Vector synthesis high-resolution electrocardiography, atrial natriuretic peptide and N-terminal prohormone brain natriuretic peptide for estimation of cardiac load in pregnancy.

AIM: We analyzed atrial natriuretic peptide (ANP), N-terminal pro-brain natriuretic natriuretic peptide (NT-proBNP) and vector synthesis high-resolution electrocardiography (ECG), to estimate cardiac load with circulatory dynamic change from pregnancy through the post-partum period.
METHODS: The subjects were singleton pregnant women (n = 19), who were divided into three stages: stage 1, 34-36 weeks of gestation; stage 2, 2-6 post-partum days; and stage 3, 1-3 months after delivery. Vector synthesis high-resolution ECG, ANP and NT-proBNP were analyzed for all subjects.
RESULTS: A pregnant woman with massive uterin liomyoma expressed largest the corrected recover time (RTc) dispersion in I + II of tow Dimensional (2D) color distribution map ANP and NT-proBNP were significantly higher in stage 2 than in stages 1 and 3.
CONCLUSIONS: ANP, NT-proBNP and vector synthesis high-resolution ECG there might be able to evaluate cardiac load of normal pregnancy.

Introduction

Circulating plasma and the circulating blood volume begin to increase at 6 weeks and at 10–12 weeks of gestation, respectively. An approximately 33% increase occurs at 21–24 weeks of gestation, compared with blood volume before pregnancy. The blood volume increases to its maximum of 45–50% at approximately 32 weeks of gestation.1, 2 The volume then becomes constant or slowly increases.3 With these changes in the circulating blood volume, right heart afterload may be triggered by pregnancy‐associated physiological events such as maternal fat accumulation, increased extracellular fluid due to elevated blood progesterone, pressure on peripheral blood vessels, and lower blood flow congestion. Peripartum cardiomyopathy and takotsubo cardiomyopathy rarely develop in the perinatal period – they occur primarily in the early post‐partum phase – but these conditions result in poor outcomes in some patients.4 Causes include reaction to deviant circulatory load in pregnancy, pregnancy‐induced hypertension, and pulmonary edema (a side‐effect of ritodrine hydrochloride). Its prediction and predictors, however, have not been clarified. Thus, we focused on items related to the evaluation of maternal cardiac volume load in publicly funded prenatal checkups: high‐resolution electrocardiograms (ECG), and peptide hormones secreted by the heart. The aim of the present study was therefore to perform detailed evaluation of cardiac load in normal pregnant women without complications such as hypertension and tocolytic therapy with ritodrine hydrochloride, using vector synthesis high‐resolution ECG.

In 2007, Nakai et al. developed an original vector synthesis 187‐channel high‐resolution ECG based on the vector projection theory by Frank,5 and reported that cardiomyopathy, cardiac load, and fetal ECG can be non‐invasively evaluated using this device.6, 7, 8, 9 The traditional ECG is displayed as a weave form converted from electric potential, but vector synthesis high‐resolution ECG can present the recover time (RT) disorientation, which may be helpful in predicting which patients with non‐sustained ventricular tachycardia (VT) are likely to have inducible VT by programmed stimulation, and more, detect the spatial distribution of high‐frequency late positional and vermicular depolarization, and increased RT dispersion suggestive of a right ventricular outflow region.6 In 2013, Terata et al. succeeded in analyzing the cardiac load of pregnant and post‐partum women using vector synthesis high‐resolution ECG without echocardiography.10

The history of the natriuretic peptide hormone family, known as heart failure markers, began with the discovery of specific granules in guinea pig atrial cells by Krich in 1956. In 1984, Kangawa and Matsuo isolated and identified atrial natriuretic peptide (ANP), which consists of 28 amino acids, from the human atrium.11 BNP hormone is separate from the N‐terminal part of pro hormone termed NT‐proBNP.12 The first measurement of NT‐proBNP was reported by Hunt.13 In this study, we try to analyze nobinvasive vector systhesis high resolution ECG, ANP and NT‐pro BNP value for evaluate from normal pregnancy to postpartum.

Methods

Patients

Normal singleton pregnant women (n = 19) attending the outpatient clinic of the gynecology department or who were admitted to the gynecology ward of Iwate Medical University Hospital (Morioka, Japan) and could be followed between November 2014 and July 2015, were enrolled in the present study. All patients provided written consent. Iwate Medical University Ethics Committee approved this study on 1 May 2014 (approval number H26–20). We classified 34–36 weeks of gestation as stage 1; 2–6 days after delivery as stage 2; and 1–3 months after delivery as stage 3.

