Coronary microvascular disease is a risk factor for left ventricular diastolic dysfunction: An AWARD substudy

doi:10.21203/rs.3.rs-5344277/v1

Background:

Left ventricular diastolic dysfunction (LVDD) caused by myocardial ischemia is an important pathogenetic factor in the development of heart failure with preserved ejection fraction (HFpEF).

Objective:

To explore the differences in LVDD triggered by two ischemic injuries (microvascular lesions and epicardial stenosis).

Methods:

Angiographic function indicators involving angiography-derived index of microcirculatory (AMR) simulating hyperemic velocity (SHV) and diagnostic indicators for LVDD including average E/e', septal e’velocity, and lateral e’velocity (based on echocardiography) were derived from records of enrolled patients suffering from coronary microvascular disease (CMVD) or obstructive coronary artery disease (CAD) (without microvascular dysfunction). The linear correlation between AMR, SHV, and echocardiographic indicators was evaluated by the Spearman's coefficient method. And logistics regression analyses evaluated risk factors for LVDD. Besides, we performed the by stratified analysis to explore Differences in AMR and SHV distribution between LVDD and non-LVDD groups. Finally, receiver operating characteristic (ROC) analyses evaluated the efficacy of AMR in recognizing LVDD.

Results:

CMVD was more susceptible to LVDD compared to obstructive-CAD (18.8% vs. 6.2%). AMR, SHV were linearly correlated with the relevant indicators of LVDD. And in the CMVD group, AMR were higher in the LVDD group than in the non-LVDD group, while SHV was opposite. Furthermore, AMR promoted LVDD (OR=1.02), whereas SHV inhibited the formation of LVDD (OR=0.59). ROC analyses revealed AMR can identify LADD.

Conclusion:

Microvascular lesions are more susceptible to LVDD.

coronary microvascular disease

left ventricular diastolic dysfunction

angiography-derived index of microcirculatory

Obstructive epicardial coronary artery disease (CAD) is considered to be the main cause of ischemic heart disease (IHD). However, it recently has been found that half of patients with chest pain do not have obstructive CAD undergoing coronary angiography (CAG). Therefore, this disease is defined as ischemia with no-obstructive coronary artery disease (INOCA). According to an American College of Cardiology report, there are approximately 3–4 million population suffering from INOCA each year ^[2], and approximately 50% of INOCA patients have coronary microvascular disease (CMVD) ^[3]. The ISCHEMIA trial has questioned the focus of IHD treatment solely on coronary stenosis ^[4]. CMVD, a component of INOCA, presents with ischemic chest pain due to an imbalance in myocardial oxygen supply ^[5]. Unlike epicardial lesions, CMVD may involve microvasculature damage caused by multiple risk factors at an earlier stage, and it can trigger heart failure with preserved ejection fraction (HFpEF) ^[6], which may be closely associated with ischemia-induced left ventricular diastolic dysfunction (LADD). Some studies have revealed that the prevalence of LADD ranges from approximately 11.1–35.5% ^[7–10]. Although patients with LVDD may be lack clinical symptoms, the prognosis remains adverse. Moreover, LVDD has been regarded as B-stage heart failure (HF) and can develop into C-stage HF ^[11]. Previous studies have shown that obstructive CAD can lead to LVDD ^[12]. However, with the understanding of microvascular anatomy and physiological function, microvascular lesions may be susceptible to LVDD in that CMVD can cause more extensive ischemia, and several studies have suggested that microcirculatory lesions are an independent predictor of HFpEF ^{[13, 14]}. Some studies have shown that women with INOCA have elevated left ventricular filling pressures ^[15], which is used to characterize LVDD. Therefore, we proposed a hypothesis that CMVD can impair coronary blood flow (CBF), leading to recurrent ischemic attacks, and eventually developing into LVDD. Besides, few studies have explored the discrepancies between myocardial ischemia in different diameters of coronary arteries (microvascular vs epicardial vessels) causing LVDD. Therefore, our study explored differences in the effects of two coronary lesions on LVDD.

