Prognostic Significance of Myocardial Blood Flow Quantification for Major Adverse Cardiac Events: A Systematic Review and Meta-analysis : Cardiology in Review

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Prognostic Significance of Myocardial Blood Flow Quantification for Major Adverse Cardiac Events: A Systematic Review and Meta-analysis

Pan, Changjie MS*,†; Yin, Ruohan MS†; Tang, Xiaoqiang MS†; Wang, Tao MS†; Hu, Chunhong MD*

Author Information

From the *Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

†Department of Radiology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, China.

The author has no conflicts of interest to report.

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 Web site (www.cardiologyinreview.com).

Supported by the Major Science and Technology Projects of Changzhou Science and Technology Bureau under Grant [number CE20205047].

The datasets generated during or analyzed during the current study are available from the corresponding author on reasonable request.

C.P. and C.H. carried out the studies, participated in collecting data, and drafted the article. R.Y. and X.T. performed the statistical analysis and participated in its design. C.P. and T.W. helped to draft the article. All authors read and approved the final article.

Correspondence: Chunhong Hu, MD, Department of Radiology, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou 215006, Jiangsu, China. E-mail: [email protected].

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.

Cardiology in Review 31(3):p 162-167, May/June 2023. | DOI: 10.1097/CRD.0000000000000446

Abstract

Coronary artery disease (CAD) refers to the atherosclerotic narrowing of coronary arteries that is often asymptomatic early in the disease course but may lead to stable or unstable angina or myocardial infarction with progressive thickening or plaque rupture.1–4 Cardiovascular disease is the leading global cause of mortality and morbidity.5–8 Common risk factors for CAD include dyslipidemia, tobacco use, hypertension, family history of CAD, diabetes mellitus, and obesity.9,10 Complications include acute coronary syndromes (ACS), ST-elevation myocardial infarction (STEMI), acute heart failure, arrhythmias, and sudden death.1–4 There is general agreement about approaches to secondary prevention of CAD and its complications,1–4 and proper management requires a proper assessment of the patients’ condition.

Angiography and coronary computed tomographic angiography can be used to determine the presence of gross stenosis and hypoperfusion, but they cannot provide a correct assessment of the general perfusion of the hearts.11,12 In addition, because of the need for arterial catheterization (which carries risks like hemorrhage and pseudoaneurysms), digital subtraction angiography is an invasive procedure,13–16 and it is ill-suited for repeated examinations in a follow-up context and is generally performed when patients report symptom recurrence. Functional perfusion tests can be used to determine epicardial perfusion. These tests include positron emission tomography (PET), single-photon emission computed tomography (SPECT), and cardiovascular magnetic resonance (CMR).17–21 All are accurate for detecting epicardial CAD; by measuring tissue blood flow, they capture microvascular disease, which is an advantage over CTA and angiography for determining the status of the whole myocardial circulation.17–21

Indeed, chronic coronary syndrome involves macrovascular epicardial CAD and microvascular dysfunction, both of which result in reduced coronary blood flow (ie, the circulation of the blood in the coronary blood vessels), leading to reduced myocardial blood flow (MBF, ie, the volume of blood transiting through tissue at a certain rate) and adverse outcomes.22–25 Transplanted hearts are susceptible to cardiac allograft vasculopathy and CAD, which are major factors limiting survival after heart transplantation because of limited coronary blood flow.26,27 Patients with normal coronary but with chest pain have an increased risk of major adverse cardiovascular events (MACEs) because of the possible presence of microvascular angina, which also leads to decreased MBF.28–30 Still, chronic coronary syndrome is amenable to medical and interventional therapies.22–25 When using PET, the absolute quantification of MBF and the ratio of stress MBF to rest MBF, known as the myocardial perfusion reserve (MPR) or coronary flow reserve (CFR), can be obtained. An alternative to PET that does not use ionizing radiation is CMR.20 Unlike PET perfusion data, CMR provides qualitative data because of the complexity and time needed for computation. Nevertheless, the development of new quantitative CMR techniques allows “perfusion mapping,” where, in addition to conventional images, perfusion maps are generated automatically on the scanner with each image pixel encoding MBF (mL/g/min).31,32

Previous studies showed that stress MBF is a reliable predictor of outcomes, independent of the presence of significant stenosis.33–37 Nevertheless, Valenta et al33 highlighted that evidence was still lacking for the routine use of MBF for the management of patients with CAD. Herzog et al34 and Murthy et al36 proposed the concept of normal/abnormal perfusion, but the application of such dichotomized variables also needs validation. MPR has been validated to be a better predictor of cardiac death than left ventricular ejection fraction.37

Still, whether stress MBF can predict MACE during long-term follow-up is unknown. Therefore, we conducted this systematic review and meta-analysis to investigate the prognostic value of MBF for MACE. The results could provide some data to back or not the use of MBF during follow-up of patients with CAD.

