Valvular calcification in liver cirrhosis: A comparison with non-cirrhotic cardiovascular controls

Table 1 Semiquantitative echocardiographic algorithm for total calcium scoring of the aortic valve and mitral annulus

Calcium scoring variable	Score
Posterior mitral annular calcification	None = 0
	1/3 calcified = 1
	2/3 calcified = 2
	3/3 calcified = 3
Posterior mitral leaflet restriction	No = 0; yes = 1
Anterior mitral annular calcification	No = 0; yes = 1
Anterior mitral leaflet restriction	No = 0; yes = 1
Mitral valve calcification	No = 0
	Mild = 1
	More than mild = 2
Subvalvular mitral apparatus calcification	No = 0; yes = 1
Aortic valve calcification	None = 0
	Nodules in < 3 leaflets = 1
	Nodules in 3 leaflets = 2
	Leaflet restriction = 3
Aortic root calcification	No = 0; yes = 1
Total	13

Table 2 Demographic and clinical characteristics of patients included in the study, n (%)

Variable	All patients (n = 246)	LC (n = 123)	Control group (n = 123)	P value	Fatty LC (n = 61)	Other causes of LC (n = 62)	P value
Age, years	64.0 (58.0-70.0)	64.0 (58.0-70.0)	64.0 (58.0-70.0)	> 0.999	64.0 (58.0-70.0)	64.5 (58.8-71.0)	0.748
Male sex	176 (71.5)	88 (71.5)	88 (71.5)	> 0.999	53 (86.9)	35 (56.5)	< 0.001a
BMI, kg/m²	28.03 ± 4.63	27.49 ± 5.35	28.50 ± 3.85	0.106	27.93 (25.26-32.32)	25.78 (22.73-29.65)	0.026
Previous cardiac surgery	18 (7.3)	1 (0.8)	17 (13.8)	< 0.001	1 (1.7)	0 (0.0)	0.492
DM	74 (30.1)	44 (35.8)	30 (24.4)	0.070	23 (37.7)	21 (33.9)	0.709
Hypertension	149 (60.6)	51 (41.5)	98 (79.7)	< 0.001a	22 (36.1)	29 (46.8)	0.273
Hyperlipidemia	103 (42.0)	29 (23.8)	74 (60.2)	< 0.001a	20 (33.3)	9 (14.5)	0.019
AF	32 (13.1)	6 (4.9)	26 (21.1)	< 0.001a	1 (1.7)	5 (8.1)	0.207
PVD	27 (11.0)	6 (4.9)	21 (17.1)	0.004	4 (6.7)	2 (3.2)	0.436