1. Data sources

This study was a prospective study. We systematically yield the clinical data from a total of 295 inpatients with chest pain who underwent CAG, admitted to the Cardiovascular Department of Xiyuan Hospital of China Academy of Chinese Medical Sciences from October 2023 to June 2024, 128 patients were ultimately included (Fig. 1). And partial CMVD patients were from the AWARD (aromatic and warming-up management in coronary microvascular disease) study cohort. This study was approved by the Ethics Committee of Xiyuan Hospital (2024XLA031-2). The study adhered to the clinical practice standards set by the Declaration of Helsinki

2 Diagnostic criteria

The diagnostic criteria for CMVD in the Chinese Multidisciplinary Expert Consensus on the Diagnosis and Treatment of Microvascular Diseases issued by China in 202018 are as follows ^[16]: (ⅰ) symptoms of myocardial ischemia; (ⅱ) objective evidence of myocardial ischemia; (ⅲ) non-obstructive coronary artery disease, with coronary artery diameter stenosis of < 50% on coronary CT angiography (CTA) or invasive CAG; and (ⅳ) objective evidence of impaired coronary microcirculatory function, impaired coronary flow reserve - coronary flow reserve (CFR) < 2.5 or < 2.0, or the slow coronary flow phenomenon (TIMI frames > 25), or the index of microvascular resistance index (IMR) > 25.

3. Inclusion criteria:

(1) CMVD group: (ⅰ) no significant stenosis in 3 coronary arteries including the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA) (stenosis < 50%); (ⅱ) quantitative flow ratio (QFR) > 0.8 in 3 coronary arteries and angiography-derived index of microcirculation (AMR) > 250 mmHg*s/m in at least 1 coronary artery ^[17].

(2) Obstructive-CAD group: (ⅰ) stenosis (> 70%) or QFR < 0.8 in at least 1 coronary artery; (ⅱ) AMR < 250 mmHg*s/m both in non-culprit vessel and in the opened culprit vessels after operations.

4. Exclusion criteria

(1) Patients who underwent coronary revascularization within 1 month before CAG, including percutaneous coronary intervention (PCI), percutaneous transluminal coronary angioplasty (PTCA), and coronary artery bypass grafting (CABG);

(2) Organic heart disease, such as severe HF, malignant arrhythmia, or valvular disease;

(3) Acute and chronic inflammation, immune diseases, or malignant tumors;

(4) Coronary occlusive lesions on CAG, or severe tortuosity of the image of CAG;

(5) Severe renal insufficiency: glomerular filtration rate < 45 mL/min;

(6) Severe coagulation disorders or bleeding;

(7) Allergy to contrast media;

(8) Abnormal ventricular wall motion in the echocardiogram;

5. Cardiac catheterization examination

After CAG, we performed angiographic functional examination. Real-time CAG images were conducted to the QFR instrument (Pulse Medical, Shanghai) and analyzed under a single angle using the software AngioPlus Core software (version V2). The process was performed by a trained cardiologist. Firstly, selecting the optimal contrast view with minimal vessel overlap was selected, and then the lumen of the target vessel detected and outlined. The contrast flow rate is derived by dividing the vessel length by the contrast fill time, which is then converted to the filling flow rate. Subsequently, frames in which the lumen contour was fully exposed were selected as analysis frames to determine the main and side branches of the analyzed vessels. According to Murray's bifurcation law, the reference vessel diameter needs to be reconstructed ^[18–22]. Finally, according to fluid dynamics, the QFR and AMR were calculated via the following equations ^[23].

$$\:\mathbf{A}\mathbf{M}\mathbf{R}=\frac{\mathbf{P}\mathbf{d}}{{\mathbf{V}\mathbf{e}\mathbf{l}\mathbf{o}\mathbf{c}\mathbf{i}\mathbf{t}\mathbf{y}}_{\mathbf{h}\mathbf{y}\mathbf{p}}}=\frac{\varvec{P}\varvec{a}\times\:\varvec{u}\varvec{Q}\varvec{F}\varvec{R}}{{\mathbf{V}\mathbf{e}\mathbf{l}\mathbf{o}\mathbf{c}\mathbf{i}\mathbf{t}\mathbf{y}}_{\mathbf{h}\mathbf{y}\mathbf{p}}}$$

1

where Pa is the aortic pressure at baseline; Pd is the distal coronary artery pressure; and Velocity_hyp indicates simulating hyperemic velocity.

6. Echocardiography examination

Well-trained echocardiographers performed routine transthoracic echocardiography and interpreted all echocardiograms: left ventricle internal dimension measured at end-diastole, left ventricle internal dimension measured at end-systole measured with M-mode, and early diastolic mitral inflow velocity/late diastolic mitral inflow velocity, early diastolic mitral inflow velocity/peak early diastolic mitral septal annular velocity (E/e'), and tricuspid regurgitation velocity (TR) measured ^[24].

The echocardiography-based diagnosis of LVDD was published in 2016 by the American Society of Echocardiography and the European Association of Cardiovascular Imaging ^[25]: (ⅰ) mitral annulus e' velocity (septal e'<7 cm/s or lateral e'<10 cm/s) ^[25]: (ⅱ) average E/e' >14; (iii) left atrial volume index > 34 ml/m²; and (iv) maximum tricuspid regurgitant velocity > 2.8 m/s.