Subject characteristics

The following patient data were recorded: age, history of pregnancy, examination at age of gestation, body mass index (BMI), blood pressure, height (cm)/fundus of the uterus (cm) ratio, gestation at delivery, neonatal birth weight and blood loss during lobar.

Peptide hormone measurement

For ANP and NT‐proBNP measurement, blood was collected from the vein into tubes containing ethylenediamine tetra‐acetic acid. The collected blood into tubes containing ethylenediamine tetra‐acetic acid was centrifuged at 4°C at × 3000g for 10 min and the supernatants were stored in polypropylene tubes at −30°C until assayed. ANP and NT‐proBNP were measured on electrochemiluminescence immunoassy.

Vector synthesis high‐resolution ECG

The set up consists of a laptop, input box containing a high‐amplitude/high‐resolution amplifier (IB‐81, Fukuda Denshi), and original software to analyze digital ECG signals (ECG Manager; ICS Iwate, Morioka, Japan). The minimum resolution was 0.076 μV, and the input signal sampling frequency was 2 kHz. Silver–silver chloride magnet electrodes (Magne Lode TE‐18‐5, Fukuda Denshi) were used. With regard to vector synthesis high‐resolution ECG indices, X‐Y‐Z lead ECG were averaged and processed through a band‐pass filter (finite impulse response [FIR] type, 45–200 Hz), and filtered QRS (fQRS) was measured in vector magnitude waveforms. The inflection points of the P, QRS, and T waves were determined using differentiation.6, 7, 8, 14 From lead vectors corresponding to the center electrode and 187 electrodes on the body surface (Fig. 1), a 187‐channel ECG was synthesized, current density determined, and a “D distribution map of RTc dispersion representing the variation of the repolarization time was prepared (Fig. 2).6, 7 Spatial distribution of the variation in heart muscle repolarization time can be evaluated using this map. The map divide four sections that I + II according to the right heart.

Figure 1

Vector‐projected property for 187 fixed‐positions on a torso surface model: 11 parallel, equally spaced transverse levels with 2‐in. spacing between the levels. Level 5 coincides with the second intercostal space and level 6 coincides with the center of the heart. A–Q, intersection with each transverse level of radial lines separated by equal angles of 11.25° emanating from the longitudinal anatomic axis of the torso. A/D, analogue–digital conversion circuit; F, left lower body; L, left upper arm; PC, personal computer; R, right upper arm; RF, right lower body; V2, precordial lead of V2.

Figure 2

Two‐dimensional RTc dispersion color distribution maps in a patient with massive uterine leiomyoma (patient 4). (a) Stage 1; (b) stage 2; (c) stage 3. Repolarization time markedly varies in quadrants I + II, indicates volume overload on the right heart system.

Statistical analysis

Data were analyzed using SPSS version 23.0. (IBM, Japan). Multiple groups were analyzed using variance (ANOVA) and Kruskal–Wallis test, data are represented by mean ± S.E. and regression curves were used to analyze correlations. P < 0.05 was regarded as significant.

Results

Subject characteristics are listed in Table 1 maternal age was 34.3 ± 5.0 years old, gravidity was 1.9 ± 1.7, and parity was 1.1 ± 0.9 height (cm)/uterine fundus (cm) ratio was 0.20 ± 0.02 birthweight was 2857.1 ± 543.0 g, and loss of blood at delivery was 887.8 ± 518.2 g.

Table 1

Subject characteristics

Patient ID no.	Age (years)	Gravidity	Parity	Height/fundus ratio	Gestational age at delivery	Blood loss at delivery (g)
1	39	4	1	0.19	34 weeks 5 days	931
2	24	0	0	0.19	37 weeks 5 days	666
3	34	3	2	0.19	37 weeks 6 days	628
4	32	2	1	0.22	37 weeks 1 day	1111
5	37	1	1	0.19	38 weeks 1 day	790
6	35	4	1	0.19	37 weeks 5 days	1079
7	39	2	1	0.21	38 weeks 4 days	1563
8	23	1	1	0.19	38 weeks 1 day	1095
9	36	6	1	0.19	39 weeks 1 day	189
10	37	1	1	0.18	38 weeks 0 days	313
11	36	0	0	0.22	36 weeks 2 days	595
12	42	1	1	0.2	41 weeks 0 days	858
13	38	1	1	0.25	37 weeks 3 days	2133
14	34	1	1	0.22	38 weeks 1 day	660
15	29	3	2	0.2	39 weeks 6 days	662
16	33	1	1	0.17	39 weeks 2 days	369
17	33	5	4	0.18	40 weeks 0 days	570
18	36	1	0	0.21	39 weeks 2 days	692
19	32	2	1	0.18	38 weeks 0 days	1114

