Evaluation of left ventricular diastolic function in patients with coronary microvascular dysfunction via cardiovascular magnetic resonance feature tracking

Introduction

Symptoms of myocardial ischemia with no obstructive coronary artery disease (INOCA) are encountered frequently in clinical practice and thus constitute a diagnostic and therapeutic challenge (1-3). Up to two-thirds of patients with INOCA are believed to have coronary microvascular dysfunction (CMD) as the functional substrate of their ischemic symptoms (4-7). CMD is defined as the impaired vasodilation of arterioles leading to a diminished coronary flow reserve (CFR) or an insufficient increase in blood flow from rest to stress (1,5).

CMD is associated with increased mortality, even without macrovascular coronary artery disease (CAD) (8,9). Moreover, accumulating evidence suggests the presence of a correlation between CMD and left ventricular (LV) diastolic dysfunction, with CMD increasing the risk of developing heart failure with preserved ejection fraction (HFpEF) outcomes (10-12). A hypothesis is proposed that the diastolic dysfunction in CMD patients can eventually progress to HFpEF. It is worth noting that patients with CMD and diastolic dysfunction have been associated a poor prognosis, an increased rate of major adverse cardiovascular events (MACEs), and a more than 5-fold rate of HFpEF hospitalization (4,13-16).

Previous studies have reported changes in the echocardiographic indices of diastolic dysfunction in patients with CMD (17,18). Cardiac magnetic resonance (CMR) cine images are more accurate and comprehensive than is echocardiography in assessing LV morphology, LV function, and tissue characterization via CMR feature tracking (CMR-FT) (19-22). However, published research in this area is limited. Our study aimed to investigate whether patients with CMD had impaired LV diastolic function as assessed with CMR-FT.

Methods

Study population

The study participants comprised consecutive patients without a prior history of CAD who had undergone stress perfusion CMR (stress CMR) at Beijing Friendship Hospital between December 2019 and August 2021. They were referred to the cardiology department for suspected myocardial ischemia due to symptoms such as chest pain. Subsequently, they underwent diagnostic coronary computed tomography angiography (CCTA) which demonstrated no evidence of significant coronary stenosis (main coronary stenosis >50% within 1 month). A final cohort of 115 patients with preserved LV ejection fraction (LVEF) was established. Patients with known CAD, including prior revascularization and/or myocardial infarction, primary cardiomyopathy (hypertrophic, dilated, and restrictive), or a prior history of heart failure, atrial fibrillation, or severe valvular disease were excluded from the final cohort. We collected baseline demographics and clinical variables of the study population, which are summarized in Table 1. This study complied with the Declaration of Helsinki (as revised in 2013) and was approved by the Beijing Friendship Hospital Medical Ethics Committee (No. 2021-P2-418-01). All patients provided written informed consent. Figure 1 depicts the study flowchart and exclusion criteria of patients.

Figure 1 Study flowchart and exclusion criteria of patients. INOCA, ischemia with no obstructive coronary artery disease; ATP, adenosine triphosphate; LGE, late gadolinium enhancement; CMR, cardiovascular magnetic resonance.