Diagnosis of LVDD: A positive result for two or more of the above indicators suggests LVDD, and a negative result for two or more suggests non-LVDD.

7. Statistical analysis

We used R-4.2.2 (https://cran.r-project.org/) software for statistical analysis. First, the "Tableone" package was used to compare the statistical significance of categorical and continuous variables in the two groups via the chi-square, Kruskal‒Wallis test, and the Nemenyi test, and P-values < 0.05 were considered statistically significant. The Shapiro Test was used to determine whether the measurements were normally distributed; if the data were normally distributed, the data were expressed as the mean ± standard deviation (X ± S), and Student’s t test was used to explore differences in variables. If the data did not conform to a normal distribution, they were expressed as medians and interquartile ranges, and nonparametric tests were used for the statisticians.

The "ggpolt" package was used to explore the linear correlation of two variables via Spearman's correlation coefficient. Therefore, we analyzed the linear correlation between the indices of LVDD (including average E/e', septal e' and lateral e' velocity) and AMR (for the obstructive-CAD group, the AMR includ all vessels before and after operations). Furthermore, the relationships between LVDD and AMR indices were investigated via binary logistic regression with the "glm" function. And the results were represented by odds ratio (OR) and 95%confidence intervals (CI). In terms of stratified analyses, we clarified the distribution differences in AMR and simulating hyperemic velocity (SHV) between the LVDD and non-LVDD groups by plotting violin plots via the "ggplot" package. Finally, the "pROC" package was used to construct receiver operating characteristic (ROC) curves to investigate the ability of the AMR to identify LVDD between macrovascular and microvascular lesions.

1. Baseline characteristics

Ultimately, 128 patients were included in this study, and there were 64 patients in each of the CMVD and obstructive-CAD groups, including 44 women and 84 men, with a median age of 65 years. There was no significant difference in the baseline characteristics between the two groups (including gender, age, blood pressure and heart rate at admission), but the prevalence of LVDD was higher in the CMVD group (18.8% vs 6.2%). Moreover, risk factors were comparable in the two groups, whereas more patients in the obstructive-CAD group underwent percutaneous coronary intervention (PCI). Regarding medication during the perioperative period, more patients in the obstructive-CAD group took lipid-lowering drugs (including statins, ezetimibe, and evolocumab), nitrates, and angiotensin converting enzyme inhibitors/angiotonin receptor blocker (ACEI/ARB) than that in the CMVD group. There was no significant difference between the two groups in laboratory examinations. In terms of echocardiography, the septal e' velocity and lateral e' velocity were higher in the obstructive-CAD group. However, the average E/e' was higher in the CMVD group. In terms of angiographic function, the QFR and AMR of 3 coronary arteries were significantly higher in the CMVD group, whereas SHV, percent diameter stenosis and minimum lumen diameter (MLD) were higher in the obstructive-CAD group (Table 1).

