Potential impact of generalized anxiety disorder on future hypertension risk: Investigating the role of psychophysiological stress pathways

Table 1 General data of patients, n (%)

Variable	GAD group (n = 96)	Non-GAD group (n = 204)	t/χ2 value	P value
Age (years)	52.3 ± 10.8	50.1 ± 11.2	1.626	0.105
Sex
Male	46 (47.9)	102 (50.0)	0.106	0.745
Female	50 (52.1)	102 (50.0)
BMI (kg/m2)	24.6 ± 3.2	24.1 ± 3.1	1.275	0.203
Smoking
Yes	22 (22.9)	56 (27.5)	0.700	0.403
No	74 (77.1)	148 (72.5)
Drinking
Yes	20 (20.8)	48 (23.5)	0.246	0.620
No	76 (79.2)	156 (76.5)
Family history of hypertension
Yes	24 (25.0)	62 (30.4)	0.920	0.338
No	72 (75.0)	142 (69.6)
Baseline SBP (mmHg)	123.4 ± 9.8	121.9 ± 10.1	1.225	0.222
Baseline DBP (mmHg)	76.8 ± 7.2	75.9 ± 7.0	1.019	0.309
Sleep quality score	9.1 ± 3.4	7.4 ± 3.1	4.153	< 0.001
Psychotropic/hypnotic meds
Yes	18 (18.8)	22 (10.8)	3.692	0.055
No	78 (81.2)	182 (89.2)	3.692	0.055
Physical activity ≥ 150 minutes/week
Yes	38 (39.6)	99 (48.5)	2.100	0.147
No	58 (60.4)	105 (51.5)	2.100	0.147
High salt intake
Yes	34 (35.4)	63 (30.9)	0.612	0.434
No	62 (64.6)	141 (69.1)	0.612	0.434
GAD-7 score	11.2 ± 3.8	2.1 ± 1.3	31.645	< 0.001

BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; GAD: Generalized anxiety disorder.

Table 2 Psychophysiological stress indicators and heart rate variability, median (P25, P75)/mean ± SD

Indicators	GAD group (n = 96)	Non-GAD group (n = 204)	t/Z value	P value
Cortisol (nmol/L)	468.2 ± 92.5	402.6 ± 85.1	4.320	< 0.001
CRP (mg/L)	2.9 (1.6, 4.8)	1.8 (1.0, 3.1)	2.892	0.004
IL-6 (pg/mL)	4.2 (3.1, 5.9)	3.1 (2.4, 4.3)	3.354	0.001
SDNN (milliseconds)	118.6 ± 28.9	136.9 ± 30.4	3.781	< 0.001
RMSSD (milliseconds)	26.4 ± 10.2	32.9 ± 11.4	3.663	< 0.001
HF (milliseconds2)	272 (188, 401)	356 (244, 510)	2.556	0.011
LF/HF	2.21 ± 0.86	1.72 ± 0.73	3.675	< 0.001

CRP: C-reactive protein; IL-6: Interleukin-6; GAD: Generalized anxiety disorder.

Table 3 Incidence of new-onset hypertension in 12 months, n (%)

Group	n	Cases of new-onset hypertension	Incidence (%)	χ2 value	P value
GAD group	96	36	37.5	44.118	< 0.001
Non-GAD group	204	14	6.9
Total	300	50	16.7

GAD: Generalized anxiety disorder.

Table 4 Comparison of clinical data, stress/inflammation, and heart rate variability indicators between the new-onset hypertension group and the non-hypertension group, mean ± SD/n (%)/median (P25, P75)