Acquisition of CMR parameters

CMR was performed using a MAGNETOM Prisma 3T magnetic resonance imaging scanner (Siemens Healthineers, Erlangen, Germany). All images were acquired using phased-array surface coils during mild expiration and electrocardiographic triggering. First, patients received adenosine triphosphate (ATP; 5 mg/mL) at an infusion rate of 0.16 mg/kg/min for approximately 4 minutes (heart rate increase ≥10 bpm or systolic blood pressure decrease ≥10 mmHg). This was followed by an intravenous administration of gadolinium (0.5 mmol/mL) at a rate of 3–4 mL/s and a subsequent 30-mL saline flush at the same flow rate to obtain the first-pass perfusion images using a T1-weighted fast gradient echo sequence for both scanners [repetition time/time to echo (TR/TE) =2.1/1.03 ms, TI =100 ms, temporal resolution =155.7 ms, flip angle =10°, voxel size =1.9×1.9×8.0 mm³]. Three perfusion short-axis slice images (base, mid, and apex) of the left ventricle were acquired. Subsequently, balanced steady-state free-precession cine images were acquired in multiple short-axis locations (every centimeter from base to apex) and 3 long-axis locations (2-, 3-, and 4-chamber views; TR/TE =3.3/1.43 ms, temporal resolution =40 ms, flip angle =50°, voxel size =1.6×1.6×6.0 mm³). Rest perfusion images were acquired in the same 3 short-axis positions as those for the stress perfusion images at least 10 minutes after termination of the ATP infusion. Late gadolinium enhancement (LGE) images were acquired at least 10 minutes after gadolinium injection. The LGE parameters were as follows: TR/TE =5.2/1.96 ms, TI =300 ms, flip angle =20°, voxel size =1.8×1.8×8.0 mm³.

LV diastolic function assessment

During image analysis, LV basic cardiac function parameters were measured. This was conducted by automatically tracing the epicardial and endocardial borders of the short-axis cine images at end diastole and end systole automatically using postprocessing software (CVI42, Circle Cardiovascular Imaging, Calgary, Canada). The automatically traced measurements were then manually adjusted as necessary. These parameters included LVEF, LV end diastolic volume (LVEDV), LV end systolic volume (LVESV), cardiac output (CO), stroke volume (SV), and cardiac index (CI).

LV diastolic function was evaluated using the time-volume curve and CMR-FT strain analysis, which enabled the quantification of LV global and regional diastolic functions (19,23,24). The former was generated by continuous the automatic tracing of endocardial borders during complete cardiac cycles with manual adjustment; the first derivative curve used to obtain the LV peak filling rate (PFR) is illustrated in Figure 2. The PFR was defined as the maximal change in the LV volume per unit time (Δ volume/Δ phase), which was the LV maximum slope of the diastolic phase. Diastolic dysfunction was characterized as a decreased peak filling rate and prolonged time-to-peak-filling rate (T-PFR) (25,26). Finally, the myocardial deformation was evaluated with CMR-FT of CMR cine images, as depicted in Figure 2. The indices reflecting LV diastolic function including LV peak longitudinal diastolic strain rate (LDSR), circumferential diastolic strain rate (CDSR), and radial diastolic strain rate (RDSR), were recorded (19,23).

Figure 2 Evaluation of LV diastolic function using CMR-derived time-volume curves and CMR-FT parameters. (A,B) LV time-volume curve and time-PFR. PFR was derived from the steepest gradient in the curve in the early diastolic phase. (C) Short axis and long axis (2-, 3-, and 4-chamber) cine images were selected to mark the endocardium (red lines) and epicardial contours (green lines) and obtain LV diastolic function indicators including RDSR, CDSR, and LDSR. The blue lines represent the LV boundary. The blue and pink circles represent the left and right ventricle intersection point. LV, left ventricular; PFR, peak filling rate; RDSR, radial diastolic strain rate; CDSR, circumferential diastolic strain rate; LDSR, longitudinal diastolic strain rate; CMR-FT, cardiovascular magnetic resonance feature tracking.

Visual assessment of CMD

The noninvasive quantification of coronary microvascular function was performed using stress CMR. Poor-quality images or incomplete data were excluded from the analysis. The presence of ischemia was evaluated according to the segmental analysis of stress perfusion images, which were recorded in 16 segments (the apical segment is typically not in the field of view) based on the American Heart Association 17-segment model (27). CMD revealed the presence of inducible myocardial ischemia in the subendocardium. Inducible ischemia was defined as the presence of a stress perfusion defect and the absence of matching LGE in ≥1 segment that persisted for ≥5 dynamics (15,28,29), as illustrated in Figure 3. The presence of dark rim artifacts (DRAs) should be excluded during the visual assessment. The characteristics of DRA in this study were considered to be the following: (I) artifacts are the most prominent when contrast arrives in the LV blood pool; (II) artifacts persist only transiently before the peak myocardial contrast enhancement; and (III) artifacts appear predominantly in the phase-encoding direction (30,31). All CMR perfusion images were analyzed by two skilled CMR readers (Cao J and He Y), with one of the readers (He Y) repeating the analyses at an interval of 1 month between analyses. Additionally, semiquantitative myocardial perfusion was analyzed using CVI42 software. This involved manually tracing contours surrounding the endocardium and epicardium to determine the LV myocardial signal intensity. The CMR-derived myocardial perfusion reserve index (MPRI), defined as the ratio of stress to rest upslope normalized to the upslope of the LV blood pool, was recorded (32,33).