MATERIALS AND METHODS

Literature Search

These systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.38 The PICOS principle was used to build the search strategy.39 PubMed, Embase, Cochrane, CNKI, and WANFANG were queried for papers published up to January 2021, followed by screening based on the inclusion and exclusion criteria. The search was made using the MeSH terms “Myocardial blood flow,” “positron emission tomography,” “cardiovascular magnetic resonance,” and “major adverse cardiac events,” as well as relevant key words. The reference lists of the retrieved papers were screened for potentially relevant papers.

Eligibility Criteria

The eligibility criteria are described here. The exposure had to be the incremental unit of stress MBF (mL/g/min), but due to the small number of studies on the subject, the dichotomization as low versus high MBF was allowed. The imaging methods had to be either PET/CT or CMR. The outcome had to be the occurrence of MACE during follow-up. Finally, only articles in English were included. This might leave out important data, but the choice was made to allow an international readership to be able to consult each included study.

Data Extraction

Study characteristics (first author, year of publication, country, and study design), protocol characteristics (imaging method, radionuclide for PET, and follow-up duration), patient characteristics (sex, sample size, baseline rest MBF, baseline stress MBF, and incidence of MACE), and the outcome (MACE, with hazard ratios [HRs], and 95% confidence intervals [CI]) were extracted by 2 different investigators (Changjie Pan and Ruohan Yin), independently, according to a prespecified protocol and forms. Any discrepancy in the 2 assessments was discussed until a consensus was reached.

Quality of the Evidence

The quality of the evidence of all included articles was assessed independently by 2 authors (Changjie Pan and Chunhong Hu) according to the Newcastle-Ottawa Scale (NOS) criteria for quality assessment of cohort studies.40 As earlier, discrepancies were resolved through discussion.

Statistical Analysis

All statistical analyses were performed using STATA SE 14.0 (StataCorp, College Station, TX). The time-to-event data were summarized as HRs and their corresponding 95% CIs. Statistical heterogeneity among studies was estimated using Cochran’s Q-test and the I2 index. High heterogeneity was indicated by an I2 > 50% and a Q-test P < 0.10, in which case the random-effects model was used; otherwise, the fixed-effects model was used. Two-sided P values less than 0.05 were considered statistically different. The potential publication bias was first planned to be examined using funnel plots and Egger’s test, but the final number of included studies in each analysis was less than 10, in which case these tests can yield misleading results.41

RESULTS

Selection of the Studies

Figure 1 presents the study selection process. The initial search yielded 343 records. After removing the duplicates (n = 109), 234 records were screened, and 84 were excluded. Then, 150 abstracts or full-text articles were assessed for eligibility, and 144 were excluded (study aim/design, n = 115; outcomes, n = 29). Finally, 6 studies were included.

F1
FIGURE 1.:
Flow diagram of the study selection process.

Table 1 presents the characteristics of the 6 included studies.42–47 There were 3 prospective cohort studies42–44 and 3 retrospective cohort studies,45–47 for a total of 2326 patients and 300 MACEs. Three studies were from Europe,42,43,47 1 was from Japan,45 1 from North America,46 and 1 international.44 Table S1 (https://links.lww.com/CIR/A38) presents the quality of the evidence. One study scored 5 stars,47 1 scored 7 stars,45 3 scored 8 stars,8,42,46 and 1 scored 9 stars.43

