Prognostic Significance of Systemic Arterial Stiffness Evaluated by Cardio-Ankle Vascular Index in Patients with Idiopathic Pulmonary Hypertension

Figures & data

Table 1 Characteristics of Patients with Idiopathic Pulmonary Arterial Hypertension in Groups of CAVI ≥8 and <8 (M±SD, n (%))

Parameters	CAVI ≥8 n = 18	CAVI <8 n = 71	Significance Between Groups
Age, years*	49.83 (31–59)	40.28 (18–59)	0.005
Male/female, n (%)	2 (11.1)/16 (88.9)	12 (16.9)/59 (83.1)	>0.05
Functional class
I, n (%)	0	2 (2.8)	>0.05
II, n (%)	2 (11.1)	20 (28.2)
III, n (%)	13 (72.2)	44 (62.0)
IV, n (%)	3 (16.7)	5 (7.0)
Pericardial effusion/ascites, n (%)	6 (33.3)	14 (19.7)	>0.05
Syncope, n (%)	4 (22.2)	18 (28.4)	>0.05
Thyroid disorders, n (%)	0	6 (7.7)	< 0.05
Hemoptysis, n (%)	2 (11.1)	2 (2.8)	>0.05
Iron deficit/anemia, n (%)	3 (16.7)	19 (26.8)	>0.05
Body mass index, kg/m^2	26.6±4.2	25.7±5.6	0.55
Duration of symptoms, months*	17.9 (5–36)	20 (3–44)	0.65
Admission SBP, mmHg	119.8±16.8	114.8±14.8	0.21
Admission DBP, mmHg	79.9±9.6	75.6±9.4	0.087
Admission HR, beats per min	85.8±15.6	82.9±13.4	0.42
Discharge SBP, mmHg	104.8±27.8	110.1±15.9	0.30
Discharge DBP, mmHg	71.6±7.2	72.8±5.5	0.45
Discharge HR, beats per min	79.0±11.9	79.3±10.7	0.95
Admission 6-MWT, m	305.9±115.0	365.6±113.3	0.05
Admission Borg, points	3.8±1.76	4.2±2.1	0.52
Admission SaO2 before 6MWT, %	92.7±5.0	95.4±3.3	0.008
Admission SaO2 after 6MWT, %	90.9±9.3	93.9±6.4	0.14
Discharge 6-MWT, m	348.2±72.7	395.1±69.4	0.081
Discharge Borg, points	3.5±1.4	3.5±1.7	0.44
SaO2 before 6MWT at discharge, %	92.6±5.6	96.1±2.7	0.024
SaO2 after 6MWT at discharge, %	89.6±10.6	94.24±4.8	0.094
Right-sided CAVI, units	8.7±1.5	6.4±0.8	< 0.001
Left-sided CAVI, units	9.2±1.1	6.5±0.9	< 0.001
Aorta BP, mmHg	98.8±14.8	99.0±8.5	0.95
PWVm, m/sec	8.9±2.6	7.8±1.5	0.11
PWVe, m/sec	8.5±2.3	7.8±1.4	0.31
Hemoglobin, g/l	151.9±18.4	142.6±19.0	0.068
Hematocrit, %	46.0±5.0	41.7±5.5	0.002
Platelets,*10^9/l	255.7±75.1	247.5±72.1	0.67
White blood cells, *10^9/l	7.4±2.1	7.7±2.5	0.64
Red blood cells, *10^12/l	5.2±0.5	5.0±0.5	0.14
Total cholesterol, mmol/l	4.6±1.4	4.7±1.0	0.83
Potassium, mmol/l	4.3±0.5	4.6±0.4	0.24
Total bilirubin, mkmol/l	26.3±26.7	21.8±18.9	0.43
GFR, mL/min/1.73 m^2	70.5±16.1	82.2±19.3	0.02
Glucose, mmol/l	4.9±0.6	5.2±0.8	0.24
NT-proBNP, pg/mL*	2441.7 (20–6754)	1142.1 (20–5992)	0.047
TSH, mkU/mL	2.3±1.4	2.1±1.2	0.62
Ferritin, ng/mL	168.0±216	100.8±133.9	0.36
International normalization ratio (INR)*	2.02 (1–3)	1.54 (1–3)	0.011
Chronic calcium channel blockers responders, n (%)	4 (22.2)	9 (12.7)	>0.05
Sildenafil, n (%)	16 (88.9)	60 (84.5)	>0.05
Mean dose, mg	101.0±35.9	70.6±23.2	0.001
Iloprost, n (%)	3 (16.7)	21 (29.6)	>0.05
Mean dose, mkg	23.3±5.7	35.0±11.4	0.1
Endothelin receptor blockers, n (%)	1 (5.6)	1 (1.4)	>0.05
Initial 2-drug combination, n (%)	3 (16.7)	21 (29.6)	>0.05
Loop diuretics, n (%)	17 (94.4)	38 (53.5)	0.04
Furosemide, n (%)	4 (22.2)	8 (10.3)	0.22
Mean dose, mg	80.0±56.6	50.0±49.3	0.34
Torasemide, n (%)	13 (72.2)	36 (46.2)
Mean dose, mg	7.5±2.5	6.3±3.5
Warfarin, n (%)	14 (77.8)	35 (49.3)	0.031
Mean dose, mg	4.33±4.59	4.47±4.11	0.92
Digoxin, n (%)	2 (11.1)	4 (5.6)	> 0.05