Blood pressure and BMI are listed in Table 2. Systolic/diastolic blood pressure in stages 1, 2, and 3 was 107.5 ± 2.6/66.1 ± 2.0 mmHg, 112.1 ± 15.7/71.2 ± 9.7 mmHg, and 116.4 ± 3.5/ 70.1 ± 9.6 mmHg, respectively. Stage 3 measurements were increased compared with stages 1 and 2, but the difference between systolic and diastolic blood pressure was not significant (P = 0.222 and P = 0.300). BMI was 23.9 ± 2.2, 24.0 ± 2.0, and 22.6 ± 2.6 for stages 1, 2, and 3, not significantly different between the stages (P = 0.141; Fig. 3).

Table 2

Physical characteristic of the study population

	BMI (kg/m2)			Blood pressure (mmHg)						Heart rate (beats/min)
				SBP	DBP	SBP	DBP	SBP	DBP
Patient ID no.	Stage 1	Stage 2	Stage 3	Stage 1		Stage 2		Stage 3		Stage 1	Stage 2	Stage 3
1	20.4	20.8	20.4	106	74	122	76	105	72	80	62	76
2	24.5	23.4	20.8	110	49	119	74	103	50	73	69	65
3	22.8	22.4	20.8	104	58	89	56	104	58	84	65	65
4	25.3	26.1	22.8	109	71	110	80	107	74	122	92	70
5	23.5	23.9	21.5	116	74	111	74	115	82	100	87	82
6	25.3	25.3	24	105	55	106	60	96	56	92	81	68
7	25.9	25.5	25.5	96	56	94	52	106	74	83	76	60
8	21.1	20.3	18.4	94	62	91	66	90	58	96	78	63
9	21.5	20.4	18.6	105	72	121	67	113	69	74	61	67
10	20.6	21.9	21.9	100	72	107	70	116	78	70	74	65
11	26.7	25.9	23.9	93	61	118	84	120	75	91	80	63
12	27.7	26.6	25.3	112	69	122	74	152	82	92	80	69
13	26.8	25.1	22.9	104	58	108	60	130	72	100	77	59
14	21.7	22.2	20.7	93	59	102	64	105	68	100	74	74
15	22.6	23.2	20.1	92	60	100	60	110	60	85	63	70
16	25.2	24.5	23	139	82	164	93	152	90	80	65	68
17	26.4	26	24.7	116	68	118	71	118	60	74	69	71
18	27.4	26.4	24.9	116	65	119	77	134	83	72	82	65
19	25.3	24.7	22.7	118	62	117	72	127	79	83	69	68

BMI, Body Mass Index; DBP, Diastolic Blood Pressure; SBP, Systolic Blood Pressure.

Figure 3

(a) Body mass index (BMI), (b) systolic blood pressure (SBP) and (c) diastolic blood pressure (DBP) vs stage (P = NS). Data given as SEM.

Table 3 lists the vector synthesis high‐resolution ECG indices, and ANP and NT‐proBNP.

Table 3

Change in vector synthesis high‐resolution ECG indices, ANP and NT‐pro BNP

High‐resolution ECG							Peptide hormone
	fQRS (ms)			RTc dispersion (ms)			ANP (pg/mL)			NT‐proBNP (pg/mL)
Patient ID no.	Stage 1	Stage 2	Stage 3	Stage 1	Stage 2	Stage 3	Stage 1	Stage 2	Stage 3	Stage 1	Stage 2	Stage 3
1	106	109	107	24	17	36	5	35.6	5.1	50	183	17
2	97	103	107	51	45	54	17.8	66.5	15.6	36	157	16
3	97	106	97	72	36	35	20.2	23.4	21.6	24	225	33
4	97	112	103	86	80	49	28.3	12.6	82.6	40	292	208
5	91	111	113	12	38	57	14.5	14.4	17	19	270	71
6	97	106	110	43	57	57	9	40.9	10.3	32	106	14
7	99	106	119	47	52	33	19.8	57.1	24.9	13	157	26
8	98	109	98	65	35	51	23.5	107	24.2	50	250	25
9	107	115	118	48	45	45	20.3	38.2	14	54	88	34
10	78	101	111	38	56	27	21.1	80.4	19	13	51	28
11	100	106	89	2	22	29	40.9	111	61.5	46	367	44
12	111	117	116	26	46	36	38.6	59.2	34	43	31	29
13	108	112	115	90	45	51	22.6	29.3	23.7	31	55	31
14	94	105	105	78	62	62	18.2	33.6	26.1	39	454	31
15	103	92	121	71	43	63	35	277	7.6	38	238	24
16	100	105	110	21	57	30	15.3	5	7.4	16	50	33
17	99	110	102	46	44	51	36.4	18.1	5.7	61	55	10
18	109	109	118	46	34	51	29.2	51	31.5	27	52	72
19	107	122	122	61	52	62	30.2	54.9	20.5	82	153	44

