Diastolic Dysfunction Is a Risk of Perioperative Myocardial Injury Assessed by High-Sensitivity Cardiac Troponin T in Elderly Patients Undergoing Non-Cardiac Surgery

Abstract

Background: High-sensitivity cardiac troponin T (hs-cTnT) is useful for detecting myocardial injury and is expected to become a prognostic marker in patients undergoing non-cardiac surgery. The aim of this pilot study evaluating the efficacy of β-blocker therapy in a perioperative setting (MAMACARI study) was to assess perioperative myocardial injury (PMI) in elderly patients with preserved ejection fraction (EF) undergoing non-cardiac surgery.

Methods and Results: In this prospective observational cohort study of 151 consecutive patients with preserved EF and aged >60 years who underwent non-cardiac surgery, serum levels of hs-cTnT were measured before and on postoperative days 1 and 3 after surgery. PMI was defined as postoperative hs-cTnT >0.014 ng/mL and relative hs-cTnT change ≥20%. A total of 36 (23.8%) of the patients were diagnosed as having PMI. The incidence of a composite of cardiovascular events within 30 days after surgery, including myocardial infarction, stroke, worsening heart failure, atrial fibrillation and pulmonary embolism, was significantly higher in patients with PMI than in patients without PMI (odds ratio (OR) 9.25, P<0.001, 95% confidence interval (CI) 2.65–32.3). Multivariate analysis revealed that left ventricular diastolic dysfunction defined by echocardiography was independently associated with PMI (OR: 3.029, 95% CI: 1.341–6.84, P=0.008).

Conclusions: PMI is frequently observed in elderly patients undergoing non-cardiac surgery. Diastolic dysfunction is an independent predictor of PMI.

More than 200 million adults worldwide undergo major non-cardiac surgery annually and of that more than 1 million adults die within 30 days of non-cardiac surgery each year.¹ Perioperative adverse cardiovascular events are common complications of non-cardiac surgery. Among them, myocardial infarction accounts for 10–40% of all causes of death.² Even without myocardial infarction, perioperative myocardial injury (PMI), which is defined as an elevation of cardiac troponin after non-cardiac surgery, occurs in 8–52% of patients who undergo non-cardiac surgery, and has been paid much attention because it is associated with an increased risk of the morbidity and mortality.^3–11

The numbers of elderly patients with several comorbid disorders and undergoing non-surgery have been increasing in recent years. And PMI is frequently observed in elderly patients.³ Several situations, including myocardial ischemia, heart failure and arrhythmia, probably induce myocardial micro-injury, but the risk of PMI remains unknown. Left ventricular (LV) diastolic dysfunction is a common comorbidity in elderly patients,¹² and is usually the result of impaired LV relaxation, with or without reduced restoring forces, and increased LV chamber stiffness, which increase the cardiac filling pressure. High LV filling pressure is associated with an increase in cardiovascular events, including pulmonary edema and arrhythmia, particularly in the perioperative period. Several studies have shown that LV diastolic dysfunction is associated with perioperative cardiovascular events in patients undergoing various types of surgery.^13–16

The aim of this study was to evaluate the incidence of PMI as assessed by high-sensitivity cardiac troponin T (hs-cTnT) level and to determine the risk factors for PMI in elderly patients with preserved ejection fraction (EF) undergoing non-cardiac surgery. This was a pilot study to determine the frequency of PMI and to determine the relationship between the incidence of PMI and cardiovascular events for planning a randomized study to reveal the efficacy of β-blocker therapy in the perioperative setting (MAMACARI study; UMIN000016908).

Methods

Patient Population

This prospective observational cohort study included consecutive patients undergoing non-cardiac surgery between January 2014 and January 2016, at the Okayama University Hospital. Patients were eligible if they were aged ≥60 years with preserved EF, were scheduled to undergo elective non-cardiac surgery under general anesthesia, and had an expected postoperative length of hospital stay of at least 3 days. We excluded patients with reduced LVEF <50%, pacemaker implantation, valve replacement, severe renal insufficiency (estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m²), treated with hemofiltration or dialysis, and who were scheduled for urgent or emergency surgery. The Medical Ethics Committee of Okayama University approved the study protocol (application no. [1603-501]).

