Risk Factors And Epigenetic Markers Of Left Ventricular Diastolic Dysfunction With Preserved Ejection Fraction In A Community-Based Elderly Chinese Population

Figures & data

Table 1 Baseline Characteristics Of Participants

Variables	Total (n=1568)	LVDD-PEF (n=177)	Non-LVDD-PEF (n=1391)	P-value
CV risk factors and biochemical parameters
Age, years	71.88±6.10	72.91±6.40	71.75±6.05	0.023
Female gender, n (%)	878 (56.0)	132 (74.6)	746 (53.6)	<0.001
Body mass index, kg/m^2	24.37±3.46	25.46±3.70	24.23±3.40	<0.001
Smoker, n (%)	354 (22.6)	28 (15.8)	326 (23.4)	0.022
Drinker, n (%)	229 (14.6)	15 (8.5)	214 (15.4)	0.014
Red blood cell, 10^12/L	4.51±0.43	4.41±0.45	4.52±0.43	0.002
Hemoglobin, g/L	135.69±12.62	131.80±13.14	136.18±12.48	<0.001
Fasting plasma glucose, mmol/L	5.69±1.71	5.91±1.87	5.66±1.69	0.076
TC, mmol/L	5.18±1.12	5.15±1.24	5.19±1.10	0.663
TG, mmol/L	1.59±0.94	1.61±0.91	1.59±0.94	0.842
HDL-C, mmol/L	1.37±0.38	1.37±0.36	1.37±0.39	0.967
LDL-C, mmol/L	3.17±0.91	3.15±1.00	3.17±0.89	0.780
UACR, mg/g	53.88±181.18	64.23±117.48	52.58±187.68	0.430
eGFR, mL/min/1.73m^2	78.60±14.32	78.17±15.46	78.65±14.17	0.674
SBP, mmHg	134.32±18.37	140.81±19.88	133.49±18.01	<0.001
DBP, mmHg	78.97±9.64	78.58±8.82	79.02±9.74	0.571
PP, mmHg	55.34±15.33	62.22±17.87	54.47±14.75	<0.001
Hypertension, n (%)	819 (52.2)	118 (66.7)	701 (50.4)	<0.001
CHD, n (%)	531 (33.9)	75 (42.4)	456 (32.8)	0.011
Diabetes, n (%)	306 (19.5)	44 (24.9)	262 (18.8)	0.057
Echocardiographic indices
E/E’	9.74±3.65	15.10±4.25	9.06±2.93	<0.001
Pulse wave velocity, m/s	9.22±2.67	9.67±2.61	9.16±2.67	0.016
Left ventricular ejection fraction, %	57.35±18.24	60.76±7.72	56.91±19.13	<0.001
Left ventricular mass index, g/m^2	92.45±29.42	118.60±35.84	89.12±26.74	<0.001
Left atrial volume index, mL/m^2	11.84±5.00	14.10±5.03	11.55±4.93	<0.001
Plaque in right carotid artery, n (%)	808 (51.5)	104 (58.8)	704 (50.6)	0.041
Carotid IMT, mm	0.61±0.15	0.64±0.16	0.61±0.15	0.027

Notes: Data are mean±standard deviation or numbers with percentages. P-value represents the comparison between LVDD-PEF group and non-LVDD-PEF group. Estimated GFR was calculated with Chronic Kidney Disease Epidemiology Collaboration equation.⁴⁰

Abbreviations: BMI, body mass index; CV, cardiovascular; CHD, coronary heart disease; eGFR, estimated glomerular filtration rate; E, peak early diastolic transmitral flow velocity; E’, early diastolic lateral mitral annular velocity; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein; LVDD-PEF, left ventricular diastolic dysfunction with preserved ejection fraction; PP, pulse pressure; TC, total cholesterol; TG, triglyceride; UACR, urinary albumin-creatinine ratio.

Table 2 Determinants Of E/E’ By Multiple Linear Regression Analysis

Determinant	E/E’
	β±SE	P-value
Age	0.000±0.016	0.999
Female gender	1.001±0.252	<0.001
Smoking	0.392±0.269	0.146
Drinking	0.145±0.282	0.608
BMI, kg/m^2	0.067±0.028	0.016
Hypertension	0.325±0.202	0.107
CHD	–0.014±0.196	0.941
Red blood cell, 10^12/L	–0.196±0.339	0.562
Hemoglobin, g/L	0.003±0.013	0.798
SBP, mmHg	–0.003±0.010	0.728
PP, mmHg	0.053±0.012	<0.001
Pulse wave velocity, m/s	–0.052±0.038	0.168
Plaque in right carotid artery	–0.218±0.185	0.239
Carotid intima-media thickness, mm	1.385±0.625	0.027

Note: The multivariate linear regression was conducted to investigate the associations of E/E’ with the significant variables in the baseline.

Abbreviations: β, the regression coefficient of variables; BMI, body mass index; CHD, coronary heart disease; E, peak early diastolic transmitral flow velocity; E’, early diastolic lateral mitral annular velocity; PP, pulse pressure; SE, standard error.

Table 3 Age- And Gender-Adjusted Multivariate Logistic Analyses

Characteristics	All Participants With LVDD-PEF
	OR	95% CI	P-value
Smoking, n (%)	1.40	0.81–2.43	0.228
Alcohol, n (%)	0.84	0.47–1.51	0.555
BMI, kg/m^2	1.10	1.05–1.15	<0.001
Red blood cell, 10^12/L	0.86	0.56–1.30	0.460
Hemoglobin, g/L	0.99	0.97–1.00	0.148
Pulse wave velocity, m/s	1.05	0.99–1.12	0.094
SBP, mmHg	1.02	1.01–1.03	<0.001
PP, mmHg	1.03	1.02–1.04	<0.001
Carotid intima-media thickness, mm	4.64	1.67–12.93	0.003
Plaque in right carotid artery, n (%)	0.71	0.52–0.99	0.042
Hypertension, n (%)	1.98	1.42–2.76	<0.001
CVD history, n (%)	1.40	1.01–1.93	0.045

Note: The multiple logistic regression was performed to identify the independent risk factors of LVDD-PEF after adjustment for age and gender.