High‐resolution ECG: fQRS and RTc dispersion. Peptide hormone: ANP and NT‐proBNP.

fQRS in stages 1, 2, and 3 was 99.8 ± 1.6 ms, 108.2 ± 1.3 ms, and 109.7 ± 1.9 ms, respectively (Table 3), showing that stage 3 was significant higher compared with stages 1 and 2 (P < 0.0001). The standard value is 44 ms, reported by Wison et al.17 RTc dispersion in stages 1, 2, and 3 was 48.8 ± 5.7 ms, 45.6 ± 3.3 ms, and 46.2 ± 2.8 ms, respectively (P = 0.827). This was not significantly different between each stage (Fig. 4), but all RTc were higher than the standard value. Figure 2 shows the 2D color distribution map of RTc dispersion in a patient with massive uterine leiomyoma (patient 4). This patient did not develop pulmonary hypertension, anterior wall infarction or dilated cardiomyopathy, and she recovered well without cardiac complications after cesarean section.

Figure 4

Comparison of two serum peptide hormone levels and index of vector synthesis high‐resolution ECGA by each stages in the study. (a) arterial natriretric peptiod (ANP), (b) N‐terminal of the prohoromon brain natrinuetric peptide (NT‐proBNP), (c) filtered QRFS (fQRS), (d) corrected recovery time (RTc). The line inside boxes indicate the mean value, and the upper and lower limits of boxes and whiskers indicate the interquartie ranges. * P < 0.005.

ANP and NT‐proBNP

The standard ANP level is 43.0 pg/mL15, and the standard NT‐proBNP level is 125 pg/mL.16 ANP in stages 1, 2, and 3 was 23.2 ± 2.4 pg/mL, 58.4 ± 14.0 pg/mL, and 23.8 ± 4.4 pg/mL, respectively. Stage 2 was higher than stages 1 and 3 (P = 0.001). NT‐proBNP was 37.6 ± 4.0 pg/mL, 170.2 ± 27.5 pg/mL, and 41.6 ± 10.0 pg/mL in stages 1–3, respectively, and again stage 2 was significantly higher than stages 1 and 3 (P < 0.0001; Fig. 4). There was weak relationship between NT‐proBNP and fQRS in stage1 compare with stage 2 and 3. (r2 = 0.22, P = 0.033; Fig. 5).

Figure 5

Regression Analysis: (a) atrial natriueric peptide (ANP) vs fQRS in stage 1 (r2= 0.057, P=0.326). (b) Relationship between NT‐proBNP and fQRS in stage 1 (r2= 0.222, P=0.0042). (c) Relationship between NT‐proBNP and RTc in stage 1 (r2= 0.018, P=0.587).

Discussion

The time‐course of vector synthesis high‐resolution ECG and changes in the peptide hormone levels were investigated in the normal singleton pregnant and post‐partum women. This confirmed that cardiac volume load resulting from increased circulating blood volume flow into the right heart system rather than the left heart system in normal pregnant and post‐partum women. A characteristic of pregnant women is that the preload increases because of an increase in circulating blood volume. With regard to changes in blood pressure, the arterial smooth muscle relaxes and vascular resistance decreases in late pregnancy. The reduction in arterial vascular resistance is more marked in diastolic pressure than in systolic pressure.17 In the lower limbs, resistance increases because the pelvic vein and inferior vena cava are pressed on,18 suggesting that the pre‐ and afterloads increase during pregnancy. In addition, the uterine weight increases in a multiple pregnancy and in a massive uterine leiomyoma, which may press on the pelvic vein and thorax and further increase cardiac load. In all patients, variation in repolarization time in quadrants I + II was large throughout the period. This phenomenon suggest right cardiac load relate to increasing circulation of blood volume in pregnancy from 20 to 32 weeks of gestation.

