Hindawi

BioMed Research International

Volume 2018, Article ID 4606053, 10 pages
https://doi.org/10.1155/2018/4606053

Research Article
ECG Markers of Hemodynamic Improvement in Patients with
Pulmonary Hypertension

Marcin Waligóra , Anna Tyrka, Piotr Podolec, and Grzegorz KopeT

Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital in Krakow,
Pradnicka 80, Kraków, Poland
Correspondence should be addressed to Grzegorz Kopeć; [email protected]

Received 31 October 2017; Revised 2 February 2018; Accepted 27 February 2018; Published 10 April 2018

Academic Editor: Dirk Bandorski

Copyright © 2018 Marcin Waligóra et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction. Several diagnostic tests have been recommended for risk assessment in pulmonary hypertension (PH), but the
role of electrocardiography (ECG) in monitoring of PH patients has not been yet established. Therefore the aim of the study
was to evaluate which ECG patterns characteristic for pulmonary hypertension can predict hemodynamic improvement in
patients treated with targeted therapies. Methods. Consecutive patients with pulmonary arterial hypertension (PAH) or chronic
thromboembolic pulmonary hypertension (CTEPH) were eligible to be included if they had had performed two consecutive
right heart catheterization (RHC) procedures before and after starting of targeted therapies. Patients were followed up from June
2009 to July 2017. ECG patterns of right ventricular hypertrophy according to American College of Cardiology Foundation were
assessed. Results. We enrolled 80 patients with PAH and 11 patients with inoperable CTEPH. The follow-up RHC was performed
within 12.6 ± 10.0 months after starting therapy. Based on median change of pulmonary vascular resistance, we divided our
patients into two subgroups: with and without significant hemodynamic improvement. 𝑅𝑉1 , max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 , and 𝑃II
improved along with the improvement of hemodynamic parameters including PVR. They predicted hemodynamic improvement
with similarly good accuracy as shown in ROC analysis: 𝑅𝑉1 (AUC: 0.75; 95% CI: 0.63–0.84), 𝑃II (AUC: 0.67, 95% CI: 0.56–0.77),
and max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 (0.73; 95% CI: 0.63–0.82). In Cox regression only change in 𝑅𝑉1 remained significant mortality
predictor (HR: 1.12, 95% CI: 1.01–1.24). Conclusion. Electrocardiogram may be useful in predicting hemodynamic effects of
targeted therapy in precapillary pulmonary hypertension. Decrease of 𝑅𝑉1 , max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 , and 𝑃II corresponds
with hemodynamic improvement after treatment. Of these changes a decrease of 𝑅 wave amplitude in 𝑉1 is associated with better
survival.