Figure 3 Example of perfusion and rest first-pass perfusion images for visual assessment. (A,B) Patients with CMD and (C,D) and patients without CMD. (A,B) A patient with a visual assessment of CMD had inducible perfusion defects in the subendocardium, which were present only under stress (white arrow) and did not manifest during rest. (C,D) A patient with a visual assessment of non-CMD had no defects on stress or rest perfusion images. CMD, coronary microvascular dysfunction.

Statistical analysis

Continuous variables were assessed for normality and are presented as the mean ± standard deviation (SD). The normally and nonnormally distributed variables between groups were compared using the independent samples t-test or nonparametric test (Mann-Whitney test or Kolmogorov-Smirnov test). The categorical variables are presented as percentages and were compared using the chi-squared test. The intraclass correlation coefficient (ICC) was used to determine inter- and intraobserver reproducibility. Reproducibility was defined as poor (ICC <0.4), good (ICC 0.4–0.75), or excellent (ICC >0.75), and 95% confidence interval (95% CI) were determined in order to visualize inter- and intraobserver variability. A P value <0.05 indicated a statistically significant difference. All statistical analyses were performed with SPSS 25.0 (IBM Corp., Armonk, NY, USA).

Results

Study demographics

A total of 80% (92/115) patients (52.5±11.8 years; 57% male) were included in the data analysis. Of the 115 patients, 23 patients were excluded for the following reasons: 7 patients had positive LGE, 4 patients had hypertrophic cardiomyopathy, 6 patients failed to complete the study, and 6 patients had poor image quality.

Of these, 73 (79%) patients (52.3±11.9 years; 54.8% male) had inducible myocardial ischemia in the subendocardium. The remaining 19 (21%) patients (48.8±11.2 years; 63.2% male) without myocardial ischemia were classified as non-CMD. Women (33/40, 82.5%) had a greater burden of CMD than did men (40/52, 77%).

At the per-segment level, 160 (11%) segments were excluded from the initial 1,472 myocardial segments due to various factors. These factors included the involvement of the outflow tract involved, scanning plane beyond the mitral valve, scanning plane of stress and rest perfusion mismatch, and inadequate image quality. Hence, the study finally included 1,312 (89%) myocardial segments. Among these segments, 665 (51%) segments were classified as CMD and 647 (49%) as non-CMD. The characteristics of the study population are presented in Table 1.

For the reproducibility of CMD diagnosis by visual assessment, our study showed that the ICC for inter- and intraobserver agreement were 0.906 (95% CI: 0.861–0.937) and 0.874 (95% CI: 0.815–0.915), respectively.

LV diastolic function evaluated using CMR

The LV basic cardiac function parameters revealed a lower MPRI and SV in the CMD group compared with the non-CMD group (MPRI: 1.49±0.3 vs. 1.86±0.6, P<0.005; SV: 71.21±15.4 vs. 76.96±9.3 mL, P=0.045; Table 2). All patients had a preserved LVEF of ≥50%. No difference between the CMD and non-CMD groups was noted in terms of LVEF (60.42±7.4 vs. 62.61±8.3%; P=0.266) and LVEDV (118.09±22.2 vs. 124.59±20.8 mL; P=0.253). The PFR and T-PFR values were also not significantly different between the 2 groups (both P values >0.05; Table 2).