Study Protocol

An outline of this study is shown in Figure 1. For each patient, baseline clinical data were obtained in the preoperative period: patients’ characteristics, physical status, comorbidities, preoperative medications on admission to hospital, and type of surgery. The data source was also used to obtain American Society of Anesthesiologists (ASA) class and Revised Cardiac Risk Index (RCRI) for all patients. RCRI assigns 1 scoring point to a patient based on 6 criteria (high-risk type of surgery, history of ischemic heart disease (IHD), history of congestive heart failure (CHF), history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine >2.0 mg/dL).¹⁷ High-risk surgery includes all intrathoracic, intraperitoneal, and suprainguinal vascular procedures. Patients with IHD were defined as those with a history of myocardial infarction, positive exercise test, current complaint of ischemic chest pain or use of nitrate therapy, or ECG with Q waves. Patients with prior coronary artery bypass grafting surgery or percutaneous coronary intervention were included in this definition only if they had a current complaint of chest pain that was presumed to be caused by ischemia. Patients with CHF were defined as those with a pertinent history, pulmonary edema, or paroxysmal nocturnal dyspnea and those for whom a physical examination showed bilateral rales or S3 gallop or a chest radiograph showed pulmonary vascular redistribution.¹⁸

Figure 1.

Study protocol. Serum levels of 5th-generation high-sensitivity cardiac troponin T (hs-cTnT) were measured before and on postoperative days (POD) 1 and 3 after non-cardiac surgery. All-cause death and cardiovascular events, including myocardial infarction, stroke, worsening heart failure, atrial fibrillation, and pulmonary embolism were assessed within 30 days of surgery.

Serum levels of 5th-generation hs-cTnT were measured before and 24 (postoperative day 1) and 72 h (postoperative day 3) after non-cardiac surgery. All plasma samples were frozen and stored at −20℃ at the hospital’s laboratory until analysis. For measurement of hs-cTnT, a commercially available Elektrochemiluminiszenz-Immunoassay on a cobas^® 8000 modular analyzer (Roche Diagnostics Ltd., Rotkreuz, Switzerland) was used. An hs-cTnT level >0.014 ng/mL was considered to be elevated, according to the standards of the laboratory.

All patients underwent ECG, chest radiography, transthoracic echocardiography, and pulmonary function testing in the preoperative period. Parameters of systolic and diastolic functions, including LVEF, mitral E/e’ ratio (E/e’) and left atrial volume index, were measured by echocardiography. Patients with 3 or all of the following conditions, average E/e’ >14, septal e’ velocity <7 cm/s or lateral e’ velocity <10 cm/s, tricuspid regurgitation velocity >2.8 m/s, left atrial volume index >34 mL/m², were diagnosed as having LV diastolic dysfunction as defined by ASE/EACVI guidelines.¹⁹

Intraoperative Variables

Information on anesthesia technique, intraoperative hemodynamics, surgical status and duration of surgery was obtained. Hemodynamic variables were electronically recorded at 5-min intervals throughout the procedure. Abnormal intraoperative hemodynamics were defined as hypotension (systolic BP <90 mmHg), hypertension (systolic BP >160 mmHg), bradycardia (heart rate <50 beats/min), tachycardia (heart rate >100 beats/min), and hypoxia (SpO₂ <92%).

Study Endpoints (Definition of PMI)

The primary outcome was the incidence of PMI, but currently, there is no accepted definition of PMI. In previous studies, several biomarkers were shown to predict cardiovascular events after non-cardiac surgery, including cardiac troponin, N-terminal pro-B-type natriuretic peptide and C-reactive protein.²⁰ Of these, hs-cTnT was the more reliable marker of adverse short-term and long-term outcomes in the perioperative setting.^21,22 Approximately 30–40% of patients had an hs-cTnT level >99th percentile prior to the surgical procedure, and the absolute or relative hs-cTnT change (∆hs-cTnT) should therefore be evaluated to identify PMI.^23,24 Eggers et al reported that the universal definition of acute myocardial infarction, together with ≥20% change in cardiac troponin I (cTnI) appears to improve the discrimination of acute from chronic causes of cTnI release.²⁵ The National Academy of Clinical Biochemists recommends that ≥20% change is indicative of myocardial infarction.²⁶ In our study, to improve the diagnostic accuracy of PMI, we used 5th-generation hs-cTnT. An hs-cTnT level >0.014 ng/mL (i.e., the 99th percentile derived from healthy individuals) was considered to be elevated. According to this evidence, we defined PMI as postoperative hs-cTnT (hs-cTnT) >0.014 ng/mL and a relative hs-cTnT change ≥20%.