TABLE 1. - Literature Search and Characteristics of the Included Studies
Study Design Country Sample Size Age, years Sex, Male (N) Rest MBF (mL/min/g) Stress MBF (mL/min/g) Imaging Radionuclide Outcomes (n events) Follow-up, years
Farhad et al 42 Prospective cohort Switzerland 318 64.6 202 1.12 2.28 PET/CT MPI 82Rb MACE (35) 1.7 (1.5–1.9)
Knott et al 43 Prospective cohort United Kingdom 1356 60.9 (13) 702 / 2.06 (0.71) CMRI / MACE (174) 1.7 (1.3–2.2)
Meinel et al 44 Prospective cohort USA, UK, Germany, Italy, China, Korea 242 61 (54–65) 111 / / CTMPI / MACE (40) 1 (0.5–1.5)
Hamaya et al 45 Retrospective cohort Japan 237 63.7 (11.3) 165 1.21 (0.85–1.72) 2.46 (1.72–3.50) CMRI / MACE (21) 2.6 (1.1–3.7)
Harms et al 46 Retrospective cohort USA 94 56 (16) 73 0.97 1.83 PET/CT 13N-ammonia MACE (24) 2.5 (1.9–3.6)
Monroy-Gonzalez et al 47 Retrospective cohort Netherland 79 51 (11) 20 1.1 (0.3) 2.1 (0.6) PET 13N-ammonia MACE (6) 8 (3–14)
CMRI indicates cardiac magnetic resonance imaging; CTMPI, computed tomography myocardial perfusion imaging; MBF, myocardial blood flow; PET, positron emission tomography.42–47

Association of MACEs With Increments of Stress MBF Units

Four studies presented stress MBF data by unit increments.42,43,46,47 The pooled HR with its 95% confidence interval suggested that an increase in stress MBF by 1 mL/g/min is a protective factor for MACE (HR = 0.32; 95% CI, 0.18–0.57; I2 = 62.9%, Pheterogeneity = 0.044) (Fig. 2).

F2
FIGURE 2.:
Forest plot of MACE by increment per unit of stress MBF (mL/g/min). MACE indicates major adverse cardiac events; MBF, myocardial blood flow.

Association of MACEs With High/Low Stress MBF

Two studies reported stress MBF as high/low.44,45 The results showed that a high-stress MBF was protective against MACEs (HR = 0.43; 95% CI, 0.24–0.78; I2 = 39.5%, Pheterogeneity = 0.199) (Fig. 3).

F3
FIGURE 3.:
Forest plot of MACE by low MBF vs high MBF. MACE indicates major adverse cardiac events; MBF, myocardial blood flow.

DISCUSSION

MBF is a reliable predictor of outcomes of CAD,22–25 but whether stress MBF can predict MACEs during long-term follow-up is unknown. Therefore, this meta-analysis aimed to investigate the prognostic value of MBF for MACE. The results suggest that quantification of stress MBF using PET/CT and CMR (either as unit increments or high/low) might have incremental predictive value for future MACEs in a population at intermediate to high cardiovascular risk. This is supported by a previous meta-analysis that applied different inclusion criteria than the present meta-analysis. Still, the results will require validation in large prospective randomized controlled trials.48

CAD is caused by a gross obstruction of the coronary blood flow that leads to myocardial ischemia and necrosis.1–4 Still, even in the absence of a gross obstruction with overt ischemia, impaired MBF can lead to general poor oxygenation of the cardiac muscle and poor myocardial outcomes that can eventually develop into MACEs.22–25 At rest, oxygenation extraction by the myocardium is maximal, and myocardial oxygenation is therefore dependent upon MBF, which is tightly regulated to prevent ischemia. This same regulation plays a role under stress conditions to increase blood flow in the heart to provide enough oxygen to the myocardium.49,50 Still, the MBF can be impaired under stress in the presence of endothelial dysfunction, external compression, or arteriole rarefaction.49,50 Under severe heart conditions, the MBF can even be impaired at rest.49 All these factors contribute to a low-level ischemic state that is conducive to MACE development and poor cardiovascular outcomes.49,50

Imaging methods are available to determine the MBF, including PET, SPECT, and CMR.17–21 PET uses radionuclides but allows the absolute quantification of MBF and MPR (or CFR). CMR involves no radiations at all20 but, until recently, could only provide a qualitative assessment of MBF.31,32 The present meta-analysis supports the concept that higher MBF, whether quantitatively or qualitatively, is associated with a lower risk of MACEs. This result is not surprising since all 6 included studies42–47 were positive studies that reported lower MACE occurrence with higher MBF. Publication bias could not be analyzed because of the small number of included studies,41 but a publication bias cannot be ruled out since all included studies reported positive associations. Of note, heterogeneity was significant in all analyses. The proportion of females was variable, from 22%46 to 75%,47 and the mean age also varies from 51 to 65 years. Since age and male sex are important risk factors for CAD,9,10 there might be variable eligibility criteria among the studies that could limit the generalizability of the included studies and result in heterogeneity. The differences in patient populations, local practices, initial invasive management, exercise, medical therapy intensity, and stenosis location all contribute to heterogeneity. These factors can also influence the accuracy of MBF for the prediction of MACEs. In addition, 3 studies used radionuclides methods,42,46,47 and 3 used non-nuclear methods.43–45 Finally, the median follow-up was variable, from 144 to 847 years. Shorter follow-up might underestimate the incidence of MACEs. Nevertheless, MBF is a measure of tissue perfusion, but ischemia is not only dependent upon perfusion (ie, oxygen supply) but also upon oxygen consumption. Therefore, an adequate measurement should also consider oxygen demand during a stress test. Future studies should examine that.

