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Grade 3 Echocardiographic Diastolic Dysfunction Is Associated With Increased Risk of Major Adverse Cardiovascular Events After Surgery: A Retrospective Cohort Study

Zhou, Yan MD, PhD*; Liu, Lin MD; Cheng, Tong MD*; Wang, Dong-Xin MD, PhD*; Yang, Hong-Yun MD; Zhang, Bao-Wei MD; Yang, Ying MD; Chen, Feng MD; Li, Xue-Ying MS§

doi: 10.1213/ANE.0000000000003807
Cardiovascular and Thoracic Anesthesiology: Original Clinical Research Report
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BACKGROUND: Diastolic dysfunction is common and may increase the risk of cardiovascular complications. This study investigated the hypothesis that, in patients with isolated left ventricular diastolic dysfunction, higher grade diastolic dysfunction was associated with greater risk of major adverse cardiovascular events (MACEs) after surgery.

METHODS: This was a retrospective cohort study. Data of adult patients with isolated echocardiographic diastolic dysfunction (ejection fraction, ≥50%) who underwent noncardiac surgery from January 1, 2015 to December 31, 2015 were collected. The primary end point was the occurrence of postoperative MACEs during hospital stay, which included acute myocardial infarction, congestive heart failure, stroke, nonfatal cardiac arrest, and cardiac death. The association between the grade of diastolic dysfunction and the occurrence of MACEs was assessed with a multivariable logistic model.

RESULTS: A total of 2976 patients were included in the final analysis. Of these, 297 (10.0%) developed MACEs after surgery. After correction for confounding factors, grade 3 diastolic dysfunction was associated with higher risk of postoperative MACEs (odds ratio, 1.71; 95% confidence interval, 1.28–2.27; P < .001) when compared with grades 1 and 2. Patients with grade 3 diastolic dysfunction developed more non-MACE complications when compared with grades 1 and 2 (uncorrected odds ratio, 1.44; 95% confidence interval, 1.07–1.95; P = .017).

CONCLUSIONS: In patients with isolated diastolic dysfunction undergoing noncardiac surgery, 10.0% develop MACEs during hospital stay after surgery; grade 3 diastolic dysfunction is associated with greater risk of MACEs.

From the Departments of *Anesthesiology and Critical Care Medicine

Cardiology

Laboratory

§Biostatistics, Peking University First Hospital, Beijing, China.

Published ahead of print 14 August 2018.

Accepted for publication August 14, 2018.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

This work is attributed to the Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital.

Institutional review board: Peking University First Hospital Ethics Committee, No. 6 Dahongluochang St, Xicheng District, Beijing 100034, China. E-mail: bdyyll@126.com.

Brief summary statement: Patients (10.0%) with isolated diastolic dysfunction developed major adverse cardiovascular events after noncardiac surgery. When compared with diastolic dysfunction of grades 1 and 2, grade 3 was independently associated with greater risk of major adverse cardiovascular events.

Trial Registration: ClinicalTrials (clinicaltrials.gov) NCT03138109.

Reprints will not be available from the authors.

Address correspondence to Dong-Xin Wang, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing 100034, China. Address e-mail to wangdongxin@hotmail.com.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Diastolic dysfunction refers to impaired left ventricular (LV) relaxation with or without an increase of filling pressure.1 It can be present in asymptomatic patients, patients with preserved ejection fraction (EF), and patients with reduced EF.2 Diastolic dysfunction as detected by comprehensive Doppler techniques is common. For example, in a study of a community population ≥45 years of age, 20.8% had mild, 6.6% had moderate, and 0.7% had severe diastolic dysfunction, with 5.6% of the population having moderate-to-severe diastolic dysfunction with normal EF.3 The prevalence of diastolic dysfunction varies among different populations; it is 2.8% in individuals 25–30 years of age and 15.8% in those >65 years of age, and the prevalence is higher in men than in women (13.8% vs 8.6%).4 Although diastolic dysfunction is often symptomless, its presence is associated with marked increases of all-cause mortality.3

According to available evidence, age, hypertension, diabetes, and LV hypertrophy are major risk factors of diastolic dysfunction.5 Along with the aging population, it can be expected that more and more patients with diastolic dysfunction will be encountered in the operating room and will constitute a big challenge for perioperative care. Indeed, in a recent meta-analysis, the presence of diastolic dysfunction is significantly associated with an increased risk of major adverse cardiovascular events (MACEs) in surgical patients.6 However, in that meta-analysis, reviewers’ overall certainty of the evidence was moderate.6 Therefore, further evidence is needed to evaluate the impact of diastolic dysfunction on postoperative outcomes.