1. Introduction Chronic overload of the right ventricle (RV) as observed

in PH leads to RV hypertrophy and dilation. This can be
Pulmonary hypertension (PH) is a severe progressive disease
reflected by several patterns in surface electrocardiogram.
characterized by narrowing and occlusion of pulmonary
Hemodynamic, autopsy, and cardiac magnetic resonance
arteries. The current treatment algorithm requires frequent
imaging (cMR) studies have shown significant correlations
assessment of the patient and escalation of therapy if low
risk status has not been achieved. Several diagnostic tests between hemodynamic burden, right ventricular hypertro-
have been recommended for risk evaluation including phys- phy, and ECG changes as reported in several studies [2–
ical examination, assessment of World Heart Organization 9]. Little is known however about whether hemodynamic
functional class (WHO-FC), 6-minute walk test (6 MWT), improvement observed in treated PH patients can be reflected
cardiopulmonary exercise testing, N-terminal pro-B type by ECG changes.
natriuretic peptide level (NT-proBNP), imaging studies, and Therefore the aim of the study was to evaluate which
right heart catheterization (RHC) [1]. Till now the role of ECG patterns characteristic for pulmonary hypertension can
electrocardiography (ECG) in monitoring of PH patients has predict hemodynamic improvement in patients treated with
not been established. targeted therapies.
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2. Methods recommended [11]: QRS duration ≥ 120 ms, with typical QRS
morphology in 𝑉1 or 𝑉2 (rsr’, rsR’, rSR’, wide and notched 𝑅),
2.1. Patients. All study participants were selected from a and 𝑆 wave duration > 𝑅 wave duration or >40 ms in I and 𝑉6 .
cohort of patients with PH diagnosed and treated in our When a pure dominant 𝑅 wave with or without a notch was
centre between June 2009 and March 2016. Patients were present in 𝑉1 , addition criterion had to be satisfied: normal 𝑅
eligible if they had pulmonary arterial hypertension (PAH) peak time in 𝑉5 and 𝑉6 but >50 ms in 𝑉1 .
or inoperable chronic thromboembolic pulmonary hyper-
tension (CTEPH) with RHC and ECG performed on the
same day at least twice: the first before starting or escalating 2.3. Right Heart Catheterization. RHC was performed in
targeted therapy and the second at least 3 months later. a supine position from the right femoral vein or right
Pulmonary hypertension was defined as a mean pulmonary internal jugular vein access using a Swan-Ganz catheter.
artery pressure (mPAP) ≥ 25 mmHg at rest as assessed by All measurements including acquisition of pressure waves
right heart catheterization. PAH was defined as precapillary were made at end expiration. Cardiac output was measured
pulmonary hypertension (pulmonary artery wedge pressure using the Fick direct oxygen consumption method. Blood
≤ 15 mmHg) with pulmonary vascular resistance > 3 Wood oxygen saturation was measured with CO-oximeter OSM3
units in the absence of other causes of precapillary PH (Radiometer, Copenhagen, Denmark). Cardiac index (CI)
such as lung diseases, chronic thromboembolic pulmonary was calculated as cardiac output divided by body surface
hypertension, or other rare diseases [1]. CTEPH was defined area (BSA). BSA was calculated from the Mosteller formula
as precapillary pulmonary hypertension (pulmonary artery [12]. Pulmonary vascular resistance (PVR) was calculated
wedge pressure ≤ 15 mmHg) after at least 3 months of effective as the difference between mean pulmonary arterial pressure
anticoagulation with a presence of mismatched perfusion (mPAP) and pulmonary artery wedge pressure divided by
defects on lung scan or multidetector CT angiography [1]. The cardiac output. Based on a median change of PVR in all study
operability assessment in all CTEPH patients was performed patients we distinguished two subgroups: with and without
by a multidisciplinary CTEPH team. Both treatment-naive hemodynamic improvement.
patients (patients who have not been previously treated with
therapies specific for pulmonary arterial hypertension) and 2.4. Statistics. Continuous variables are reported using
patients already treated with PAH targeted medications could means and standard deviations. Categorical variables are
have been included. Main exclusion criteria were age < 18 described as counts and percentages. Continuous variables
years and lack of informed consent. Clinical assessment were compared using the Student 𝑡-test or Mann–Whitney
included demographic information, patient’s medical history, 𝑈 test when appropriate. The 𝜒2 -test was used to compare
NT-proBNP, 6 MWT distance (6 MWD), assessment of the categorical variables. McNemar’s test was used to compare
WHO-FC, resting 12-lead ECG, and RHC. Patients were paired data of meeting right ventricular hypertrophy criteria
treated with PAH specific drugs according to European Soci- before and after addition of targeted therapy. The Bonferroni
ety of Cardiology (ESC) guidelines [1] and local standards. correction was applied when changes in several ECG patterns
All-cause mortality was ascertained by data collection (1) were compared between patients with and without hemo-
from medical registry of hospital, (2) from the Department dynamic improvement. The relationship between changes
of Nationals’ and Foreigners’ Affairs, or (3) through phone of ECG and hemodynamics was estimated by Pearson or
follow-up. Patients were enrolled between June 2009 and Spearman correlation tests. Several receiver-operating char-
March 2016 and the observation period was extended until acteristics (ROC) curves were drawn to compare the accuracy
July 2017. The baseline assessment was at the time of RHC of changes in different ECG patterns in predicting hemo-
which resulted in diagnosis of PH or escalation of targeted dynamic improvement. Univariate Cox regression analysis
therapy. The study protocol conforms to the ethical guidelines was used to assess significant associations between changes
of the 1975 Declaration of Helsinki and was approved by in ECG and survival. Statistical analysis was performed with
the institutional ethics committee. Informed consent was Statistica PL software [Dell Inc. (2016), Dell Statistica (data
obtained from each patient before starting the study. analysis software system), version 13; software.dell.com] and
MedCalc Statistical software version 16.8 (MedCalc software
2.2. Electrocardiography. A 12-lead standard ECG (10 mm = bvba, Ostend, Belgium; https://www.medcalc.org; 2016). The
1 mV, 25 mm/s) was acquired in a supine position during significance level was set at alpha level of 0.05.
quiet respiration. For the purpose of the present study we
assessed several parameters proposed by American College 3. Results
of Cardiology Foundation and the Heart Rhythm Society
(AHA/ACCF/HRS) [10] to diagnose RV hypertrophy. We 3.1. Patients. Between June 2009 and March 2016, 158 patients
assessed quantitative parameters: 𝑅𝑉1 , 𝑅 : 𝑆𝑉1 , 𝑆𝑉5 , 𝑆𝑉6 , 𝑅aVR , were diagnosed with PAH and 46 with CTEPH. Among them
𝑆𝑉1 , 𝑅𝑉5,6 , 𝑅 : 𝑆𝑉5 , 𝑅 : 𝑆𝑉6 , 𝑅 : 𝑆𝑉5 to 𝑅 : 𝑆𝑉1 , (𝑅I + 𝑆III ) − (𝑆I + 80 patients with PAH and 11 with inoperable CTEPH were
𝑅III ), max 𝑅𝑉1,2 +max 𝑆I,aVL −𝑆𝑉1 , 𝑅𝑉1 + 𝑆𝑉5,6 , 𝑅 peak 𝑉1 (QRS included in the present analysis. Excluded PAH patients did
duration < 0.12 sec), and 𝑃II , as well as qualitative patterns: not have follow-up RHC (Eisenmenger’s syndrome; 𝑛 = 55,
presence of QR in 𝑉1 , RSR𝑉1 (QRS duration > 0.12 sec), 𝑆 > lack of consent; 𝑛 = 2, lost to follow-up; 𝑛 = 1, premature
𝑅I,II,III , 𝑆I and 𝑄III , 𝑅 : 𝑆𝑉1 > 𝑅 : 𝑆𝑉3,4 , and negative 𝑇-waves death; 𝑛 = 12), permanent pacemaker stimulation (𝑛 =
in leads 𝑉1 –𝑉3 . Right bundle branch block (RBBB) was as 5), or insufficient quality of ECG recordings (𝑛 = 3). We
BioMed Research International 3