Notes: *The data of the nonparametric sensitivity analysis (Mann–Whitney test) are presented as mean (minimal – maximal) values. The parameters with significant differences are presented in bold type.

Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; CAVI, cardio-ankle vascular index; GFR, glomerular filtration rate; HR, heart rate; PWVe, pulse wave velocity for elastic arteries; PWVm, pulse wave velocity for muscular arteries; 6-MWT, six minute walk test; RHC, right heart catheterization; SBP, systolic blood pressure; SaO2, oxygen saturation.

Table 2 Echocardiography and Right Heart Catheterization Parameters in Groups of CAVI ≥8 and <8 (M±SD)

Parameters	CAVI ≥8 n = 18	CAVI <8 n = 71	Significance Between Groups
Transthoracic echocardiography parameters
Aorta diameter, cm	3.1±0.45	2.88±0.42	0.54
LA square, cm^2	20.01±13.95	16.49±3.5	0.055
Index of LA, mL/m^2	25.3±5.2	23.45±7.0	0.54
RA area, cm^2	28.0±8.15	25.53±8.8	0.31
Index of RA, mL/m^2	60.38±33.1	51.68±27.8	0.28
LV end-diastolic volume, mL	73.79±18.94	87.35±16.69	0.009
LV end-systolic volume, mL	25.71±9.56	33.55±10.33	0.01
Stoke volume, mL	48.3±12.9	54.24±9.2	0.058
LV ejection fraction, %	64.9±6.3	62.36±6.7	0.19
E/e’ratio	8.8±2.9	7.7±2.2	0.12
Mitral valve E/A	0.69±0.16	0.99±0.36	0.007
DT, msec	245.8±59.47	196.54±38.25	0.001
IVRT, mm/sec	110.2±34.4	97.3±28.9	0.09
RV wall thickness, mm	0.77±0.12	0.62±0.20	0.006
RV diastolic area, cm^2	31.56±8.48	31.82±8.38	0.93
RV systolic area, cm^2	22.58±8.32	22.57±7.86	0.99
TAPSE, mm	13.38±2.15	15.98±4.4	0.018
Tricuspid valve regurgitation, m/sec	4.8±0.78	4.6±0.67	0.76
PA diameter, cm	2.25±0.35	3.15±0.87	0.11
Vena cava inferior diameter, cm	2.13±0.35	3.43±11.7	0.64
Calculated SBP PA, mmHg	97.0±25.58	85.38±26.44	0.10
Diastolic RV/LV eccentric index	1.53±0.24	1.69±0.44	0.1
Systolic RV/LV eccentric index	1.63±0.22	1.85±0.56	0.47
Right heart catheterization
mPAP, mmHg	57.4±16.75	59.47±16.58	0.66
Mean right ventricle blood pressure, mmHg	38.5±17.62	36.55±14.1	0.63
Mean right atrium pressure, mmHg	11.38±7.1	8.76±4.7	0.08
PAWP, mmHg	8.7±3.6	8.16±2.7	0.55
Cardiac output, l/min	3.92±0.85	4.20±1.18	0.67
Cardiac index, l/min/m^2	2.05±0.44	2.29±0.73	0.27
Stroke volume, mL	53.6±17.0	52.5±17.9	0.85
Stroke volume index, mL/m^2	27.9±8.8	29.1±10.8	0.73
PVR, dyn*s*cm^−5	1144.64±340.6	1107.37±501.5	0.82
SVR, dyn*s*cm^−5	1823.54±579	1705.1±456.9	0.46

Note: The parameters with significant differences are presented in bold type.