Previous CVI or TIA	13 (5.3)	3 (2.5)	10 (8.1)	0.084	1 (1.7)	2 (3.2)	> 0.999
COPD	18 (7.3)	4 (3.3)	14 (11.4)	0.025	2 (3.3)	2 (3.2)	> 0.999
Smoking history	142 (60.4)	53 (46.9)	89 (73.0)	< 0.001a	28 (51.9)	25 (42.4)	0.349
Previous MI	51 (20.8)	5 (4.1)	46 (37.4)	< 0.001a	3 (5.0)	2 (3.2)	0.677
CKD stage	-	-	-	0.812	-	-	0.648
I-II	212 (86.5)	104 (85.2)	108 (87.8)	-	49 (81.7)	55 (88.7)	-
III	21 (8.6)	12 (9.8)	9 (7.3)	-	8 (13.3)	4 (6.5)	-
IV	9 (3.7)	4 (3.3)	5 (4.1)	-	2 (3.3)	2 (3.2)	-
V	3 (1.2)	2 (1.6)	1 (0.8)	-	1 (1.7)	1 (1.6)	-
LVEF, %	65.0 (55.5-65.0)	65.0 (65.0-65.0)	59.0 (50.0-65.0)	< 0.001a	65.0 (65.0-65.0)	65.0 (65.0-65.0)	0.394
LVEF < 50%	25 (10.2)	3 (2.5)	22 (17.9)	< 0.001a	1 (1.7)	2 (3.2)	> 0.999
Aortic valve calcification	125 (50.8)	79 (64.2)	46 (37.4)	< 0.001a	41 (67.2)	38 (61.3)	0.574
Aortic root calcification	177 (72.0)	84 (68.3)	93 (75.6)	0.256	47 (77.0)	37 (59.7)	0.052
Total aortic valve Ca score	1.0 (1.0-2.0)	1.0 (1.0-2.0)	1.0 (1.0-2.0)	0.104	2.0 (1.0-2.0)	1.0 (0.75-2.0)	0.083
Posterior mitral annulus calcification	130 (52.8)	71 (57.7)	59 (48.0)	0.160	39 (63.9)	32 (51.6)	0.203
Posterior mitral leaflet restriction	11 (4.5)	4 (3.3)	7 (5.7)	0.538	2 (3.3)	2 (3.2)	> 0.999
Anterior mitral annular calcification	32 (13.0)	17 (13.8)	15 (12.2)	0.850	11 (18.0)	6 (9.7)	0.202
Anterior mitral leaflet restriction	3 (1.2)	1 (0.8)	2 (1.6)	> 0.999	1 (1.6)	0 (0.0)	0.496
Mitral valve calcification	131 (53.3)	47 (38.2)	84 (68.3)	< 0.001a	23 (37.7)	24 (38.7)	> 0.999
Subvalvular mitral apparatus calcification	107 (43.5)	51 (41.5)	56 (45.5)	0.607	30 (49.2)	21 (33.9)	0.101
Total mitral valve Ca score	2.0 (1.0-3.0)	2.0 (0.0-3.0)	2.0 (1.0-3.0)	0.253	2.0 (1.0-3.0)	1.0 (0.0-3.0)	0.086
Total Ca score	3.0 (2.0-5.0)	3.0 (1.0-5.0)	3.0 (2.0-4.0)	0.799	3.0 (2.0-5.0)	3.0 (1.0-5.0)	0.043