Secondary outcomes were all-cause death and cardiovascular events, including myocardial infarction, stroke, worsening heart failure, atrial fibrillation (AF), and pulmonary embolism (PE), within 30 days after surgery. Myocardial infarction was defined according to the universal definition.²⁷ Among the composite endpoints, the incidence of AF was significantly higher in the PMI group.

Statistical Analysis

Statistical analysis was performed using SPSS 11.0 for Windows (SPSS, Chicago, IL, USA). Continuous data are presented as means (SD) if normally distributed. In the case of abnormal distribution, medians and interquartile ranges are presented. The mean differences between groups were analyzed using Student’s t-test. Proportional differences were analyzed using Fisher’s exact analysis. Categorical variables were analyzed using the chi-squared test. The relative change in hs-cTnT and differences between groups were analyzed using the Friedman test and Wilcoxon signed-ranks test. Based on previous studies,^4–11,28 we assumed the incidence of PMI would be 30%. Event rates were estimated to be 25% and 5% in patients with and without PMI, respectively. A total of 148 patients (34 with PMI, 114 without PMI) would be needed to detect this difference at α=0.05 and a power of 0.80. Kaplan-Meier analysis was used to assess event-free survival after surgery. The composite cardiovascular event-time curve was separated into curves for the PMI and non-PMI groups, and the curves were compared by log-rank test. Univariate logistic regression models were calculated for known predictive factors of PMI that were assessed in the study. Multivariate modeling included factors that were associated with cardiac LV diastolic function in the univariate analysis. A P-value <0.05 was considered significant.

Results

Incidence of PMI Assessed by hs-cTnT

In total, 151 patients were eligible for inclusion in this study; 36 (23.8%) were diagnosed as having PMI. The clinical characteristics of the patients with and without PMI are presented in Table 1. There were no significant differences in patients’ ages, sex or BMI. RCRI score, percentage of patients with a history of heart failure, the concentrations of preoperative hs-cTnT and plasma brain natriuretic peptide and incidence of LV diastolic dysfunction were significantly higher in the PMI group than in the non-PMI group. The surgical and procedural variables of patients with and without PMI are presented in Table 2. There were no significant differences in surgical specialty, anesthesia, intraoperative hemodynamics, surgical status and duration of surgery between the 2 groups. Intraoperative tachycardia (heart rate >100 beats/min) was significantly higher in the PMI group than in the non-PMI group.

Table 1. Clinical Characteristics of Study Participants

	Non-PMI group (n=115)	PMI group (n=36)	P value
Age, years	74±8	77±8	0.054
Male sex, n (%)	66 (57)	24 (67)	0.322
Height, cm	158±9	157±9	0.765
Body weight, kg	58±12	54±12	0.119
Body mass index, kg/m2	23.2±4.2	21.7±3.4	0.059
RCRI score*	1 (1–1)	2 (2–2)	0.023
RCRI factors, n (%)
High-risk procedures	59 (51)	24 (67)	0.106
History of ischemic heart disease	35 (30)	11 (31)	0.989
History of heart failure	7 (6)	9 (25)	0.001
History of cerebrovascular disease	15 (13)	5 (14)	0.896
Renal failure, creatinine ≥2.0 mg/dL	2 (2)	1 (3)	0.697
Preoperative insulin use	10 (9)	3 (8)	0.946
History, n (%)
Hypertension	84 (73)	26 (72)	0.923
Diabetes mellitus	34 (30)	12 (33)	0.668
Dyslipidemia	58 (50)	11 (31)	0.037
Medications, n (%)
Platelet inhibitor	21 (18)	4 (11)	0.314
β-blocker	27 (23)	8 (22)	0.876
Statins	37 (32)	5 (14)	0.033
ASA class, n (%)			0.388
1	33 (29)	9 (25)
2	68 (59)	20 (56)
3	14 (12)	7 (19)
Preoperative laboratory tests
Plasma BNP, pg/mL*	38 (19–73)	70 (54–115)	0.005
eGFR, mL/min/1.73 m2	67± 17	65±23	0.799
hs-cTnT, ng/mL/1,000
Preoperative*	8 (5–15)	14 (11–17)	0.002
Postoperative day 1*	11 (7–16)	24 (20–35)	<0.001
Postoperative day 3*	9 (6–13)	18 (14–25)	<0.001
Rhythm, n (%)			0.215
Sinus rhythm	109 (95)	32 (89)
AF	6 (5)	4 (11)
Echocardiography
Left atrial volume index*	34 (31–39)	36 (31–45)	0.192
E/e’*	12.0 (9.9–15.0)	14.6 (11.1–17.0)	0.048
e’, cm/s*	4.9 (4.2–6.0)	4.8 (4.0–6.1)	0.731
LVEF, %*	67 (62–70)	64 (59–68)	0.113
Tricuspid regurgitation velocity, m/s*	2.4 (2.2–2.5)	2.6 (2.3–3.0)	<0.001
Diastolic dysfunction, n (%)	23 (20)	16 (44)	0.003