excluded the CTEPH patients who were referred to pul- without hemodynamic improvement are showed in Table 2.
monary endarterectomy or pulmonary balloon angioplasty. The follow-up ECG showed that after addition of PAH
Overall the study sample included 91 patients aged 52.6 ± specific therapy in the whole sample none of ECG parameters
16.4 (68.1% females). The patients had idiopathic PAH (IPAH; changed significantly. However when sample was divided into
𝑛 = 54, 59.3%), PAH associated with connective tissue patients with and without hemodynamic improvement we
disease CTD-APAH (𝑛 = 16, 17.6%), and PAH associated found differences in changes of the following parameters:
with congenital heart diseases (CHD-APAH; 𝑛 = 10, 11%) or 𝑅𝑉1 , max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 , and 𝑃II as shown in
inoperable CTEPH (𝑛 = 11, 12.1%). Patients were in WHO- Table 3 and Table S1. Changes of fulfilling these RVH criteria
FC II (𝑛 = 9, 9.9%), III (𝑛 = 61; 67%), or IV (𝑛 = 21, 23.1%) at before and after addition of targeted treatment are presented
initial assessment. Majority of patients were newly diagnosed in Figure 1. Similar observations were also present when
and treatment-naive (𝑛 = 71, 78%) and were initially treated only patients without RBBB were assessed as presented in
with a monotherapy of either phosphodiesterase-5 inhibitor Tables S2 and S3. Changes in these ECG patterns correlated
(PDE-5i) in 35 (49.2%), endothelin receptor antagonist (ERA) with changes of several hemodynamic parameters including
in 14 (17.7%), parenteral prostacyclin analogue in 10 (14.1%), ΔPVR, ΔmPAP, and ΔCI as shown in Table 4. In Figure 2.
inhaled iloprost 4 (5.6%), or calcium channel blocker in 8 we compare three ROC analyses to show how changes in dif-
(11.3%). The other patients (𝑛 = 20) were already treated ferent ECG parameters predicted significant hemodynamic
with targeted therapies: riociguat, 1 (1.1%); ERA, 4 (4.4%); improvement in ROC analysis (𝑝 = 0.56 for comparison
PDE-5i, 9 (9.9%); PDE-5i and ERA, 4 (4.4%); PDE-5i and of Δ𝑅𝑉1 and Δ max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 , 𝑝 = 0.4 for
inhaled iloprost, 1 (1.1%); and inhaled iloprost and ERA, 1 comparison of Δ𝑅𝑉1 and Δ𝑃II , and 𝑝 = 0.18 for comparison
(1.1%). In this group follow-ups were gathered after addition of Δ max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 and Δ𝑃II ).
of the following treatment: parenteral prostacyclin analogue The RBBB was diagnosed in 17 patients at baseline
in 17 (85%), PDE-5i in 1 (5%), ERA in 1 (5%), and inhaled assessment (complete in 9 and incomplete in 8 patients). In
iloprost in 1 (5%). this group we did not find any differences in changes of ECG
The follow-up RHC was performed within 12.6 ± 10.0 patterns with and without hemodynamic improvement as
months after study enrollment. The median change of pul- presented in Tables S4 and S5.
monary vascular resistance was −2.1 [−4.5; 0.7] Wood Units
which was 17% of the baseline PVR value. Based on this value, 3.3. Electrocardiography Changes and Long-Term Follow-Up.
we divided our patients into two groups: with significant During prospective observation of a mean of 27.9 ± 9.5
hemodynamic improvement (decrease of PVR ≥ 17% from months, 20 patients died (22.0%). In univariate Cox pro-
baseline value, 𝑛 = 46) and without significant hemodynamic portional hazard models, change in 𝑅𝑉1 was significantly
improvement (decrease of PVR < 17% from baseline value, associated with mortality (HR: 1.12, 95% CI: 1.01–1.24, 𝑝 =
𝑛 = 46). Baseline clinical and hemodynamic characteristics 0.02). Changes in the other criteria were not significantly
of these two subgroups were similar as shown in Table 1. associated with mortality. At follow-up 𝑅𝑉1 increased in
Patients with hemodynamic improvement had added par- 36 (39.6%) patients, decreased in 48 (52.7%) patients, and
enteral prostacyclin analogues more frequently than patients remained unchanged in 7 (7.7%) patients. We observed 12
without hemodynamic improvement [18 (39.1%) versus 9 (33.3%), 7 (14.6%), and 1 (14.3%) deaths in the respective
(20%), 𝑝 = 0.05]. No differences were observed with groups.
reference to other therapies: PDE-5 inhibitors [16 (34.5%)
versus 20 (44.4%), 𝑝 = 0.35], ERA [5 (10.9%) versus 10
(22.2%), 𝑝 = 0.15], inhaled iloprost [3 (6.5%) versus 2 4. Discussion
(4.4%) versus, 𝑝 = 0.67], or CCB [4 (8.7%) versus (8.9%),
𝑝 = 0.97]. After addition of specific treatment we found the In the present study we showed that hemodynamic improve-
following changes of hemodynamic parameters in a group ment in PAH patients treated with targeted therapy is
with and without hemodynamic improvement, respectively: reflected by favorable changes in several ECG patterns. This
mPAP −8.7 ± 10.8 mmHg (𝑝 < 0.001) and +0.8 ± 11.3 mmHg referred only to the group without RBBB. Additionally we
(𝑝 = 0.64), cardiac index +0.59 ± 0.9 l/kg/m2 (𝑝 < 0,001) showed that in this group of patients a change in amplitude of
and −0.14 ± 0.56 l/kg/m2 (𝑝 = 0.1), mRAP −2.5 ± 5.5 mmHg 𝑅 wave in 𝑉1 after targeted treatment is associated with long-
(𝑝 = 0.02) and −0.9 ± 4,2 mmHg (𝑝 = 0.45), and PVR term survival.
−5.4 ± 4.5 WU (𝑝 < 0.01) and +1.9 ± 4.8 WU (𝑝 = 0.01).
4.1. Electrocardiographic Signs of Pulmonary Hypertension.
3.2. ECG Changes after Treatment. Patients without com- Structural changes in right atrium and right ventricle such
plete or incomplete RBBB accounted for majority of the as hypertrophy or dilation as observed in PH are reflected
study group (𝑛 = 74, 81.3%). Twelve patients presented by several ECG patterns [2, 13–20]. Some of them including
atrial fibrillation during initial assessment; therefore they qR in lead 𝑉1 [21–23], 𝑝 wave amplitude in lead II [21],
did not have 𝑃 wave amplitudes calculated (6 in group resting heart rate [24], 𝑝 wave duration [25], precordial elec-
with significant hemodynamic improvement and 6 in group trocardiogram voltage (sum of 𝑅 wave in 𝑉1 and maximum
without it). Twenty-four patients had no S𝑉1 and were not 𝑆 wave amplitude in 𝑉5 or 𝑉6 ) [26], QRS duration [27],
eligible for calculations of criteria using 𝑆 wave. Baseline and QTc duration [28] have been shown to have prognostic
electrocardiographic characteristics of patients with and impact in patients with IPAH, ES, or CTEPH. Despite that,
 4

