complications

Beneficiaries: surgical patients, clinicians (surgeons and anaesthetists), pharmaceutical companies, secondary care providers, researchers

Output: Control of peri-operative heart rate with beta-blockers reduces cardiac complications, but increases the risk of stroke or death. Trials of these drugs used 'one size fits all' dosing and did not titrate dosage to heart rate, which may have resulted in over-dosing or under-dosing. These dosing regimes were used because evidence based heart rate targets were not available. This work aims to develop 'safe' heart rate ranges, which could be used as targets to guide heart rate lowering therapy in new clinical trials.

Impact: One in ten patients suffer cardiac injury after surgery. These patients are more likely die. New treatments are needed to reduce cardiac complications. Improved clinical trials of heart rate therapy have the potential to develop new treatments, which could reduce morbidity and mortality of thousands of surgical patients every year.

3. A new model for identifying patients at risk of cardiac complications

Beneficiaries: surgical patients, clinicians (surgeons and anaesthetists), secondary care providers, researchers

Output: Heart rate has been widely overlooked as a constituent of pre-operative risk prediction tools. If associations between pre-operative resting heart rate or exercise-induced change in heart rate and post-operative cardiac complications were identified, then the next step would be to develop a new risk prediction model. This could be used to identify surgical patients at high risk of cardiac events. Any new model would require validation in a large and independent cohort, which may require collecting data de novo.

Impacts: Clinicians and patients would benefit from increased accuracy of pre-operative assessment. This could identify patients who may benefit from medical treatment before surgery, which could improve outcomes. Hospitals would benefit from improved pre-operative assessment, by reducing cancellations for medical reasons on the day of surgery, and through improved allocation of post-operative resources (e.g. ICU beds).

4. Improving understanding of peri-operative myocardial injury.

Beneficiaries: Clinicians and researchers

Output: My PhD will improve our understanding of the mechanism(s) of peri-operative myocardial injury, laying the foundation for subsequent research in this area.

Impact: Facilitating further research into the short and long term consequences of myocardial injury. I aim to start this work toward the end of my PhD or as an early post-doctoral project.