Table 1

Baseline table
		Total (N = 128)	obstructive-CAD (N = 64)	CMVD(N = 64)	P
Baseline characteristic
Female n (%)		44(34.4%)	19(29.7%)	25(39.1%)	0.264
Age (mean (SD		65.00[56.75, 70.00]	63.00[53.75, 70.00]	65.50 [57.75, 69.00]	0.513
Systolic pressure (mmHg)		135.00[123.80,149.00]	135.00 [123.75, 151.25]	134.00 [123.75, 146.00]	0.429
Diastolic pressure (mmHg)		84.00[76.00, 81.25]	85.00 [76.00, 93.25]	83.00 [75.75, 90.25]	0.327
Heart rate (bpm)		73.00[65.00, 81.25]	74.00 [65.00, 84.50]	72.00 [65.00, 78.50]	0.347
PCI n (%)		46(35.9%)	33(51.6%)	13(20.3%)	0.000
LVDD		16(12.5%)	4(6.2%)	12(18.8%)	0.033
Risk factors
Smoking n (%)		44(34.4%)	25(39.1%)	19(29.7%)	0.264
Drinking n (%)		44(34.4%)	21(32.8%)	23(35.9%)	0.710
Hypertension n (%)		96(75%)	51(79.7%)	45(70.3%)	0.221
Diabetes n (%)		46(35.9%)	24(37.5%)	22(34.4%)	0.713
Hyperlipidemia n (%)		60(46.9%)	34(53.1%)	26(40.6%)	0.156
Hyperuricemia n (%)		10(7.8%)	4(6.2%)	6(9.4%)	0.742
Medication
Aspirin n (%))		126(98.4%)	64(100.0%)	62(96.9%)	0.248
Clopidogrel n (%)		120(93.4%)	64(100.0%)	56(87.5%)	0.011
Statin n (%)		118(92.2%)	64(100.0%)	54(84.4%)	0.003
Ezetimibe n (%)		38(29.7%)	27(42.2%)	11(17.2%)	0.002
Evolocumab n (%)		13(10.2%)	10(15.6%)	3(4.7%)	0.041
Nitrates n (%)		51(39.8%)	35(54.7%)	16(25.0%)	0.001
CCB n (%)		56(43.8%)	30(46.9%)	26(40.6%)	0.476
ACEI/ARB n (%)		62(48.4%)	37(57.8%)	25(39.1%)	0.034
Beta-blocker n (%)		64(50.0%)	34(53.1%)	30(46.9%)	0.480
Echocardiography
Left atrium (mm)		36.00 [34, 38.74]	35.50 [33.00, 38.25]	37.00 [34.75, 40.00]	0.107
Left ventricle (mm)		45.50[43.00, 48.00]	46.00 [43.00, 48.00]	45.00 [42.00, 48.00]	0.427
Ejection fraction		63.00 [60.00, 65.00]	63.00 [60.00, 65.00]	63.00 [60.00, 65.00]	1
Mitral valve E-peak (m/s)		0.615[0.50, 0.78]	0.60 [0.50, 0.80]	0.62 [0.52, 0.70]	0.758
Mitral valve A-peak (m/s)		0.83 ± 0.19	0.82 ± 0.19	0.85 ± 0.20	0.384
Septum e' velocity (cm/s)		6.00 [5.00, 8.00]	7.00 [5.00, 8.00]	6.00 [5.00, 6.78]	0.013
Lateral e' velocity (cm/s)		8.00 [7.00, 10.12]	9.10 [7.38, 11.00]	8.00 [7.00, 9.55]	0.014
Average E/e'		8.60 [6.60, 10.83]	7.95 [6.00, 9.93]	8.95 [7.33, 12.05]	0.011
Tricuspid regurgitation velocity (m/s)		1.52 [2.00, 2.40]	2.10 [1.62, 2.40]	1.80 [0.00, 2.50]	0.25
Laboratory examination
CRP (mg/L)		1.01[0.56, 2.39]	0.98 [0.56, 2.24]	1.06 [0.62, 2.46]	0.462
TNI (ng/L)		0.009[0.006,0.013]	0.01 [0.01, 0.01]	0.01 [0.01, 0.01]	0.082
CK-MB (ng/L)		1.63[1.19, 2.21]	1.62 [1.20, 2.21]	1.60 [1.15, 2.21]	0.634
MYO (ng/L)		29.45[24.5, 36.82]	29.14 [23.42, 37.18]	29.96 [25.34, 36.33]	0.348
BNP (pg/L)		78.23[46.08, 139.40]	73.85 [46.96, 182.25]	81.55 [44.12, 133.73]	0.682
AST (U/L)		18.75[13.90, 25.65]	18.55 [14.38, 28.63]	18.90 [12.78, 22.58]	0.466
ALT (U/L)		19.40[16.95, 24.70]	20.85 [17.08, 24.92]	19.20 [16.48, 24.63]	0.585
BUN (mg/dL)		15.02 ± 4.39	15.30 ± 4.38	14.75 ± 4.41	0.484
Creatinine (µmol/L)		71.97 ± 14.09	72.33 ± 14.62	71.61 ± 13.65	0.774
Uric acid (µmol/L)		333.23 ± 85.97	343.03 ± 82.72	323.44 ± 88.66	0.198
Glucose (mmol/L)		5.67[5.17, 6.72]	5.76 [5.19, 6.80]	5.62 [5.14, 6.46]	0.536
TC (mmol/L)		3.89[3.29, 4.80]	3.62 [3.14, 4.72]	4.08 [3.52, 4.81]	0.087