Table 1: Baseline characteristics of the study group and a comparison of patients regarding hemodynamic improvement.
Whole group No hemodynamic improvement Hemodynamic improvement 𝑝
𝑁 91 45 46
Age [years] 52.6 ± 16.4 51.3 ± 16.9 53.8 ± 15.9 0.48
Sex (females) 62 (68.1%) 32 (71.1%) 30 (65.2%) 0.55
Etiology
IPAH [𝑛, (%)] 54 (59.3%) 27 (60%) 27 (58.7%) 0.9
CTD-APAH [𝑛, (%)] 16 (17.6%) 8 (17.8%) 8 (17.4%) 0.96
CHD-APAH [𝑛, (%)] 10 (11%) 7 (15.6%) 3 (6.5%) 0.17
Inoperable CTEPH [𝑛, (%)] 11 (12.1%) 3 (6.7%) 8 (17.4%) 0.12
6MWD [m] 325.5 ± 105.9 328.3 ± 114.8 322.6 ± 97.3 0.8
NT-proBNP [pg/mL] 2608.3 ± 3139.5 2397.5 ± 2358.9 2824.0 ± 3792 0.52
WHO-FC [mean ± SD] 3.08 ± 0.57 3.0 ± 0.58 3.15 ± 0.55 0.2
RHC:
mRAP [mmHg] 6.8 ± 4.6 6.4 ± 3.8 7.3 ± 5.4 0.39
PAWP [mmHg] 8.1 ± 3.8 8.5 ± 4.0 7.9 ± 3.6 0.47
SpO2 in Ao [%] 91.5 ± 7.3 91.5 ± 7.3 91.6 ± 7.5 0.94
SpO2 in PA [%] 59.7 ± 10.7 59.7 ± 11.7 58.7 ± 9.9 0.99
CI [l/min/m2 ] 1.97 ± 0.59 1.97 ± 0.63 1.97 ± 0.55 0.98
PVR [WU] 14.4 ± 8.3 15.7 ± 9.2 13.2 ± 7.1 0.15
Time between consecutive RHC procedures 12.6 ± 10.0 11.3 ± 8.2 13.9 ± 11.4 0.23
Abbreviations. IPAH: idiopathic pulmonary arterial hypertension; CTD-APAH: pulmonary arterial hypertension associated with connective tissue disease; CHD-APAH: pulmonary arterial hypertension associated
with congenital heart disease; CTEPH: chronic thromboembolic pulmonary hypertension; 6MWD: 6-minute walking test distance; NT-proBNP: N-terminal pro-B type natriuretic peptide level; WHO-FC: World
Health Organization functional class; RHC: right heart catheterization; mRAP: mean right atrial pressure; PAWP: pulmonary artery wedge pressure; SpO2 : oxygen saturation; Ao: aorta; PA: pulmonary artery; CI:
cardiac index; PVR: pulmonary vascular resistance.
BioMed Research International
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Table 2: Baseline electrocardiography characteristics.