^aP values remained statistically significant after Bonferroni correction (Bonferroni corrected P value: Pc = 0.05/27 = 0.0018).

Data are presented as n (%), median with interquartile range, or mean ± SD. LC: Liver cirrhosis; BMI: Body mass index; DM: Diabetes mellitus; AF: Atrial fibrillation; PVD: Peripheral vascular disease; TIA: Transient ischemic attack; COPD: Chronic obstructive pulmonary disease; MI: Myocardial infarction; CKD: Chronic kidney disease; LVEF: Left ventricular ejection fraction; CVI: Cerebrovascular insult; Ca: Calcium.

Table 3 Univariate and multivariate binary logistic regression analyses of factors associated with aortic valve calcification

Variable	Univariate OR	95%CI	P value	Variable	Model	Multivariate OR	95%CI	P value
Age	1.072	1.039-1.106	< 0.001a	Age	Ia	1.075	1.038-1.113	< 0.001a
					IIa	1.043	1.004-1.084	0.030
					IIIa	1.040	0.996-1.087	0.076
Male sex	0.966	0.555-1.681	0.903	Gender, male	Ia	1.043	0.548-1.982	0.899
					IIa	1.083	0.554-2.116	0.816
					IIIa	1.734	0.785-3.831	0.174
BMI (kg/m²)	0.970	0.917-1.027	0.296	BMI (kg/m²)	Ia	0.958	0.899-1.021	0.187
					IIa	0.929	0.868-0.995	0.036
					IIIa	0.906	0.837-0.981	0.014
Fatty LC	3.432	1.796-6.556	< 0.001a	Fatty LC	Ia	3.323	1.611-6.853	0.001a
					IIa	2.835	1.334-6.028	0.007a
					IIIa	3.873	1.529-9.807	0.004a
Other causes of LC	2.650	1.414-4.967	0.002	Other causes of LC	Ia	2.637	1.311-5.302	0.007a
					IIa	2.552	1.234-5.279	0.011
					IIIa	2.790	1.180-6.598	0.019
Previous cardiac surgery	8.815	1.981-39.225	0.004	Previous cardiac surgery	IIIa	26.363	4.907-141.635	< 0.001a
Smoking	0.637	0.376-1.079	0.093	Smoking	IIIa	0.655	0.310-1.384	0.267
MI	0.558	0.298-1.047	0.069	MI	IIIa	0.464	0.177-1.215	0.118
PVD	2.113	0.909-4.910	0.082	PVD	IIIa	2.505	0.836-7.502	0.101
CVI/TIA	3.450	0.926-12.860	0.065	CVI/TIA	IIIa	4.141	0.744-23.049	0.105
Aortic root calcification	1.635	0.932-2.868	0.087	Aortic root calcification	IIIa	0.420	0.171-1.028	0.058
Mitral annular calcification	4.364	2.540-7.477	< 0.001a	Mitral annulus calcification	IIa	3.964	2.035-7.721	< 0.001a
					IIIa	6.278	2.718-14.500	< 0.001a
Aortic valve Ca score	2.113	1.736-2.572	< 0.001a	-	-	-	-	-
Mitral valve Ca score	1.480	1.225-1.788	< 0.001a	-	-	-	-	-
Total Ca score	2.113	1.736-2.572	< 0.001a	-	-	-	-	-

^aP values remained statistically significant after Bonferroni correction (Univariate analysis: Bonferroni corrected P value: Pc = 0.0018; Multivariate analysis: Model I: Pc = 0.01, model IIa: Pc = 0.0083, model IIIa: Pc = 0.0042).

Model I: Adjusted for age, sex, body mass index (BMI), and liver cirrhosis. Model IIa: Adjusted for age, sex, BMI, liver cirrhosis, and mitral annular calcification. Model IIIa: Adjusted for age, sex, BMI, previous cardiac surgery, smoking history, myocardial infarction, peripheral vascular disease, prior cerebrovascular insult or transient ischemic attack, aortic root calcification, and mitral annular calcification. OR: Odds ratio; CI: Confidence interval; BMI: Body mass index; LC: Liver cirrhosis; MI: Myocardial infraction; PVD: Peripheral vascular disease; CVI: Cerebrovascular insult; TIA: Transient ischemic attack; Ca: Calcium.

Table 4 Univariate and multivariate binary logistic regression analysis of variables related to mitral annular calcification