Abbreviations: E/eʹ ratio, maximum velocity of the E-wave of mitral valve inflow divided by the maximal velocity of E; DT, deceleration time; IVRT, isovolumetric relaxation time; LA, left atrium; LV, left ventricle; mPAP, mean pulmonary artery pressure; PA, pulmonary artery; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RA, right atrium; RV, right ventricle; SBP PA, systolic blood pressure in pulmonary artery; SVR, systemic vascular resistance; TAPSE, tricuspid annular plane systolic excursion.

Figure 1 Survival since the time of study initiation (n = 89).

Table 3 Cox Proportional Hazards Regression Analysis in General IPAH/HPAH Population

Parameters and significance	Parameters	Unadjusted OR (CI), Significance
Clinical characteristics
Significant	Gender (1-male, 0-female)	2.7 (1.06–6.87), P=0.038
	SBP at discharge	0.98 (0.97–1.00), P=0.041
	Functional class (1- III–IV f.c., 0- I–II f.c.)	2.06 (1.01–4.20), P=0.046
	Ascites/pericardial effusion (1-yes, 0-no)	5.84 (2.09–16.25), P=0.001
	6MWT distance at admittance	0.996 (0.992–1.00), P=0.055
	SaO2 after 6MWT at admittance	0.95 (0.91–0.99), P=0.017
Not significant	Age	1.009 (0.975–1.044), P=0.6
	Syncope (1-yes, 0-no)	1.04 (0.39–2.82), P=0.93
	6MWT Borg score	1.15 (0.94–1.42), P=0.18
	SaO2 baseline	0.96 (0.86–1.07), P=0.45
	Duration of symptoms	1.002 (0.999–1.006), P=0.23
	6MWT distance at discharge	0.997 (0.99–1.005), P=0.47
	SaO2 after 6MWT at discharge	1.01 (0.93–1.09), P=0.84
	Iron deficit/anemia (1-yes, 0- no)	2.37 (0.21–26.5), P=0.48
	Admission SBP	0.98 (0.94–1.01), P=0.12
	Admission DBP	0.99 (0.95–1.04), P=0.86
	Admission heart rate	1.01 (0.98–1.04), P=0.49
Concomitant therapy
Significant	Warfarin therapy (1-yes, 0-no)	3.92 (1.16–13.25), P=0.028
Not significant	Loop diuretics (1-yes, 0-no)	1.44 (0.64–3.25), P=0.38
Laboratory tests
Significant	INR	1.95 (1.14–3.32), P=0.014
	NT-proBNP > 1500 pg/mL	3.55 (1.56–8.09), P=0.003
	Bilirubin level	0.98 (0.96–1.01), P=0.27
Not significant	Glomerular filtration rate	0.99 (0.96–1.02), P=0.40
	Hematocrit	16.3 (0.07–55.3), P=0.23
Systemic arterial stiffness parameters
Significant	Aorta blood pressure	0.95 (0.90–0.99), P=0.025
	CAVI	1.28 (1.02–1.61), P=0.037
	CAVI ≥ 8	2.34 (1.04–5.28), P=0.041
Not significant	PWVm	1.04 (0.74–1.47), P=0.81
	PWVe	0.95 (0.76–1.18), P=0.63
Echocardiography parameters
Significant	Left atrial area	1.04 (1.00–1.08), P=0.032
	Right atrial area	1.07 (1.03–1.12), P=0.001
	Right atrial index	1.02 (1.009–1.032), P=0.001
	Diastolic right ventricle area	1.07 (1.011–1.14), P=0.02
	TAPSE	0.90 (0.82–0.99), P=0.034
Not significant	Right ventricle thickness	1.57 (0.14–18.3), P=0.72
	Tricuspid regurgitation velocity	0.83 (0.14–4.8), P=0.84
	Calculated SBP	1.013 (0.99–1.027), P=0.074
	E/A ratio	0.81 (0.22–2.94), P=0.75
Right heart catheterization parameters
Significant	RA pressure	1.17 (1.06–1.29), P=0.001
Not significant	PAPm	0.98 (0.95–1.02), P=0.38
	PAWP	0.48 (0.08–2.95), P=0.43
	PVR	0.99 (0.99–1.001), P=0.35
	Cardiac index	0.82 (0.36–1.89), P=0.64
	Cardiac output	1.06 (0.62–1.81), P=0.83

Abbreviations: CAVI, cardio-ankle vascular index; CI, confident interval; DBP, diastolic blood pressure; OR, odds ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAPm, mean pulmonary artery blood pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RA, right atrium; SaO2, oxygen saturation; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion.