TG (mmol/L)		1.24[0.95, 1.71]	1.23 [0.92, 1.62]	1.27 [0.98, 1.86]	0.297
HDL (mmol/L)		1.12[0.92, 1.28]	1.05 [0.91, 1.24]	1.17 [0.98, 1.31]	0.076
LD-C (mmol/L)		2.13[1.52, 2.81]	2.04 [1.52, 2.72]	2.17 [1.51, 2.90]	0.329
LP-α (mmol/L)		85.69[50.57, 203.5]	96.40 [47.45, 214.99]	73.72 [51.89, 177.64]	0.508
CK (ng/L)		76.94[56.65, 122.95]	75.90 [60.25, 96.90]	78.81 [54.80, 136.96]	0.832
Hemoglobin A1C n (%)		6.64[5.90, 6.92]	6.50 [6.00, 7.00]	6.25 [5.80, 6.60]	0.054
Coronary functional examination
Before PCI
LAD	QFR	0.89 [0.71, 0.96]	0.71 [0.46, 0.80]	0.95 [0.93, 0.98]	< 0.05
	AMR (mmHg*s/m)	259.00 [196.00, 306.25]	196.00 [131.00, 222.50]	308.00 [291.50, 336.25]	< 0.05
	Simulated hyperemic velocity (cm/s)	12.80 [10.90, 15.43]	15.35 [12.97, 18.05]	11.10 [9.80, 12.60]	< 0.05
	Diameter stenosis (%)	35.35 [23.40, 54.40]	54.40 [43.65, 65.05]	23.55 [19.60, 32.42]	< 0.05
	MLD (mm)	1.56 [1.07, 2.07]	1.09 [0.78, 1.49]	1.98 [1.62, 2.33]	< 0.05
LCX	QFR	0.91 [0.82, 0.97]	0.83 [0.80, 0.91]	0.96 [0.93, 0.98]	< 0.05
	AMR (mmHg*s/m)	249.50 [228.50, 312.00]	233.50 [213.50, 246.50]	297.00 [270.50, 332.25]	< 0.05
	Simulated hyperemic velocity (cm/s)	13.15 [11.00, 15.62]	14.45 [13.00, 17.58]	11.85 [10.17, 13.53]	< 0.05
	Diameter stenosis (%)	32.65 [23.70, 45.42]	44.05 [30.35, 55.73]	24.95 [21.03, 34.95]	< 0.05
	MLD (mm)	1.56 [1.22, 2.02]	1.43 [0.94, 1.89]	1.74 [1.44, 2.15]	< 0.05
RCA	QFR	0.96 [0.88, 0.99]	0.88 [0.80, 0.95]	0.98 [0.96, 1.00]	< 0.05
	AMR (mmHg*s/m)	243.00 [212.50, 277.50]	217.00 [180.00, 239.00]	274.50 [241.75, 297.50]	< 0.05
	Simulated hyperemic velocity (cm/s)	15.70 [13.40, 19.42]	18.05 [15.60, 21.10]	14.55 [12.38, 16.50]	< 0.05
	Diameter stenosis (%)	28.80 [16.15, 44.83]	43.35 [29.30, 56.40]	19.00 [12.70, 27.70]	< 0.05
	MLD (mm)	2.24 [1.66, 2.77]	1.69 [1.21, 2.12]	2.63 [2.36, 3.03]	< 0.05
After PCI
LAD	QFR	-	0.91[0.86, 0.94]	-	-
	AMR (mmHg*s/m)	-	217.5[200.8, 240]	-	-
	Simulated hyperemic velocity (cm/s)	-	18.00[15.03, 22.30]	-	-
	Diameter stenosis (%)	-	31.51 ± 9.23	-	-
	MLD (mm)	-	1.69 ± 0.42	-	-
LCX	QFR	-	0.89 ± 0.06	-	-
	AMR (mmHg*s/m)	-	224.38 ± 21.24	-	-
	Simulated hyperemic velocity (cm/s)	-	17.86 ± 21.24	-	-
	Diameter stenosis (%)	-	37.36 ± 10.52	-	-
	MLD (mm)	-	1.66 ± 0.51	-	-
RCA	QFR	-	0.90 ± 0.07	-	-
	AMR (mmHg*s/m)	-	199.11 ± 25.91	-	-
	Simulated hyperemic velocity (cm/s)	-	21.93 ± 5.02	-	-
	Diameter stenosis (%)	-	36.56 ± 11.41	-	-
	MLD (mm)	-	1.94[1.27, 1.91]	-	-
Abbreviation: LVDD: left ventricular diastolic dysfunction; PCI: percutaneous coronary intervention; CCB: calcium channel blocker; ACEI/ARB: angiotensin converting enzyme inhibitors/Angiotonin Receptor Blocker; CRP: C-reactive protein; TNI: troponin I; CK-MB: creatine kinase isoenzyme-MB; MYO: myoglobin; BNP: brain natriuretic peptide; AST: aspartate transaminase; ALT: alanine aminotransferase; BUN: blood urea nitrogen; TG: triglyceride; TC: cholesterol; HDL: high density lipoprotein; LDL: low density lipoprotein; Lp(α): lipoprotein(α); CK: creatine kinase; LAD: left anterior descending artery; LCX: left circumflex artery; RCA: right coronary artery; QFR: quantitative flow ratio; AMR: Angiography-derived index of microcirculatory; MLD: minimum lumen diameter.