Data are expressed as mean±standard deviation, n (%) or *median (interquartile range). AF, atrial fibrillation; ASA, American Society of Anesthesiologists; BNP, B-type natriuretic peptide; eGFR estimated glomerular filtration rate; hs-cTnT, high-sensitivity cardiac troponin T; LVEF, left ventricular ejection fraction; PMI, perioperative myocardial injury; RCRI, Revised Cardiac Risk Index.

Table 2. Surgical and Procedural Variables

	Non-PMI group (n=115)	PMI group (n=36)	P value
Surgical specialty, n (%)
General	45 (39)	11 (31)	0.353
Thoracic	22 (19)	12 (33)	0.075
Vascular	6 (5)	1 (3)	0.543
Neurosurgery	5 (4)	1 (3)	0.674
Orthopedic	12 (10)	3 (8)	0.713
Otolaryngology	6 (5)	0 (0)	0.162
Gynecological	4 (3)	2 (6)	0.578
Urology	3 (3)	2 (6)	0.388
Other	9 (8)	2 (6)	0.647
Anesthesia, n (%)
Inhalation anesthesia	79 (69)	28 (78)	0.295
Epidural	50 (43)	21 (58)	0.119
Nerve block	9 (8)	2 (6)	0.647
Intraoperative hemodynamics, n (%)
Hypotension (SBP <90 mmHg)	43 (37)	18 (50)	0.178
Hypertension (SBP >160 mmHg)	6 (5)	1 (3)	0.543
Bradycardia (HR <50 beats/min)	0 (0)	1 (3)	0.073
Tachycardia (HR >100 beats/min)	4 (3)	5 (16)	0.021
Hypoxia (SpO2 <92%)	6 (5)	3 (8)	0.491
Surgical status
Intraoperative blood loss, mL	85 (10–240)	102 (50–203)	0.687
Intraoperative total transfusion, mL	2,189 (1,350–2,950)	2,050 (1,655–3,038)	0.598
Duration of surgery, min*	229 (142–327)	238 (161–334)	0.536

Data are expressed as n (%) or *median (interquartile range). HR, heart rate; SBP, systolic blood pressure; SpO₂, arterial oxygen saturation.

The changes in hs-cTnT concentrations in the perioperative period are shown in Figure 2. In PMI group, hs-cTnT significantly increased on the day of surgery, and decreased 3 days after surgery.

Figure 2.

Perioperative levels of high-sensitivity cardiac troponin T (hs-cTnT) in the (A) PMI and (B) non-PMI groups. PMI, perioperative myocardial injury.

Incidence of Composite of In-Hospital Cardiovascular Events

As shown in Table 3, the incidence of postoperative AF was higher in the PMI group than in the non-PMI group. None of the patients were diagnosed with myocardial infarction according to the universal definition, and the 30-day mortality rate was 0% in both groups. The incidence of the composite of major perioperative events within 30 days after non-cardiac surgery, including myocardial infarction, stroke, worsening heart failure, AF and PE, was significantly higher in patients with PMI than in patients without PMI (odds ratio (OR) 9.25, P<0.001, 95% confidence interval (CI) 2.65–32.3). Figure 3 shows the Kaplan-Meier curves of the cardiovascular event-free survival in patients with and without PMI. It was significantly higher in patients without PMI than in patient with PMI. The details about each event are presented in Table S1.