Atrial natriuretic peptide, BNP, and NT‐proBNP are well‐known heart failure markers.19, 20 When an increase in the preload stimulates the heart muscle to extend, ANP and BNP are secreted primarily by the atrial and ventricular muscles.21 ANP secreted by the atria reflects the circulating blood volume, and BNP secreted by the ventricles primarily serves as an index of left ventricular dysfunction.22

fQRS was significantly high in stage 3 compared with stages 1 and 2; in addition, RTc dispersion in all stages was higher than the standard value. This shows that the effect of cardiac load related to conduction system that continue to postpartum. On the 2D distribution map of RTc dispersion, there was a marked variation in quadrants I + II in all three stages. ANP and NT‐proBNP levels were high in stage 2 compared with stage 1 and 3, in those fact say that right cardiac load spread to stimulate to product ANP and NT‐proBNP during pregnant, and then it may be reach to peak point at stage 2, also it could be prediction the heart frailer when a pregnant woman had sever pregnancy induced hypertension or high dose of ritodrine sulfate by intravenous infusion with bed‐rest fQRS and NT‐proBNP reflect increasing blood volume from 20 to 32 weeks of gestation, and also, induced production of NT‐proBNP with changed myocardium and conduction system of cardiac load at stage 1. Finally, it could appear index of the vector synthesis high resolution ECG and value of peptide hormone after reflection of the circulating blood volume, we think that It can be said this is a feature of the pregnant woman circulation system.

Particularly, the emphasis to say that regard to the pregnancy‐induced hypertension and long‐term bed‐rest to treat threatened premature labor with therapy of ritodrine hydrochloride is a β2 receptor stimulator has problematic side effects such as tachycardia, increased cardiac output, and peripheral vascular dilatation.23, 24 The frequency of pulmonary edema due to the side effect of ritodrine hydrochloride is only approximately 0.3%, but it is common.25 Stage 2 ANP and NT‐proBNP may be as possible indicators of cardiac load in the normal pregnancy, however we think that those phenomenon indicate that ANP and NT‐proBNP after the increasing blood volume prevent damage of myocardial. In the postpartum, circulating blood flow with pressure into the pulmonary artery, subsequently reperfuses to the left heart system through the right heart system, which may lead to persistently high NT‐proBNP value and change of RTc. This phenomenon is consistent with Marey's law. Based on the stage 3 findings, peptide hormone level normalizes with the recovery of normal circulatory dynamics in the post‐partum period, but the right ventricle may still be the center of the ECG phenomena, and improvement in the myocardial load may require time.

Interestingly, NT‐proBNP was 40 pg/mL (stage 1), 292 pg/mL (stage 2) and 208 pg/mL (stage 3) in the present patient 4 with massive uterine leiomyoma. All of these levels were higher than in the other patients, despite the fact that ANP was almost normal during the observation period. In addition, the 2D RTc dispersion color distribution map showed that the repolarization time markedly varied in quadrants I + II, indicating that volume overload burden was placed on the right heart system, although the patient recovered without cardiac complications after cesarean section. We therefore consider that NT‐proBNP has more impact than ANP as a biomarker of cardiac load. Cardiomyopathy is a group of heart diseases that involve abnormal mechanical function, which often causes ventricular hypertrophy and dilation, or abnormal electrophysiological function, or both,26 meaning that, the right heart failure is occurred by low blood pressure and low cardiac output state which according to rise of venous pressure induced pulmonary congestion, and lead to the left heart failure finally, therefore, These cases need to observe by a cardiologist for evaluation of cardiac fiction. In routine pregnancy examination, it is difficult to evaluate maternal cardiac load. This study has shown, however, that ANP, NT‐proBNP, and fQRS are involved in pregnancy‐related changes in circulatory dynamics during pregnancy and the post‐partum period in normal pregnant women.

Given that pregnant women with cardiomyopathy are rare, we did not have such patients in hospital in the study period. Therefore, we could not evaluate pathologic cardiac function of such cases. In conclusion, however, this study shows that the use of ANP, NT‐proBNP and vector synthesis high‐resolution ECG may be effective as a screening test to prevent cardiomyopathy for pregnant and post‐partum women. Particularly, the 2D RTc dispersion distribution map can be used to visualize cardiac load regions in normal pregnant and post‐partum women. Given that the present sample size was small, further study with a larger sample size and comparisons with conventional electrophysiological studies and echocardiography are required to verify the clinical usefulness of vector synthesis high‐resolution ECG for evaluating cardiac load in normal pregnant and post‐partum women before development of cardiac complications.

Disclosure

The authors declare no conflicts of interest.