No hemodynamic Hemodynamic 𝑝
improvement improvement
HR [bpm] 79.0 ± 17.2 76.4 ± 16.4 0.46
Sinus rhythm [𝑛 (%)] 39 (86.7%) 40 (87.0%) 0.97
𝑅𝑉1 [mm] 6.5 ± 5.7 4.2 ± 3.0 0.02
𝑅𝑉1 > 6 mm [𝑛 (%)] 17 (37.8%) 13 (28.3%) 0.34
𝑅 : 𝑆𝑉1 [mm]1 6.9 ± 12.0 3.2 ± 4.6 0.09
𝑅 : 𝑆𝑉1 > 1.0 [𝑛 (%)] 36 (80%) 29 (63%) 0.08
𝑆𝑉5 [mm] 9.5 ± 5.5 8.6 ± 4.5 0.39
𝑆𝑉5 > 10 mm [𝑛 (%)] 17 (37.8%) 17 (37%) 0.94
𝑆𝑉6 [mm] 6.5 ± 4.6 6.1 ± 3.8 0.64
𝑆𝑉6 > 3 mm [𝑛 (%)] 33 (73.3%) 35 (76%) 0.76
𝑅aVR [mm] 3.2 ± 2.3 2.5 ± 2.1 0.17
𝑅aVR > 4 mm [𝑛 (%)] 9 (20%) 5 (10.9%) 0.62
𝑆𝑉1 [mm] 2.6 ± 4.0 2.8 ± 3.4 0.78
𝑆𝑉1 < 2 mm [𝑛 (%)] 29 (64.4%) 26 (56.5%) 0.44
𝑅𝑉5,6 [mm] 7.9 ± 4.3 7.7 ± 3.3 0.83
𝑅𝑉5,6 < 3 mm [𝑛 (%)] 3 (6.7%) 3 (6.5%) 0.98
𝑅 : 𝑆𝑉5 [mm] 1.3 ± 1.0 1.8 ± 2.7 0.25
𝑅 : 𝑆𝑉5 < 3 mm [𝑛 (%)] 15 (33.3%) 12 (26%) 0.45
𝑅 : 𝑆𝑉6 [mm] 1.9 ± 1.9 2.7 ± 4.5 0.31
𝑅 : 𝑆𝑉6 < 3 mm [𝑛 (%)] 1 (2.2%) 4 (8.7%) 0.18
𝑅 : 𝑆𝑉5 to 𝑅 : 𝑆𝑉1 [mm]1 3.0 ± 6.4 6.4 ± 19.4 0.35
𝑅 : 𝑆𝑉5 to 𝑅 : 𝑆𝑉1 < 0.04 [𝑛 (%)]1 1 (2.2%) 1 (2.2%) 1
(𝑅I + 𝑆III ) − (𝑆I + 𝑅III ) [mm] −8.8 ± 9.5 −5.3 ± 9.9 0.1
(𝑅I + 𝑆III ) − (𝑆I + 𝑅III ) < 15 mm 0.99
44 (97.8%) 45 (97.8%)
[𝑛 (%)]
max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1
13.5 ± 11.3 9.2 ± 7.2 0.03
[mm]
max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 > 0.96
36 (80%) 37 (80.4%)
6 mm [𝑛 (%)]
𝑅𝑉1 + 𝑆𝑉5,6 [mm] 16.3 ± 9.7 12.8 ± 6.1 0.05
𝑅𝑉1 + 𝑆𝑉5,6 > 10.5 [𝑛 (%)] 33 (73.3%) 29 (63%) 0.29
𝑅𝑉1 peak [mm] 40.5 ± 13.8 38.8 ± 20.6 0.54
𝑅 peak 𝑉1 > 35 msec in baseline1 0.75
21 (65.6%) 21 (61.2%)
[𝑛 (%)]
𝑃II [mm]3 1.48 ± 0.6 1.7 ± 0.8 0.29
𝑃II > 0,25 mV [𝑛 (%)]3 1 (2.6%) 5 (12.2%) 0.11
Qualitative patterns:
qR in 𝑉1 [𝑛 (%)] 21 (46.7%) 17 (40%) 0.35
RSR𝑉1 (QRS duration > 0.12 sec) 3 (6.7%) 4 (8.7%) 0.72
𝑆 > 𝑅 in I 34 (75.6%) 26 (56.5%) 0.06
𝑆 > 𝑅 in II 12 (26.7%) 8 (17.4%) 0.29
𝑆 > 𝑅 in III 7 (15.6%) 9 (15.6%) 0.62
𝑆I and 𝑄III 25 (55.6%) 26 (56.5%) 0.93
𝑅 : 𝑆𝑉1 > 𝑅 : 𝑆𝑉3,4 20 (64.5%) 20 (55.6%) 0.46
Negative 𝑇-wave 𝑉1 through 𝑉3 25 (55.6%) 27 (58.7%) 0.76
1
Calculated for patients who had all required waves present; 2 calculated according to guidelines, only for patients with QRS < 120 msec; 𝑛 = 32 and 𝑛 = 34,
respectively; 3 calculated only for patients in sinus rhythm; 𝑛 = 39 and 𝑛 = 40, respectively.
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Table 3: Changes of quantitative electrocardiographic parameters after PAH specific treatment.