Table 3. 30-Day Cardiovascular Events

Outcome	Non-PMI group (n=115)	PMI group (n=36)	OR (95% CI)	P value
Mortality	0	0	NA
Myocardial infarction	0	0	NA
Worsening heart failure	0	1 (2.8)	NA
AF*	4 (3.5)	5 (13.9)	4.48 (1.13–17.7)	0.021
Pulmonary embolism	0	3 (8.3)	NA
Stroke	0	0	NA
Composite of major events†	4 (3.5)	9 (25.0)	9.25 (2.65–32.3)	<0.001

Data are expressed as n (%). *Included paroxysmal AF in the perioperative period and excluded persistent/chronic AF before surgery. ^†Composite of death, myocardial infarction, worsening heart failure, AF, pulmonary embolism, and stroke. CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Figure 3.

Kaplan-Meier analysis of event-free survival after surgery. The composite cardiovascular event-time curve is separated into the PMI and non-PMI groups, and the curves were compared by the log-rank test. PMI, perioperative myocardial injury.

We re-evaluated the optimal definition of PMI for predicting cardiovascular events after surgery. The association of PMI with cardiovascular events was assessed, and we concluded that the combination of 1-day postoperative hs-cTnT >0.014 and relative hs-cTnT increase ≥20% had the best sensitivity (69%), specificity (80%), positive predictive value (25%), and negative predictive value (97%). There was no significant difference in cardiovascular events between the groups. The details are presented in Table S2.

Risk Factors for PMI

We assessed the independent risk factors of experiencing PMI using multiple logistic regression analysis. Univariate as well as multivariate logistic analysis revealed that LV diastolic dysfunction was an independent risk factor of PMI (OR 3.029, 95% CI 1.341–6.84, P=0.008) (Table 4).

Table 4. Independent Risk Factors of Perioperative Myocardial Injury

	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	OR	95% CI	P value
Age, >70 years	1.611	0.709–3.66	0.255
Sex, male	1.485	0.677–3.257	0.324
Body mass index, ≥25	0.689	0.325–2.102	0.689
Duration of surgery ≥300 min	0.956	0.415–2.2	0.915
RCRI 2 or ≥2	1.498	0.704–3.189	0.294
Tachycardia, ≥100 beats/min	4.476	1.133–17.68	0.032	3.904	0.940–16.208	0.061
Diastolic dysfunction	3.2	1.437–7.126	0.004	3.029	1.341–6.84	0.008

Abbreviations as in Tables 1,3.

Discussion

By measuring the temporal changes in the levels of ultra-high-sensitive-cardiac TnT before and after surgery, we found that 23.8% of elderly patients showed ≥20% increase in hs-cTnT, compared with their baseline levels, after non-cardiac surgery, and this was not associated with signs of myocardial infarction. Multiple logistic regression analysis demonstrated that LV diastolic dysfunction is an independent predictor of PMI. To our knowledge, this is the first study to report a close association between LV diastolic dysfunction and PMI in elderly patients undergoing non-cardiac surgery.

According to several large cohort studies, elevated postoperative hs-cTnT levels are significantly associated with 30-day mortality.^3–11 In the VISION study, among 21,842 patients aged ≥45 years who underwent non-cardiac surgery, 3,904 (17.9%) was diagnosed with MINS (myocardial injury after non-cardiac surgery). Most (93.1%) of the patients who were diagnosed with MINS had not experienced any ischemic symptoms. It was reported that the incidence of a non-ischemic etiology, such as sepsis, AF or PE, was much greater than that of an ischemic etiology. The current study showed that the rate of acute coronary syndrome with any revascularization was lower than 0.2% in the patients who underwent non-cardiac surgery.²⁹ Because of the small sample size in our study, it is not unreasonable that there were no cases of cardiac death or myocardial infarction.