In addition, the LV global diastolic strain rates were not considerably distinct between the 2 groups (Table 2). However, when LV was divided into 16 segments for analysis and at the per-segment level, the ischemic segments revealed a remarkably lower regional CDSR {median 1.26 [interquartile range (IQR), 1.01–1.57] vs. median 1.32 (IQR, 1.00–1.65), P=0.019}, and regional RDSR [median −2.28 (IQR, −3.06 to −1.65) vs. median −2.45 (IQR, −3.41 to −1.64), P=0.006] compared with the non-CMD segments. Furthermore, the regional LDSR was substantially higher in the CMD segments compared with the non-CMD segments [median 1.76 (IQR, 1.21–2.48) vs. median 1.55 (IQR, 1.18–2.26), P=0.003] (Table 3).

Discussion

In this study, CMR parameters were used to verify the altered LV diastolic function in patients with CMD. First, the incidence of CMD was found to be higher in patients with signs and symptoms of ischemia but not in those with signs of obstructive CAD. Second, LV global diastolic function did not decrease in patients with CMD. Third, the regional LV diastolic function of CMD patients decreased.

Our findings are consistent with those of previous studies in terms of the clinical characteristics of CMD. Waheed et al. (34) reported that women typically had a greater burden of CMD, which was also reflected in our study. Of the female patients in this group, 82.5% (33/40) had CMD, whereas only 77% (40/52) of men had CMD. Moreover, all recruited patients with INOCA in both the CMD and non-CMD groups exhibited cardiovascular (CV) risk factors (hypertension, diabetes, hypercholesterolemia, smoking, and drinking). Differences in LV diastolic parameters between the 2 groups could still be observed, suggesting that the impaired LV diastolic function in patients with CMD cannot be attributable to the CV risk factors. As for the incidence of CMD, several studies have reported CMD in a large proportion (one-half to two-thirds) of patients with INOCA (35,36). Interestingly, in Wei et al.’s study, CMD was present in 83% of women (25). The aforementioned CV risk factors eventually led to the development of CMD, indicating that the prevalence of CMD in this study population was relatively high.

Regarding regional CMD, previous studies (37,38) have confirmed that microcirculation abnormalities have a patchy distribution in the myocardial wall rather than a diffuse distribution, which is consistent with our visual evaluation. According to The European Society of Cardiology (ESC) Working Group on Coronary Pathophysiology and Microcirculation position paper (39), the mechanisms underlying CMD in patients nonobstructive CAD are still not completely understood, but they likely involve both functional and structural changes. Additionally, endothelial dysfunction is a key mediator in the pathogenesis of CMD, and it is believed that with advancement in medical technology, the future study of CMD will be more thorough and clearer.

Evaluation of LV global diastolic function using LV filling curves

Notably, no PFR or T-PFR differences were observed between the patients with and without CMD in this study. In the study by Mendoza et al., reduced PFR and prolonged T-PFR were found to reflect one aspect of LV global diastolic dysfunction, and LV filling curves could be used to discern the volumetric filling changes that occurred with graded severity of diastolic dysfunction. Moreover, the PFR decreased during the progression from normal diastolic function to grade 1 diastolic dysfunction and then increased during the progression from grade 1 diastolic dysfunction to grade 3 diastolic dysfunction (40). Therefore, even if PFR does not decrease, this does not necessarily mean that LV diastolic function is normal. In our study, the PFR in the CMD group did not decrease, which is in line with the findings of Wei et al.’s study (25). Moreover, the same results were obtained even in patients with HFpEF (26). In our study, the LV global diastolic function evaluated using LV filling curves did not decrease in patients with CMD, indicating that these parameters were not sufficiently sensitive to detect early LV diastolic dysfunction.