No hemodynamic Hemodynamic 𝑝∗
improvement improvement
Δ𝑅𝑉1 [mm] +1.38 ± 3.9 −0.82 ± 2.0 0.002
Δ𝑅 : 𝑆𝑉1 [mm] −1.0 ± 4.91 −0.6 ± 1.41 1
Δ𝑆𝑉5 [mm] +0.17 ± 4.7 −1.1 ± 4.0 1
Δ𝑆𝑉6 [mm] +1.3 ± 5.6 −0.91 ± 3.9 0.45
Δ𝑅aVR [mm] −0.1 ± 2.0 −0.7 ± 1.9 1
Δ𝑆𝑉1 [mm] −0.46 ± 3.0 −0.48 ± 2.7 1
Δ𝑅𝑉5,6 [mm] −0.7 ± 4.4 0 ± 3.1 1
Δ𝑅 : 𝑆𝑉5 [mm] −0.2 ± 1.2 +0.2 ± 1.2 1
Δ𝑅 : 𝑆𝑉6 [mm] −0.8 ± 1.9 +0.3 ± 2.8 0.6
Δ𝑅 : 𝑆𝑉5 to 𝑅 : 𝑆𝑉1 [mm] −1.6 ± 4.01 +1.2 ± 4.91 1
Δ(𝑅I + 𝑆III ) − (𝑆I + 𝑅III ) [mm] −2.1 ± 6.9 +0.9 ± 4.1 0.2
Δ max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 [mm] +3.4 ± 7.4 −1.0 ± 4.6 0.002
Δ𝑅𝑉1 + 𝑆𝑉5,6 [mm] +1.7 ± 6.7 −1.9 ± 4.3 0.06
Δ𝑅 peak 𝑉1 [mm] −2.9 ± 22.22 −11.3 ± 23.42 1
Δ𝑃II +0.5 ± 1.0 −0.1 ± 0.7 0.03
1
Calculated for patients who had all required waves present; 2 calculated according to guidelines, only for patients with QRS < 120 msec; 𝑛 = 32 and 𝑛 = 34,
respectively. ∗ 𝑝 values were mathematically adjusted using Bonferroni correction for multiple comparisons.