Although less common than other cardiovascular diseases, such as myocardial infarction and heart failure, venous thromboembolism has been receiving much attention worldwide. According to a Spanish national registry, in-hospital death of patients diagnosed with PE after surgery was approximately 9%.³⁰ In those patients, elevated levels of troponin were associated with right ventricular dysfunction caused by PE. An elevated troponin level was used as a prognostic marker of myocardial damage in patients with PE.³¹ Therefore, we defined composite cardiovascular events as myocardial infarction, stroke, worsening heart failure, AF, and PE within 30 days after surgery.

Currently, there is no accepted definition of PMI based on hs-cTnT. In previous studies, PMI was defined by the absolute or relative change in hs-cTnT before and after non-cardiac surgery. Gillmann et al reported that a preoperative hs-cTnT ≥0.018 ng/mL and a perioperative increase in hs-cTnT ≥0.006 ng/mL were independently associated with major adverse cardiac events in vascular surgery patients.²⁴ Noordzij et al suggested that a relative change in hs-cTnT >50% from baseline value seemed to be appropriate for diagnosis of myocardial injury.²¹ Eggers et al tested the best cutoff value to diagnose acute myocardial infarction among changes in hs-cTnT ≥20%, ≥50%, or ≥100% from baseline. They found that a change >50% was associated with the most frequent false-negative results in diagnosing acute myocardial infarction.²⁵ Therefore, in this study we used ≥20% increase in hs-cTnT compared with baseline as the definition of PMI to avoid under-diagnosis of PMI. Thus, the incidence of PMI (23.8%) was higher than we expected, but we consider that this definition had sufficient sensitivity for PMI.

There are several possible mechanisms of PMI. The main pathology is known to be myocardial ischemia, possibly from preexisting coronary artery disease, plaque rupture or imbalance between myocardial oxygen supply and demand. Anemia and hemodynamic instability caused by major bleeding during surgery may accelerate myocardial ischemia.²⁷ Interestingly, the incidence of coronary artery stenosis is poorly correlated with postoperative myocardial infarction, and it was proven that revascularization before high-risk surgery does not improve the long-term outcome.³² Our study demonstrated that LV diastolic dysfunction was an independent factor associated with PMI in the current elderly patients. LV diastolic dysfunction is commonly observed in elderly patients, and is well associated with increased LV filling pressure, which can cause endocardial ischemia.^12,19,33 In the perioperative period, surgical stress, bleeding, hydration, and some types of anesthesia might worsen LV diastolic function and cause subendocardial ischemia. Previous clinical studies showed that LV diastolic dysfunction is a predictor of adverse cardiovascular outcomes in patients undergoing non-cardiac surgery.^13–16 However, diastolic dysfunction has been defined in various ways in the past few decades, and the clinical importance of LV diastolic dysfunction in the preoperative period remains unclear. The present study is the first study to show a relationship between PMI and diastolic dysfunction as defined by the new ASE/EACVI guidelines.¹⁹

In this study, the incidence of AF was higher in the PMI group. It is well known that perioperative AF is associated with an increased risk of perioperative death. LV diastolic dysfunction increases the risk of AF.^34–36 Possible micro-embolism in the coronary circulation and tachycardia-induced subendocardial myocardial ischemia may be associated with an increased risk of PMI. In contrast, PMI might be a trigger for the occurrence of perioperative AF. Therefore, we should evaluate LV diastolic dysfunction in each elderly patient undergoing non-cardiac surgery for risk stratification of PMI and perioperative AF.

Study Limitations

This study was performed in a small population of patients who were undergoing non-cardiac surgery. There was no significant difference in mortality between the PMI and non-PMI groups in this small population, probably because of an underpowered analysis. A further large-scale study is needed.

Conclusions

PMI was frequently observed in elderly patients undergoing non-cardiac surgery and is an important surrogate marker for 30-day cardiovascular events. Diastolic dysfunction was an independent predictor of PMI.

Acknowledgments

We thank Kaoru Akazawa, Megumi Kondo and Masayo Ohmori for their excellent technical assistance.

Conflict of Interests

All authors have no financial disclosures that are relevant to this article. We have no grants to disclose.

Funding

None.

Supplementary Files

Supplementary File 1

Table S1. Details of each event case

Table S2. Relationship between each definition for PMI and different cardiovascular events

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0747

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