2. Correlation analysis

(1) Linear correlation analysis

Regarding average E/e', the maximum AMR values (AMRmax) in the 3 coronary arteries and the AMR in the LAD were positively correlated with average E/e' (R = 0.2, P = 0.025; R = 0.3, P < 0.01), yet there was no linear relationship between the AMR in the LCX and RCA and average E/e'. The slowest SHV (SHVmin) in the 3 coronary arteries and the SHV in the LAD were negatively correlated with the average E/e' (R=-0.18, P = 0.045; R=-0.32, P < 0.01), yet the SHV of the LCX and RCA were not linearly correlated with average E/e' E/e' (Fig. 2).

With respect to the septal e' velocity, the AMRmax and AMR in the LAD were negatively correlated with the septal e' velocity (R=-0.28, P < 0.01; R=-0.19, P = 0.033). The SHV in LAD was positively correlated with the septal e' velocity (R = 0.34, P < 0.01) (Fig. 3).

In terms of the lateral e' velocity, the AMRmax and AMR in the LAD and LCX were negatively correlated with the e' velocity (R=-0.28, P < 0.01; R=-0.20, P = 0.026; R=-0.23, P = 0.01). The SHV in the LAD was positively correlated with the lateral e' velocity (R = 0.28, P < 0.01) (Fig. 4).

(2) Logistic regression

The results revealed that creatinine, the SHVmin, and SHV in the LAD were negatively correlated with LVDD (OR = 0.94; OR = 0.59, OR = 0.81). CK-MB and the AMRmax, but AMR of the LAD were positively correlated with LVDD (OR = 1.32, OR = 1.02, OR = 1.02) (Table 2).

Table 2

logistics regression
	β	OR	95%Cl down	95%Cl upper	P
CK-MB	0.28	1.32	1.01	1.74	0.046
Creatinine	-059	0.94	0.90	0.98	0.007
AMRmax	0.02	1.02	1.01	1.03	0.002
SHVmin	-0.52	0.59	0.36	0.97	0.037
AMR-LAD	0.02	1.02	1.02	1.03	0.000
SHV-LAD	-0.21	0.81	0.68	0.97	0.019
Abbreviation: OR: odds ratio; CI: confidence interval; CK-MB: creatine kinase isoenzyme-MB; AMR: Angiography-derived index of microcirculatory; AMRmax:: the maximum AMR value of three coronary arteries; SHV: Simulated hyperemic velocity; SHVmin: the minimum SHV value of three coronary arteries; LAD: left anterior descending artery; AMR-LAD: the AMR value of LAD; SHV-LAD: the SHV value of LAD.

(3) Stratified analysis

In the CMVD subgroup, the study population was future divided into two groups, the LVDD group and the non-LVDD group, based on the presence of LVDD in order to explore the differential distribution of the indicators of angiographic function between two groups. The results revealed that the AMRmax and AMR in the LAD were significantly higher in the LADD group (P < 0.05), whereas the SHVmin was lower in the LADD group (P < 0.05) (Fig. 5).

3. Receiver operating characteristic (ROC) curve

The results showed that the AMRmax and AMR in the LAD could effectively identify LVDD. The areas under curves (AUC) were 0.72 (95% CI: 0.67–0.87, p = 0.004), and 0.78 (95% CI: 0.64–0.93, p < 0.01), respectively (Fig. 6).