Figure 2 Kaplan–Meier survival of idiopathic pulmonary arterial hypertension patients in relation to cardio-ankle vascular index (CAVI).

Table 4 Cox Proportional Hazards Regression Model Analysis in General IPAH/HPAH Population

	Models	OR (CI), Significance
CAVI adjusted to demographic and laboratory data with statistical significance at univariate analysis	Gender (1 - male, 0 - female)	2.33 (1.11–8.02), 0.033
	Functional class (1- III–IV f.c., 0 - I–II f.c.)	1.88 (1.36–2.6), 0.005
	Ascites/pericardial effusion (1 - yes, 0 - no)	7.9 (1.84–23.9), 0.005
	SBP at discharge	0.97 (0.95–0.99), 0.002
	International Normalization Ratio	2.61 (1.08–6.29), 0.033
	NT-proBNP>1500 pg/mL (1 - yes, 0 - no)	3.17 (1.17–8.59), 0.023
	6MWT at admittance	0.99 (0.985–0.998), 0.008
	SaO2 after 6MWT at admittance	0.92 (0.87–0.97), 0.002
	CAVI	1.27 (1.08–1.95), 0.04
	Warfarin (1 - yes, 0 - no)	2.88 (0.96–7.25), 0.32
CAVI adjusted to EchoCG parameters with statistical significance at univariate analysis	Right atrial area	1.1 (1.02–1.19), 0.018
	Left atrial area	(0.86–1.19), 0.88
	TAPSE	0.97 (0.75–1.25), 0.78
	Diastolic right ventricle area	1.093 (1.005–1.19), 0.037
	CAVI	1.70 (1.073–2.69), 0.024
CAVI adjusted to RHC parameter with statistical significance at univariate analysis	Right atrial pressure	1.17 (1.06–1.29), 0.001
	CAVI	1.15 (1.009–1.48), 0.049
Multivariate analysis	Gender (1 - male, 0 - female)	2.21 (1.1–10.0), 0.048
	Functional class (1 - III–IV f.c., 0 - I–II f.c.)	1.33 (1.11–1.99), 0.048
	Ascites/pericardial effusion (1 - yes, 0 - no)	5.8 (0.88–7.2), 0.076
	SBP at discharge	0.99 (0.97–1.006), 0.17
	International Normalization Ratio	2.54 (0.95–6.7), 0.062
	NT-proBNP>1500 pg/mL (1 - yes, 0 - no)	2.2 (1.063–7.6), 0.021
	6MWT at admittance	0.99 (0.99–1.004), 0.36
	SaO2 after 6MWT at admittance	0.87 (0.79–0.96), 0.008
	Right atrial area	1.017 (0.95–1.42), 0.85
	Right atrial pressure	1.21 (1.07–1.36), 0.003
	CAVI	1.13 (1.001–1.871), 0.05

Note: The significant parameters are presented in bold type.

Abbreviations: CAVI, cardio-ankle vascular index; CI, confident interval; OR, odds ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SBP, systolic blood pressure; SaO2, oxygen saturation; TAPSE, tricuspid annular plane systolic excursion.

Table 5 The Comparison of Different Arterial Stiffness Measurement Methods (Adapted with T. Miyoshi and H. Ito)⁴⁵

Methods	Dependency on Blood Pressure	Sensor	Measured Arteries
PWV carotid-femoral	Dependent	Applanation tonometry	Segment (carotid, ascending, descending, abdominal aorta, femoral)
PWV ankle-brachial	Dependent	Plethysmography cuff	Segment (descending, abdominal, femoral, ankle, brachial)
PWV heart-ankle	Dependent	Plethysmography cuff	Segment (ascending, descending, abdominal aorta, femoral, ankle)
CAVI	Less dependent	Plethysmography cuff	Segment (ascending, descending aorta, abdominal, femoral, ankle)
Stiffness parameter β	Less dependent	Ultrasound	Local (only in place of probe – carotid or abdominal or femoral)

Abbreviations: PWV, pulse wave velocity; CAVI, cardio-ankle vascular index.

Miyoshi T, Ito H. Assessment of arterial stiffness using the cardio-ankle vascular index. Pulse. 2016;4(1):11–23. doi:10.1159/000445214

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