(%)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0
28.3% p = 0.02
+ max S）,；６， RV1 > 6 ＧＧ

HI
13.0%

n-HI 37.8% p = 0.1

51.1%
− SV1 > 6 ＧＧ

HI 80.4% p = 0.02
Ｇ；Ｒ RV1,2

63.0%

n-HI 80.0% p = 0.69

84.4%
12.2%
P）） > 2.5 ＧＧ

HI p = 0.25
5.1%

n-HI 2.6% p = 0.04

21.1%

Baseline
Follow-up
HI: patients with hemodynamic improvement
n-HI: patients without hemodynamic improvement

Figure 1: Changes of fulfilling right ventricular hypertrophy criteria in a study group before and after addition of targeted treatment.

little is known about dynamics of ECG changes during the 4.2. Correlations between ECG and Hemodynamics in PAH.
course of the disease. In a single study of Tonelli et al. Only few studies have evaluated the relationship between
[29] electrocardiograms were assessed at time of diagnosis surface ECG and hemodynamics in PH. The first study
of pulmonary hypertension and before death. The study was conducted before the era of PAH specific treatment by
showed that some ECG parameters altered as the disease Kanemoto in 47 patients with IPAH [8]. In that study the
progressed. There was an increase in median heart rate; 𝑅 : amplitude of 𝑅𝑉1 and 𝑅 : 𝑆𝑉1 correlated with the pulmonary
𝑆𝑉1 ratio; and duration of PR interval, QRS complex, and QTc. artery systolic pressure (𝑟 = 0.46, 𝑝 < 0.01, and 𝑟 =
Favorable dynamics of electrocardiogram was also shown in 0.50, 𝑝 < 0.01, resp.), and an amplitude of 𝑅𝑉1 > 1.2 mV
our study, but only in the group of patients with significant indicated a pulmonary artery systolic pressure of more than
hemodynamic improvement. On the other hand, patients in 90 mmHg with a sensitivity of 94% and a specificity of 47%.
whom we did not observe hemodynamic improvement ECG Additionally, amplitude of the 𝑅𝑉5 (𝑟 = 0.46, 𝑝 < 0.01), 𝑅𝑉6
parameters worsened. (𝑟 = 0.46, 𝑝 < 0.01), 𝑅 : 𝑆𝑉5 (𝑟 = 0.39, 𝑝 < 0.01), and 𝑅 : 𝑆𝑉6
BioMed Research International 7

Table 4: Correlation between changes in ECG criteria and hemodynamic variables.