In this study, 128 people were ultimately included, and there were 64 patients in each of the CMVD and obstructive-CAD groups. To prevent bias, we included all patients suffering from unstable angina with the following exclusion criterion: patients with myocardial infarction or the presence of left ventricular wall motion abnormalities on echocardiogram. Overall, the results showed that the baseline characteristics were comparable between the two groups, whereas more patients underwent PCI in the past in the obstructive-CAD group, which was related to epicardial stenosis caused by atherosclerosis. Accordingly, after coronary revascularization, the diastolic function may be improved to a greater extent. A study from Japan revealed that coronary revascularization significantly reduced left ventricular filling pressure ^[26]. Moreover, nitrates, lipid-lowering and ACEI/ARB drugs were more frequently prescribed in the obstructive-CAD group, which is associated with cardiologists’ strategies. There was no significant difference between the two groups in laboratory examinations, which suggests that risk factors such as hypertension, diabetes mellitus, and hyperlipidemia adversely affect endothelial function ^{[28, 29]}, leading to endocardial and epicardial vascular lesions. With respect to the indicators of angiographic function, the CMVD group had significantly higher levels of QFR and AMR, but significantly lower levels of SHV and MLD, which is dependent on the inclusion criteria (MR > 250 mmHg*s/m and non-obstructive epicardial coronary artery in the CMVD group, while AMR < 250 mmHg*s/m in the obstructive-CAD group). Regarding echocardiographic, the results indicated that the average E/e' was higher in the CMVD group. Studies have reported that the average E/e' can be used to estimate left ventricle filling pressures ^[30]. Previous studies have also shown that the average E/e' is a predictor of mortality ^{[31, 32]}. Furthermore, the septal e' velocity and lateral e' velocity were significantly lower in the CMVD group than in the control group, indicating left ventricular perfusion defects during diastole and further suggesting abnormal diastolic function. LVDD is defined as preserved left ventricular systolic function with diastolic restriction, and impaired filling pressure ^{[33, 34]}. There are two patterns for diastole: active and passive components. In early diastole, rapid filling is an active mode (due to low left ventricular pressure), while late filling, a passive mode, is determined by atrial contraction and left atrial pressure ^[35]. LVDD is caused by abnormal myocardial energy metabolism ^{[38, 39]} and the ventricles are unable to receive low-pressure blood from the left atrium in the early diastole stage, thus, the filling velocity is slow ^[36], resulting in decreased velocity in the left ventricular wall during diastole stage. However, the average E/e' is calculated by dividing the peak early-diastolic by the average of septal e' velocity and lateral e' velocity ^[37]. Consequently, the higher average E/e' is more than 14, the greater the degree of abnormal diastolic function. Because the decrease in left ventricular filling pressure triggered the compensatory contraction of the left atrium ^[37], and increased flow velocity of the mitral valve at the diastole stage. Ali Aldujeli revealed that patients, underwent PCI due to STEMI, with coronary microcirculation dysfunction (CMD) had higher left ventricular end-diastolic volume, left atrial volume index, and tricuspid regurgitation peak velocity, whereas the average e’ were lower ^[38]. Another study reported that microvascular injury in female swine may cause an increased left ventricular end-diastolic stiffness and a trend towards a reduced E/A ratio, while ejection fraction was maintained, which associate with systemic inflammation and myocardial oxidative stress ^[39]. It has been previously proposed that CMD induced by a chronic proinflammatory state leads to uncontrolled cardiomyocyte hypertrophy, stiffening, and fibrosis causing diastolic dysfunction ^[40]. Furthermore, these changes were accompanied by an increase in total collagen, which together with the increased passive stiffness of single cardiac myocytes, translated into higher LV stiffens, as demonstrated by a decreased E/A ratio ^[41].

Diastolic dysfunction can be a result of a decrease in ventricular compliance, which is determined mainly by myocardial mass and myocardial composition ^{[38, 42]}. Its pathology is characterized by extensive ischemic injury leading to ventricular muscle stiffness. In this study, we found that the prevalence of LVDD was significantly greater in the CMVD group (12.8% vs 6.2%) with statistical significance. The coronary microvasculature accounts for 90% of the entire coronary artery, whereas the epicardial vessels account for only 10%. Therefore, ischemia caused by extensive microvascular lesions is more susceptible to LVDD. Because the subendocardial microvasculature is subjected to higher myocardial tone, it is more likely to lead to myocardial ischemia compared to the epicardial vessels ^[43]. Additionally, a decrease in the elasticity of vessels for microvasculature under some adverse factors may develop a "binding effect" on the wall of the left ventricle, ultimately leading to LVDD ^[44]. Overall, CMVD may be more susceptible to LVDD than obstructive CAD is. LVDD has been recognized as a characteristic of HFpEF, which has become a major cause of hospitalization for the elders ^[45]. Abhayaratna revealed that about 44% of the patients presenting with an EF higher than 50% have congestive heart failure, and 20.8% of the population with heart failure had mild diastolic dysfunction. In addition, 5.6% of the population have moderate or severe diastolic dysfunction with normal EF, and diastolic dysfunction were predictive of all-cause mortality ^[46]. A cohort study from The Irbesartan in HFPEF trial (I-PRESERVE) demonstrated that diastolic dysfunction was present in 69% of the patients with HFpEF ^[47]. Therefore, early prevention of LVDD can mitigate the progression of heart failure. A cohort study showed that 81% of patients with HFpEF had CMD ^[48]. Similarly, PROMIS-HFpEF study also showed among 202 patients with HFpEF, 75% (95% confidence interval 69–81%) had CMD (defined as CFR < 2.5) ^[49]. Furthermore,

CMD has been a prognostic factor for HFpEF, a study reported that CMD (defined as caIMR ≥ 25) was independently predictive of adverse outcomes (adjusted hazard ratio 2.93, 95%CI: 1.28–6.70 ^[50].