Evaluation of LV diastolic function using CMR-FT diastolic strain rates

The CMR strain technique to assess LV diastolic function was proposed several years ago (41) and has been used in a variety of diseases (17,19,24-26). The Women’s Ischemia Syndrome Evaluation (WISE) study (42) demonstrated that diastolic function is impaired in women with signs and symptoms of ischemia without CAD, as assessed by CMR tissue tagging. Our study further stratified patients with INOCA into a CMD group and a non-CMD group, with decreased LV diastolic function being found to be more pronounced in CMD myocardial segments. Although our study demonstrated no reduction in CMR parameters indicating LV global diastolic function, this could be explained by the lack of ischemia in the myocardial segment during the early compensatory stage in patients with CMD.

In contrast to the studies by Taqueti et al. (16) and Shah et al. (10), in which stress myocardial perfusion positron emission tomography (PET) and adenosine stress transthoracic Doppler echocardiography were examined, respectively, our study used the CMR-FT technique to characterize cardiac morphology and diastolic function. The findings from the studies that patients with CMD have more impaired LV diastolic dysfunction than do non-CMD individuals were in concordance with our results. The aforementioned studies reported that the patients with impaired CFR or CMD a worse diastolic function, including both a lower e¢ and higher E/e¢, as compared with the patients with preserved CFR or an absence of CMD. The LV ejection fractions in both groups were preserved, and there were no statistically significant differences in this regard. However, the pathophysiological mechanism underlying this phenomenon is still unclear (43).

CMD leading to increased LV diastolic stiffening has recently been proposed as the mechanism underlying the pathogenesis of HFpEF (44-47) due to the fact that the prevalence of CMD is high in both patients with HFpEF and patients with INOCA (10,12,16). We found that the prevalence of CMD assessed using stress CMR was 79% in the population of patients with INOCA. Thus, coronary microvascular ischemia caused by CMD may lead to myocardial injury, worsen LV global mechanics, and result in LV dysfunction. In particular, microvascular endothelial dysfunction and increased profibrotic cytokine may contribute to reduced coronary microvascular density and increased myocardial fibrosis, eventually progressing to HFpEF (16,44,48). Meanwhile, a recent PET study (16) reported a link between CMD and diastolic dysfunction in patients with angina and no obstructive CAD. Our study also demonstrated that CMD segments had a slightly impaired LV diastolic function compared with non-CMD segments. These findings thus suggest that one of the pathophysiological mechanisms underlying HFpEF is LV diastolic dysfunction and stiffness due to coronary microvascular ischemia.

Our study also a few limitations that should be noted. First, a single-center study design was employed with relatively small cohorts. Thus, future multicenter studies with larger cohorts are needed to confirm our findings. Second, we did not include a normal healthy population as a control group. Third, strain indicators, such as global longitudinal strain (GLS), which can serve as the marker of subclinical LV dysfunction, were not included in this article (49). This issue was addressed in our other studies in which CMD myocardial segments exhibited remarkably lower longitudinal strain (LS) and circumferential strain (CS). Moreover, biomarkers such as brain natriuretic peptide and cardiac troponin can serve as markers of LV dysfunction. However, heart failure biomarkers were not examined in this study, which limits scope of clinical applicability. However, we will collect this patient information in later studies. Finally, in this study we did not employ CFR, the gold standard for CMD. However, the technology is invasive and complex to operate, so our study did not examine this technology. Moreover, as confirmed by several studies (50-54), the sensitivity and specificity of stress CMR for the diagnosis of CMD are comparable to those of the invasive or noninvasive gold standard, but with CMR involving less pain, radiation dose, and cost to patients.

Conclusions

Our study found CMD myocardial segments to have decreased LV diastolic function but normal LVEF. These findings point to the early diastolic impairment in CMD and establish a link between CMD and HFpEF. However, LV global diastolic function did not decrease in patients with CMD in the early compensatory phase. Further studies are warranted to confirm whether there is an association between CMD and LV diastolic function in those patients with INOCA.

Acknowledgments

Funding: This study received funding from the National Natural Science Foundation of China (No. 81971569).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-47/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Beijing Friendship Hospital Medical Ethics Committee (No. 2021-P2-418-01). Written informed consent was obtained from all patients in this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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