Still, despite the possible publication bias and the high heterogeneity, the results are globally supported by previous studies that did not enter the present meta-analysis.33–35,51–54 Herzog et al34 that CFR determined13N-ammonia-PET was a strong predictor of MACE over 3 years. A previous meta-analysis showed that coronary microvascular dysfunction was associated with a 5-fold risk of MACEs.55 Green et al48 showed that in patients with known/suspected CAD, impaired CFR was associated with MACEs. It has been shown that obesity had a detrimental impact on CFR, while leptin levels could improve CFR,35 suggesting possible avenues to improve CFR. Murthy et al36 showed that CFR was independent of sex, which is in itself a major predictor of MACE. Tio et al37 showed that patients with ischemic heart disease (IHD) and low CFR were at high risk of cardiac death. Majmudar et al54 that impaired CFR was associated with MACEs in all patients with cardiomyopathies, irrespective of their ischemic nature. These results might suggest a subgroup of patients in whom CFR could be determined to improve patient management, but additional studies are necessary. A study suggested that CFR could be used as a guide for revascularization deferral in patients with diabetes.56 Combinations of CRF with CAS biomarkers like troponins also showed good value for predicting MACEs,57 and predictive models should be explored in future studies.

Valenta et al33 suggested in 2013 that MBF would be a game-changer in the management of chronic CAD. Guerraty et al51 showed that CFR was more strongly associated with MACEs than the traditional risk factors. It has been suggested that CFR improves the stratification of the risk of MACE in patients with IHD.52 Still, impaired MBF is currently not included in the guidelines from the American College of Cardiology/American Heart Association for patients with stable ischemic heart disease3 even though impaired MBF is not uncommon since there are about 500,000 to 1 million new diagnoses of nonobstructive angina in the United States of America each year,58–60 in whom impaired MBF can be highly suspected.61 Still, conventional CT coronary angiography recommended by the guidelines62,63 fails to detect impaired MBF, which requires additional examinations that might not be readily available everywhere and increase healthcare costs. Still, since the present meta-analysis and the literature strongly suggest the prognostic value of MBF, authoritative organizations should examine the value of MBF. Still, the relationship of MBF with traditional risk factors and their management (eg, diabetes, hypertension, hyperlipidemia, and smoking) need to be studied.28 The ISCHEMIA trial showed that the patients with stable CAD would not benefit from an initial invasive strategy.64 The present meta-analysis was not performed only in patients with stable CAD but in any patients with a heart condition. This meta-analysis might suggest that whether the patients were operated on or not, MBF could be used to follow-up patients with CAD to determine the need for operation or reoperation during follow-up. Future studies should discriminate the value of MBF during follow-up between patients with an initial conservative versus invasive management and among more precise patient populations.

This study has limitations. Despite the best meta-analysis strategy, meta-analyses inherit all the limitations of their included studies, and caution must be considered while extrapolating our results. Not all included studies used a rest and stress protocol.42,45–47 In addition, extracting the MFR was not possible. This meta-analysis only included 6 studies, and the reported data did not allow for a meta-analysis of the cutoff points for prognostic significance. It will have to be determined specifically using studies that report different cutoff points along with sensitivity, specificity, and accuracy. Finally, most of the included studies were single-center observational studies limited by a relatively small sample size.

CONCLUSIONS

Quantification of stress MBF using PET/CT and CMR might have incremental predictive value for future MACEs in a population at intermediate to high cardiovascular risk. The results will require validation in large prospective randomized controlled trials.

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Keywords:

myocardial blood flow; coronary artery disease; major adverse cardiac events; positron emission tomography; coronary magnetic resonance

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