Variable	New-onset hypertension group (n = 50)	Non-hypertensive group (n = 250)	Statistical values	P value
Age (years)	57.8 ± 9.6	50.4 ± 11.0	t = 4.851	< 0.001
Sex
Male	28 (56.0)	120 (48.0)	χ2 = 1.080	0.299
Female	22 (44.0)	130 (52.0)
BMI (kg/m2)	26.1 ± 3.1	24.1 ± 3.1	t = 4.164	< 0.001
Smoking
Yes	18 (36.0)	60 (24.0)	χ2 = 3.240	0.072
No	32 (64.0)	190 (76.0)
Drinking
Yes	14 (28.0)	54 (21.6)	χ2 = 0.980	0.322
No	36 (72.0)	196 (78.4)
Family history of hypertension
Yes	20 (40.0)	66 (26.4)	χ2 = 3.780	0.052
No	30 (60.0)	184 (73.6)
GAD
Yes	36 (72.0)	60 (24.0)	χ2 = 44.118	< 0.001
No	14 (28.0)	190 (76.0)
Sleep quality score	9.8 ± 3.2	8.1 ± 3.4	t = 3.393	< 0.001
Baseline SBP (mmHg)	128.6 ± 8.7	121.6 ± 9.8	t = 5.081	< 0.001
Baseline DBP (mmHg)	78.6 ± 6.9	76.1 ± 7.1	t = 2.327	0.021
Cortisol (nmol/L)	495.3 ± 90.2	430.8 ± 92.1	t = 4.600	< 0.001
CRP (mg/L)	3.4 (2.1, 5.2)	2.0 (1.1, 3.4)	Z = 3.592	< 0.001
IL-6 (pg/mL)	4.8 (3.6, 6.4)	3.3 (2.5, 4.7)	Z = 3.848	< 0.001
SDNN (milliseconds)	112.4 ± 26.7	130.9 ± 30.1	t = 4.375	< 0.001
RMSSD (milliseconds)	25.1 ± 9.8	30.9 ± 11.0	t = 3.740	< 0.001
HF (milliseconds2)	260 (180, 390)	330 (220, 490)	Z = 2.758	0.006
LF/HF	2.30 ± 0.84	1.88 ± 0.79	t = 3.259	0.001
Psychotropic/hypnotic meds
Yes	10 (20.0)	30 (12.0)	χ2 = 2.250	0.134
No	40 (80.0)	220 (88.0)	χ2 = 2.250	0.134
Physical activity ≥ 150 minutes/week
Yes	17 (34.0)	120 (48.0)	χ2 = 3.240	0.072
No	33 (66.0)	130 (52.0)	χ2 = 3.240	0.072
High salt intake
Yes	24 (48.0)	73 (29.2)	χ2 = 6.750	0.009
No	26 (52.0)	177 (70.8)	χ2 = 6.750	0.009
GAD-7 score	10.4 ± 5.6	4.1 ± 4.3	t = 8.980	< 0.001

BMI: Body mass index; GAD: Generalized anxiety disorder; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; CRP: C-reactive protein; IL-6: Interleukin-6.

Table 5 Firth-penalized multivariable logistic regression analysis affecting new-onset hypertension

Variable	β	SE	χ2	P value	OR	95%CI
GAD (yes vs no)	0.837	0.324	6.684	0.010	2.31	1.23-4.38
Age (10 years per increase)	0.255	0.106	5.780	0.016	1.29	1.05-1.59
Male (yes vs no)	0.166	0.309	0.289	0.591	1.18	0.64-2.16
BMI (per 1 kg/m2 increase)	0.095	0.042	5.040	0.025	1.10	1.01-1.20
Smoking (yes vs no)	0.223	0.318	0.492	0.482	1.25	0.67-2.35
Drinking (yes vs no)	0.165	0.317	0.271	0.602	1.18	0.63-2.22
Sleep quality score (1 point per increase)	0.086	0.043	3.980	0.046	1.09	1.00-1.19
Baseline SBP (per 10 mmHg increase)	0.385	0.119	10.340	0.001	1.47	1.16-1.87
Family history of hypertension (with vs without)	0.372	0.301	1.525	0.217	1.45	0.80-2.62
Psychotropic/hypnotic meds (yes vs no)	0.301	0.365	0.681	0.409	1.35	0.66-2.77
Physical activity ≥ 150 minutes/week (yes vs no)	-0.412	0.294	1.961	0.161	0.66	0.37-1.18
High salt intake (yes vs no)	0.561	0.301	3.472	0.062	1.75	0.97-3.16

BMI: Body mass index; GAD: Generalized anxiety disorder; SBP: Systolic blood pressure; OR: Odds ratio; CI: Confidence interval.

Table 6 Mediating pathway and effect of generalized anxiety disorder and new-onset hypertension

Mediating pathway	Indirect effects (ab)	Bootstrap 95%CI	P value	Mediated proportion (%)
Pathway 1: GAD → cortisol ↑ → new-onset hypertension	0.106	0.028-0.214	0.008	18.0
Pathway 2: GAD → HRV composite score ↓ → new-onset hypertension	0.085	0.017-0.187	0.014	14.5
Pathway 3a: GAD → CRP ↑ → new-onset hypertension	0.035	-0.002 to 0.090	0.066	6.0
Pathway 3b: GAD → IL-6 ↑ → new-onset hypertension	0.041	0.001-0.10	0.045	7.0
Pathway 4 (chain): GAD → cortisol ↑ → HRV ↓ → new-onset hypertension	0.024	-0.001 to 0.066	0.058	4.0
Cortisol ↑ + HRV ↓ combined mediation				32.5

Heart rate variability in the mediation model refers to the prespecified standardized heart rate variability composite score; individual heart rate variability indices were not entered simultaneously to avoid multicollinearity. HRV: Heart rate variability; GAD: Generalized anxiety disorder; CI: Confidence interval; CRP: C-reactive protein; IL-6: Interleukin-6.