Regarding the correlation analysis, we found that AMR and SHV (basically from the LAD) were linearly correlated with the LVDD. Because of the heterogeneity of flow distribution, endocardial vessels in the anterior wall of the left ventricle receive more compression (compared to the posterior and basal walls), so the vessel in the LAD was more susceptible to microvascular injury ^[51]. Similarly, the European Association of Percutaneous Cardiovascular Interventions consensus recommends the LAD as the primary vessel for evaluating microcirculatory dysfunction ^[52]. The AMRmax and SHVmin in this study were mostly derived from the AMR and SHV in the LAD, so we can clarify why the indicators of angiographic function examination in the LCX and RCA do not correlate with LADD. Notably, the flow velocity and AMR are inversely related. Therefore, the relationship between the SHV and AMR and the indicators characterizing LVDD is opposite. David et al. included 330 patients with INOCA and reported that average E/e' was negatively correlated with coronary blood flow (CFR) but positively correlated with the index of microcirculatory resistance (IMR), demonstrating the correlation between cardiac diastolic function and CMVD ^[53]. Iryna Dykun et al. reported that left ventricular ejection time (LVET) is correlated with CMD, because CMD is determined only by left ventricular end-diastolic pressure in this study ^[54]. In terms of the logistic regression, the result revealed that AMR promoted LADD, in other words each 1-unit increase in AMRmax was associated with a 2% increase in the incidence of LVDD (OR = 1.0). However, SHV had the opposite effect (OR = 0.59). Moreover, the stratified analysis showed that in the CMVD group, patients with LVDD had significantly greater AMR and lower SHV levels than those in the non-LVDD group. ROC curve analysis showed that AMR was well differentiated from LVDD (AUC > 0.7). Thus, the AMR can be considered a specific marker for LVDD. Notably, the ROC curve in this study was intended to illustrate the ability of the AMR to identify LADD in the two coronary lesion subgroups rather than explore the threshold of the AMR for diagnosing LADD.

The diagnosis of LVDD was only based on echocardiography in this study, however, we strictly adhered to the guidelines for diagnosing LVDD. Moreover, there were fewer INOCA patients with AMR < 250 mmHg*s/m in all coronary arteries, thus, we did not calculate the cutoff value for the AMR diagnosis of LADD. However, we clarified the effects of two ischemic states (microvascular and epicardial vessels) on LVDD.

Our study concluded that microvascular lesions were more extensive than epicardial lesions, thus predisposing it to LVDD and ultimately to HFpEF. Moreover, the index of microcirculatory resistance may be a specific marker of LVDD. All in all, we should emphasize the adverse pathological effects of microvasculature lesions.

AMR	Angiography-derived index of microcirculatory
ACEI	Angiotensin converting enzyme inhibitors
ARB	Angiotonin receptor blocker
AUC	Areas under curves
CI	Confidence intervals
CAG	Coronary angiography
CABG	Coronary artery bypass grafting
CAD	coronary artery disease
CBF	Coronary blood flow
CTA	Coronary CT angiography
CFR	Coronary flow reserve
CMVD	Coronary microvascular disease
HFpEF	Heart failure with preserved ejection fraction
IMR	Index of microvascular resistance index
INOCA	Ischemia with no-obstructive coronary artery disease
IHD	Ischemic heart disease
LAD	Left anterior descending artery
LCX	Left circumflex artery
LVDD	Left ventricular diastolic dysfunction
LDL-C	Low-density lipoprotein-C
AMRmax	Maximum AMR
OR	Odds ratio
PCI	Percutaneous Coronary Intervention
PTCA	Percutaneous Transluminal Coronary Angioplasty
QFR	Quantitative flow ratio
ROC	Receiver operating characteristic
RCA	Right coronary artery
SHV	Simulating hyperemic velocity
SHVmin	Slowest SHV
TR	Tricuspid regurgitation velocity
UA	Unstable angina

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Xiyuan Hospital(2024XLA031-2). We informed the patient that the clinical data would be used for publication and obtained consent from all participants.

Consent for publication

All authors read the version finally approved for publication.

Data Availability Statement

The data can be obtained from the corresponding author.

Acknowledgements

Not applicable.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

This work was supported by CACMS Innovation Fund (No.CI2021A00901).

Author Contributions

Fuhai Zhao contributed to the study conception and design; Wei Wen, Mengjie Gao, and Yi Chi statistically analyzed and interpreted the data and drafted the manuscript. Keji Chen, Mingwang Liu, Beili Xie, and Lulian Jiang revised the article critically.

Authors' information

Not applicable.

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No competing interests reported.

Graphicabstract.pptx

Coronary microvascular disease is a risk factor for left ventricular diastolic dysfunction: An AWARD substudy

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