This study was aimed to investigate the hypothesis that, in patients with isolated echocardiographic diastolic LV dysfunction, higher grade diastolic dysfunction was associated with greater risk of MACEs after noncardiac surgery.

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METHODS

Study Design

This retrospective cohort study was approved by the Peking University First Hospital Ethics Committee (2015 [965]). Because of the retrospective nature and that no patient follow-up was performed, the requirement for written informed consent was waived by the ethics committee. The trial was registered at clinicaltrials.gov (NCT03138109; principal investigator: Y.Z.; date of registration: May 3, 2017).

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Patient Collection

Patients who had preoperative results of echocardiographic examination were screened for study inclusion. As a routine practice in the study center, those who were ≥60 years of age or had history of cardiovascular disease were required to undergo echocardiographic examination before surgery. The inclusion criteria were adult (≥18 years of age) patients who were diagnosed as diastolic LV dysfunction by echocardiography within 90 days before surgery and underwent noncardiac surgery in Peking University First Hospital from January 1, 2015 to December 31, 2015. The exclusion criteria include congenital heart disease, moderate-to-severe valvular disease (stenosis or insufficiency), atrial fibrillation or other tachyarrhythmia, pericarditis, unsatisfied echocardiogram, LV EF <50%, American Society of Anesthesiologists (ASA) classification of V or higher, or missed or incomplete preoperative echocardiographic results.

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Transthoracic Echocardiography

All enrolled patients received echocardiographic examination within 90 days before surgery. Two types of ultrasound machines (Philips IE33 [Philips Medical Systems, Andover, MA] and GE Vivid E9 [GE Vingmed Ultrasound AS, Horten, Norway]) were used, with the probe frequency of 2–4 MHz and frame rate of >50 frames/s. Patients were examined at rest in the left lateral position. Standard 2-dimensional and Doppler images were collected by cardiologists. Images were interpreted by cardiologists with ≥5 years of working experience.

Data collection included left atrial diameter, peak E (early diastolic) and A (late diastolic) velocities, deceleration time (DT) from E peak, pulsed-wave tissue Doppler image E′ velocity (in centimeters per second), mitral E/A ratio, and mitral E/e′ ratio. The e′ wave was measured on the septal side of the mitral valve. Diastolic dysfunction was diagnosed according to the echocardiographic examination results and categorized into 3 grades based on 2009 version of recommendations, that is, grade 1 (mild diastolic dysfunction or impaired relaxation phase: E/A <0.8, DT >200 milliseconds, E/e′ ≤8), grade 2 (moderate diastolic dysfunction or pseudonormal phase: E/A 0.8–1.5, DT 160–200 milliseconds, E/e′ 9–12), and grade 3 (severe diastolic dysfunction or restrictive filling phase: E/A ≥2, DT <160 milliseconds, E/e′ ≥13).1 Cardiologists (L.L. and B.-W.Z.) were consulted when there was difficulty in categorizing the grades according to the criteria listed above.

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Baseline and Intraoperative Data Collection

Patients were screened in the electronic record system of the Department of Cardiology according to the inclusion and exclusion criteria. For enrolled patients, detailed data collection was performed in the electronic record system of the hospital. Preoperative data included demographic data (age, body mass index, and sex), comorbidity, medication, results of echocardiographic examination (including grade of diastolic dysfunction), and ASA physical status classification. Intraoperative data included diagnosis, anesthetic information (type, duration, fluid infusion, use of vasoactive drugs, and urine output), surgical information (type, duration, and blood loss), and the complexity of the surgical procedure (divided into low, moderate, or high risk according to the modified Johns Hopkins surgical criteria).7