Abbreviations: BMI, body mass index; CHD, coronary heart disease; LVDD-PEF, left ventricular diastolic dysfunction with preserved ejection fraction; PP, pulse pressure.

Table 4 Independent Risk Factors Of LVDD-PEF According To Multivariate Logistic Analysis

Characteristics	All Participants With LVDD-PEF
	OR	95% CI	P-value
Age, years	1.00	0.97–1.03	0.959
Female gender, n (%)	2.46	1.47–4.13	0.001
Smoking, n (%)	1.32	0.74–2.38	0.349
Alcohol, n (%)	0.78	0.42–1.45	0.433
BMI, kg/m^2	1.09	1.04–1.14	<0.001
Red blood cell, 10^12/L	1.14	0.64–2.04	0.656
Hemoglobin, g/L	0.99	0.96–1.01	0.184
Pulse wave velocity, m/s	0.98	0.91–1.04	0.457
SBP, mmHg	0.99	0.98–1.01	0.542
PP, mmHg	1.03	1.01–1.05	0.013
Carotid intima-media thickness, mm	4.20	1.40–12.55	0.010
Plaque in right carotid artery, n (%)	0.76	0.54–1.08	0.123
Hypertension, n (%)	1.44	0.98–2.12	0.061
CHD, n (%)	1.18	0.84–1.67	0.342

Abbreviations: BMI, body mass index; CHD, coronary heart disease; LVDD-PEF, left ventricular diastolic dysfunction with preserved ejection fraction; PP, pulse pressure.

Table 5 Details Of Differentially Methylated Regions Between Two Groups

Chromosome ID	Gene	Position	Sequence	CpG Average Methylation Rate (LVDD-PEF)	CpG Average Methylation Rate(On-LVDD-PEF)	Methylation Level	P-value
chr6	HIST1H2BK	27,104,360	TGCGT	0.8894	1.0000	Up	3.47E-04
chr8	SQLE	126,010,016	CCGAG	0.3629	0.1592	Down	6.66E-04
chr19	HAUS8	17,159,455	GCGGT	0.8629	0.9929	Up	7.01E-04
chr16	RPUSD1	834,438	TCCGG	0.8674	0.9944	Up	7.01E-04
chr14	SERPINA1	94,842,512	ACGAT	0.8847	0.6853	Down	6.66E-04
chr3	C3orf14	62,304,166	CCGCA	0.4845	0.7394	Up	6.66E-04
chr12	H2AFJ	14,926,526	ACGTC	0.3989	0.1758	Down	6.66E-04
chr17	GPRC5C	72,426,882	TCCGG	0.0657	0.0000	Down	3.47E-04
chr10	SLC18A2	118,998,720	GCCGG	0.8604	0.6956	Down	6.66E-04
chr12	CRACR2A	3,724,126	GTCGA	0.8977	0.7078	Down	6.66E-04
chr1	ALDH4A1	19,196,984	CCGCG	0.6769	0.8556	Up	6.66E-04
chr16	CDH1	68,770,945	CCGGC	0.1670	0.4064	Up	6.66E-04
chr10	RPP38	15,138,567	TCGGC	0.4501	0.2537	Down	6.66E-04
chr12	TMEM5	64,171,827	GCGTG	0.8839	0.7125	Down	6.66E-04
chr1	SNRPE	203,829,891	TCGCC	0.7204	0.5765	Down	6.66E-04
chr2	SLC4A3	220,491,676	GCCGA	0.9615	0.8632	Down	6.66E-04
chr7	DLX6	96,633,631	TGCGG	0.5183	0.2596	Down	6.66E-04
chr12	DDN	49,387,748	ACGAT	0.6767	0.8044	Up	6.66E-04
chr2	ACTG2	74,119,725	GGCGT	0.9395	0.8066	Down	6.66E-04
chr17	NXN	701,013	ACGTA	0.8804	0.6484	Down	6.66E-04
chr7	RAPGEF5	22,156,921	GCGAC	0.9399	0.8115	Down	6.66E-04
chr1	IFI6	27,992,184	AACGG	0.9280	0.7766	Down	6.66E-04
chr10	RGS10	121,259,187	GCGAC	0.5834	0.7209	Up	6.66E-04
chr4	SCD5	83,549,420	CTCGA	0.8263	0.6728	Down	6.66E-04
chr6	PPP2R5D	42,951,221	GTCGC	0.9417	0.7943	Down	6.66E-04

Table 6 Candidate Genes Selected For Validation

Gene Symbol	Gene ID	Summary
RGS10	6001	GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins
CRACR2A	84,766	A protein coding gene related to calcium ion binding and GTPase activity
ACTG2	72	Cardiac vascular smooth muscle contraction

Abbreviations: ACTG2, actin gamma smooth muscle 2; CRACR2A, calcium release activated channel regulator 2A; RGS10, regulator of G-protein signaling 10.

Figure 1 Cluster analysis of genes with significantly altered methylation for upstream (n=25). Each column represents a sample, and each row represents the methylation level of a gene. The color code for the heatmap is displayed in the upper right corner, values range from −2 (sample with the lowest methylation for the considered genes) to 2 (sample with the highest methylation for the considered genes).

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