Variable	Univariate binary logistic regression			Variable	Multivariate binary logistic regression
	OR	95 %CI	P value		Model	OR	95%CI	P value
Age	1.140	1.094-1.187	< 0.001a	Age	Ib	1.141	1.092-1.193	< 0.001a
					IIb	1.102	1.041-1.167	< 0.001a
					IIIb	1.067	1.000-1.137	0.050
Gender, male	0.999	0.572-1.744	0.996	Gender, male	Ib	0.868	0.428-1.759	0.694
					IIb	0.715	0.303-1.684	0.442
					IIIb	0.439	0.157-1.228	0.117
BMI, kg/m2	1.104	1.038-1.173	0.002	BMI, kg/m2	Ib	1.102	1.026-1.183	0.008a
					IIb	1.166	1.067-1.273	< 0.001a
					IIIb	1.169	1.061-1.288	0.002a
DM	2.035	1.150-3.603	0.015	DM	IIIb	1.049	0.425-2.587	0.917
Hypertension	1.623	0.969-2.719	0.066	Hypertension	IIIb	1.214	0.457-3.221	0.697
Hyperlipidemia	2.055	1.217-3.471	0.007	Hyperlipidemia	IIIb	2.423	0.900-6.521	0.080
AF	2.655	1.141-6.175	0.023	AF	IIIb	3.181	0.811-12.473	0.097
PVD	3.941	1.440-10.785	0.008	PVD	IIIb	1.708	0.352-8.286	0.506
COPD	4.303	1.212-15.274	0.024	COPD	IIIb	5.163	0.861-30.966	0.072
CKD III	2.857	1.010-8.082	0.048	CKD III	IIIb	0.726	0.130-4.068	0.716
LVEF (%)	0.957	0.928-0.987	0.006	LVEF (%)	IIIb	0.969	0.923-1.016	0.194
MI	2.484	1.263-4.886	0.008	MI	IIIb	3.060	1.014-9.237	0.047
Fatty LC (NAFLD and AFLD)	2.017	1.063-3.828	0.032	Fatty LC (NAFLD and AFLD)	Ib	2.677	1.204-5.954	0.016
					IIb	4.461	1.573-12.656	0.005a
					IIIb	16.693	3.843-72.512	< 0.001a
Other causes of LC	1.195	0.648-2.204	0.569	Other causes of LC	Ib	1.475	0.692-3.148	0.314
					IIb	3.173	1.135-8.871	0.028
					IIIb	12.719	3.068-52.736	< 0.001a
AVC	4.364	2.547-7.477	< 0.001a	AVC	IIb	5.307	2.444-11.522	< 0.001a
					IIIb	8.079	3.263-20.004	< 0.001a
Aortic root calcification	8.948	4.587-17.457	< 0.001a	Aortic root calcification	IIb	7.185	2.827-18.257	< 0.001a
					IIIb	15.987	4.630-55.203	< 0.001a
Mitral valve calcification	3.670	2.161-6.232	< 0.001a	Mitral valve calcification	IIb	4.790	2.077-11.044	< 0.001a
					IIIb	4.229	1.634-10.947	0.003
Posterior mitral leaflet restriction	3.762	0.796-17.786	0.095	Posterior mitral leaflet restriction	IIIb	17.862	1.036-307.871	0.047
Subvalvular mitral apparatus calcification	2.911	1.710-4.956	< 0.001a	Subvalvular mitral apparatus calcification	IIb	1.901	0.910-3.972	0.087
					IIIb	1.458	0.640-3.321	0.369
Aortic valve Ca score	2.761	1.980-3.850	< 0.001a	-	-	-	-	-
Mitral valve Ca score	13.895	7.248-26.638	< 0.001a	-	-	-	-	-
Total Ca score	4.800	3.233-7.128	< 0.001a	-	-	-	-	-

^aP values remained statistically significant after Bonferroni correction (Bonferroni corrected P value: Pc = 0.05/number of comparisons; Pc = 0.0018 for univariate analysis, 0.01 for model I, 0.0055 for model IIb, and 0.0022 for model IIIb of the multivariate binary logistic regression analysis, respectively).

Model I: Adjusted for age, sex, body mass index (BMI), and liver cirrhosis; Model IIb: Adjusted for age, sex, BMI, liver cirrhosis, aortic valve calcification, aortic root calcification, mitral valve calcification, and subvalvular mitral apparatus calcification; Model IIIb: Adjusted for age, sex, BMI, liver cirrhosis etiology, aortic valve calcification, aortic root calcification, mitral valve calcification, subvalvular mitral apparatus calcification, posterior mitral leaflet restriction, diabetes mellitus, hypertension, hyperlipidemia, atrial fibrillation, peripheral vascular disease, chronic obstructive pulmonary disease, chronic kidney disease stage, left ventricular ejection fraction (%), and previous myocardial infarction. OR: Odds ratio; CI: Confidence interval; BMI: Body mass index; DM: Diabetes mellitus; AF: Atrial fibrillation; PVD: Peripheral vascular disease; COPD: Chronic obstructive pulmonary disease; CKD: Chronic kidney disease; LVEF: Left ventricular ejection fraction; MI: Myocardial infraction; NAFLD: Non-alcoholic fatty liver disease; AFLD: Alcoholic fatty liver disease; LC: Liver cirrhosis; AVC: Aortic valve calcification; Ca: Calcium.