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Postoperative Outcomes

The primary end point was the occurrence of MACEs during hospitalization after surgery, including acute myocardial infarction, congestive heart failure, stroke, nonfatal cardiac arrest, and cardiac death.8,9 Diagnosis of acute myocardial infarction required clinical symptoms and/or new electrocardiographic abnormalities and a cardiac troponin I of >0.05 ng/mL; congestive heart failure required signs and symptoms of heart failure and a B-type natriuretic peptide ≥400 pg/mL; stroke required new-onset localized neurological symptoms or unconsciousness, confirmed by computed tomography or magnetic resonance imaging scanning; nonfatal cardiac arrest required the occurrence of sudden cardiac arrest but successful resuscitation, that is, spontaneous circulation returned and patient survived; and cardiac death required sufficient evidence to prove that death occurred due to cardiac causes.10–13

Secondary end points included admission to intensive care unit after surgery, incidence of non-MACE complications during hospitalization, length of stay in hospital after surgery, and in-hospital mortality. Non-MACE complications were generally defined as new-onset medical conditions other than MACEs that were unfavorable to patient recovery and required therapeutic intervention during hospitalization after surgery. The diagnostic criteria for each individual non-MACE complication are listed in Supplemental Digital Content, Table 1, http://links.lww.com/AA/C584.

Postoperative outcomes were assessed by 2 investigators (Y.Z. and T.C.) who reviewed the electronic medical documents of all enrolled patients; these included the medical histories; results of physical, laboratory, and auxiliary examinations; medical consultation records; and records of death discussion. The occurrence of MACEs and non-MACE complications was diagnosed according to the predefined definitions and was cross-checked by the 2 investigators. Cardiologists (L.L. and B.-W.Z.) and/or a senior anesthesiologist (D.-X.W.) were consulted when there were discrepancies regarding diagnosis.

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Statistical Analysis

According to previous studies,14–17 we assumed that the incidence of postoperative MACEs would be 7.1% and 18.0% in patients with grade 2 and grade 3 diastolic dysfunction, respectively. With significance set at 0.05/3 = 0.0167 and power set at 90%, the calculated sample size needed to compare 3 proportions was 296 patients in each group. For comparison among 3 groups, we needed ≥888 patients.18

For comparative analysis, patients were divided into 3 groups according to their grades of diastolic dysfunction. Continuous variables with normal distribution were compared with 1-way analysis of variance; those with nonnormal distribution were compared with the Kruskal–Wallis H test. The Kolmogorov–Smirnov test was used for testing normality. Categorical variables were compared with the χ2 test or continuity correction χ2 test. Rank variables were compared with the Kruskal–Wallis H test.

Factors that were possibly associated with the development of MACEs were screened with univariable logistic regression analyses and tested for collinearity. Because the number of patients with grade 1 diastolic dysfunction was relatively small and there was no significant difference between grades 1 and 2 diastolic dysfunction regarding their association with postoperative MACE development, patients with grades 1 and 2 diastolic dysfunction were combined for further analyses. Those who had P values <.10 in univariable analysis were included in a multivariable logistic regression model to identify an association between the severity of diastolic dysfunction and the development of MACEs.

A two-tailed test was performed whenever appropriate, and P values of <.05 were considered statistically significant. For multiple comparisons among 3 grades of diastolic dysfunction, the criterion of significance was adjusted with Bonferroni correction (P < .05/3 = .0167). Statistical analyses were performed with SPSS 17.0 software (SPSS, Chicago, IL) and R (3.2.3), Statistics Department of the University of Auckland, Auckland, New Zealand.

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RESULTS

Patient Population

Figure.

Figure.

Table 1.

Table 1.

Table 2.

Table 2.

From January 1, 2015 to December 31, 2015, 4347 patients who underwent echocardiographic examination within 90 days before surgery were screened. Of these, 2976 met the inclusion/exclusion criteria and were included in the final analysis (Figure). Among included patients, 262 (8.8%) were diagnosed as diastolic dysfunction grade 1, 1611 (54.1%) grade 2, and 1103 (37.1%) grade 3. The baseline and intraoperative data are listed in Tables 1–2 and Supplemental Digital Content, Table 2, http://links.lww.com/AA/C584.

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Occurrence of Postoperative MACEs and Non-MACE Complications

Table 3.

Table 3.

Among the included 2976 patients, 297 (10.0%) developed ≥1 MACE during hospital stay after surgery. For those who developed MACEs, 247 (8.3%) were congestive heart failure, 110 (3.7%) acute myocardial infarction (including 5 ST-elevation myocardial infarction and 105 non–ST-elevation myocardial infarction), 13 (0.4%) stroke, and 4 (0.1%) cardiovascular death (Table 3). The MACEs (80.1% [238 of 297]) occurred within 3 days after surgery (Supplemental Digital Content, Figure 1, http://links.lww.com/AA/C584). Post hoc multiple comparisons showed a higher incidence of postoperative MACEs in patients with grade 3 diastolic dysfunction (grade 2 vs grade 1: 7.3% [118/1611] vs 7.3% [19/262], P = .971; grade 3 vs grade 1: 14.5% [160/1103] vs 7.3% [19/262], P = .001; grade 3 vs grade 2: 14.5% [160/1103] vs 7.3% [118/1611], P < .001). When compared to patients with grades 1 and 2 diastolic dysfunction, those with grade 3 diastolic dysfunction developed more MACEs (uncorrected odds ratio [OR], 2.05; 95% confidence interval [CI], 1.61–2.62; P < .001); they also developed more non-MACE complications (uncorrected OR, 1.44; 95% CI, 1.07–1.95; P = .017) (Table 3; Supplemental Digital Content, Table 3, http://links.lww.com/AA/C584).

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Factors in Association With Development of Postoperative MACEs

Table 4.

Table 4.

After testing for collinearity, 24 factors that were identified by univariate analyses (P < .10) were included in a multivariable model. Multivariable logistic regression analysis (backward stepwise method) identified 16 factors that were significantly associated with the development of postoperative MACEs. Of these, grade 3 diastolic dysfunction was associated with an increased risk of postoperative MACEs when compared with grades 1 and 2 (OR, 1.71; 95% CI, 1.28–2.27; P < .001). Among 15 other factors, age ≥70 years (compared with <50 years), body mass index <18.5 kg/m2 (compared with 18.5–24.9 kg/m2), hypertension, coronary heart disease, arrhythmia, renal insufficiency, regular glucocorticoid therapy, symptomatic diastolic dysfunction, ASA classification grades III and IV (compared with grades I and II), intraoperative use of vasopressors or antihypertensives, intraoperative fluid infusion rate ≥9.0 mL/kg/h (compared with <5.0 mL/kg/h), cancer surgery, duration of surgery ≥120 minutes (compared with <120 minutes), and medium- and high-grade complexity of surgery (compared with low-grade complexity) were associated with increased risk of MACEs, whereas body mass index ≥30 kg/m2 (compared with 18.5–24.9 kg/m2) was associated with a decreased risk of MACEs (Table 4).

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DISCUSSION

Our results showed that, in patients with isolated echocardiographic diastolic dysfunction, 10.0% developed MACEs after noncardiac surgery. Higher-grade (grade 3) diastolic dysfunction was associated with a greater risk of postoperative MACEs.

The reported incidences of MACEs vary in different patient populations. For example, in patients with isolated diastolic LV dysfunction undergoing vascular surgery, the incidence of postoperative adverse cardiovascular events ranged from 18% to 38%.14,15 In patients with diastolic dysfunction who underwent liver transplantation, the incidence of cardiovascular complications was 4% and the rate of mortality was 14% early after surgery.16 In a study of patients undergoing noncardiac surgery by Cho et al,17 the incidence of postoperative MACEs was 7.1% in all patients, but it was higher (about 8%) in those with an E/e′ ratio >15 (indicating the presence of diastolic dysfunction) than in those with an E/e′ ratio ≤15. The present study was performed in patients with isolated echocardiographic diastolic dysfunction who underwent noncardiac surgery. Postoperative MACEs developed in 10.0% of our patients, within the range of the previously reported incidences.

The impacts of diastolic LV dysfunction on postoperative outcomes remain controversial. Some studies reported that the existence of diastolic dysfunction did not influence postoperative outcomes,16,19,20 whereas some others found that preoperative diastolic dysfunction was associated with increased complications and even mortality after surgery.14,21,22 Reasons leading to conflicting results may include differences in sample size, target patients, and perioperative care management. A recent meta-analysis concluded that perioperative diastolic dysfunction is an independent risk factor for adverse cardiovascular outcomes after noncardiac surgery with, however, moderate certainty of evidence.6 Furthermore, in the above studies, the definitions of diastolic dysfunction were different, and the impacts of diastolic dysfunction severity on the outcomes were not clear. In the present study, all included patients had isolated echocardiographic diastolic dysfunction, of which the severity was diagnosed according to the guidelines.1 Our results showed that, after correction for confounding factors, high-grade (grade 3) diastolic dysfunction was associated with a higher risk of postoperative MACEs; the presence of symptomatic diastolic dysfunction before surgery was also associated with a higher risk of postoperative MACEs. Therefore, considering our results together with others, care should be taken when managing patients with high-grade diastolic dysfunction, especially those with clinical symptoms, during the perioperative period, although further studies are needed to clarify this problem.

In our results, low body mass index (<18.5 kg/m2) was correlated with increased risk, whereas high body mass index (>30 kg/m2) was correlated with reduced risk of postoperative MACEs. Romero-Corral et al23 also reported that, in patients with coronary artery disease, those who were overweight (25–29.9 kg/m2) had lower mortality. In line with previous studies,14,24 preoperative hypertension, coronary heart disease, arrhythmia, and renal insufficiency were also associated with an increased risk of postoperative MACEs in our patients. Long-term glucocorticoid therapy increases the risk of cardiovascular disease.25–27 This was also the case in surgical patients. In the present study, patients receiving vasoactive drugs (vasopressors and/or antihypertensives) were at an increased risk of MACEs. This phenomenon might be attributed to the hemodynamic fluctuations during surgery9 but requires further investigation. As expected, rapid fluid infusion rate, prolonged duration of surgery, and complex surgery were associated with increased postoperative MACEs.

Our study had several limitations. First, because preoperative echocardiographic examination was mainly performed in the elderly or those with cardiovascular diseases, patients included in the study were actually “high-risk” ones. This limited the generalizability of our results. Second, we only included patients with diastolic LV dysfunction. And, due to the selection of “high-risk” patients, those with grade 1 diastolic dysfunction were less and were combined with grade 2 for analysis. These limited our insight into the impact of low-grade diastolic dysfunction on the outcomes. Third, limited by the method detecting diastolic dysfunction, patients with atrial fibrillation or other tachyarrhythmia, moderate-to-severe valvular disease, or pericarditis were not assessed for diastolic function. Results of our study cannot be extrapolated to these patients. Last, due to the retrospective design, residual confounding cannot be excluded. Despite these, our results provide clues for further investigation.

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CONCLUSIONS

In patients with isolated echocardiographic diastolic dysfunction, 10% develop MACEs during hospital stay after noncardiac surgery; grade 3 diastolic dysfunction is independently associated with increased risk of postoperative MACEs. E

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DISCLOSURES

Name: Yan Zhou, MD, PhD.

Contribution: This author helped conceive and design the study, perform data collection and analysis, and draft the manuscript.

Name: Lin Liu, MD.

Contribution: This author helped collect data on echocardiographic examination.

Name: Tong Cheng, MD.

Contribution: This author helped collect perioperative data.

Name: Dong-Xin Wang, MD, PhD.

Contribution: This author helped design the study, analyze the data, and critically revise the manuscript.

Name: Hong-Yun Yang, MD.

Contribution: This author helped collect laboratory test results.

Name: Bao-Wei Zhang, MD.

Contribution: This author helped design the study and collect data on echocardiographic examination.

Name: Ying Yang, MD.

Contribution: This author helped design the study and collect data on echocardiographic examination.

Name: Feng Chen, MD.

Contribution: This author helped collect data on echocardiographic examination.

Name: Xue-Ying Li, MS.

Contribution: This author helped perform statistical analysis.

This manuscript was handled by: Nikolaos J. Skubas, MD, DSc, FACC, FASE.

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