ΔPVR ΔmPAP ΔCI

𝑅 𝑝 𝑅 𝑝 𝑅 𝑝
Δ𝑅𝑉1 [mm] 0.33 0.002 0.21 0.05 −0.23 0.03
Δ max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 [mm] 0.33 0.002 0.26 0.01 −0.31 0.004
Δ𝑃II [mm] 0.23 0.04 0.13 0.26 −0.25 0.03

100

80

60
Sensitivity

40

20

0
0 20 40 60 80 100
100 − Ｍpecificity

RV1 > 6 ＧＧ
Ｇ；Ｒ RV1,2 + max S）,；６， − SV1 > 6 ＧＧ
P）） > 2.5 ＧＧ

Figure 2: Electrocardiographic predictors of hemodynamic improvement. Δ𝑅𝑉1 (AUC: 0.75, 95% CI: 0.63–0.84, 𝑝 = 0.0005), Δ max 𝑅𝑉1,2 +
max 𝑆I,aVL − 𝑆𝑉1 (AUC: 0.73, 95% CI: 0.63–0.82, 𝑝 < 0.0001), and Δ𝑃II (AUC: 0.67, 95% CI: 0.56–0.77, 𝑝 = 0.007).

(𝑟 = 0.48, 𝑝 < 0.01) correlated with cardiac index. In another and normalization of negative 𝑇𝑉1–𝑉3 were observed 1 month
study Cheng at al. assessed the relationship between ECG after PEA. Additional changes such as increase of 𝑆𝑉1 ,
patterns and hemodynamics in 194 IPAH patients [7]. The increase of 𝑅 : 𝑆𝑉6 , and decreased prevalence of 𝑆I 𝑄III pattern
study showed correlations between 𝑃II and mPAP (𝑟 = 0.35, were observed at 1-year follow-up [30]. Of these changes only
𝑝 ≤ 0.001) and CI (𝑟 = −0.22, 𝑝 = 0.002); 𝑅𝑉1 and mPAP a decrease in 𝑃II correlated with lowering of mPAP and PVR.
(𝑟 = 0.36, 𝑝 ≤ 0.001); 𝑆𝑉6 and mPAP (𝑟 = 0.26, 𝑝 = 0.03) and In another study of 30 patients who underwent percutaneous
CI (𝑟 = −0.22, 𝑝 = 0.003). These studies made the background pulmonary valve implantation due to severe RVOTO, the
for the hypothesis that ECG can be a valuable tool to monitor improvement in some ECG patterns such as reduction of
hemodynamics in PH. The correlations between changes in 𝑅aVR , 𝑅𝑉1 , 𝑆𝑉5 , 𝑆𝑉6 , and Sokolow–Lyon index correlated with
Δ𝑅𝑉1 , Δ max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 , and Δ𝑃II and hemody- regression in RV mass and volume [9].
namic parameters were relatively low. Therefore other factors
modifying this relationship should be considered, such as 4.4. Changes of ECG after Targeted Treatment for PAH.
diverse dynamics of reversed RV remodeling in response to So far, only two studies have assessed ECG changes after
improving hemodynamics in individual patients. PAH targeted therapy. In first of them Henkens et al. [31]
assessed the relationship between hemodynamic response to
4.3. ECG Changes after Mechanical Reduction of Right Ventri- treatment and changes of selected ECG parameters such as
cle Overload. ECG changes after reduction of right ventricu- heart rate, 𝑃 wave amplitude, QRS axis and duration, and 𝑇
lar overload were well shown in CTEPH patients treated with wave axis in 81 PAH patients. Hemodynamic response was
pulmonary endarterectomy (PEA) and in patients operated defined as a decrease of PVR to less than 500 dyne⋅s⋅cm−5 .
for right ventricular outflow tract obstruction (RVOTO). Within 13.1 months of treatment, the responders had lower
In one cohort of 99 patients with CTEPH who underwent values of heart rate and 𝑃 wave amplitude, less rightwards
pulmonary endarterectomy (PEA), the decrease of 𝑃II , 𝑅𝑉1 oriented QRS axis, and more rightwards 𝑇 wave axis than
8 BioMed Research International

the nonresponders. However in another small study of 6. Conclusions

36 PAH patients, changes in none of the assessed ECG
patterns (heart rate, QRS duration, calculated QT inter- Electrocardiogram may be useful in predicting hemody-
val, premature ventricular contractions, right axis devia- namic effects of targeted therapy in precapillary pulmonary
tion, right bundle branch block, and some measurements hypertension. Decrease of 𝑅𝑉1 , max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 ,
of right ventricular hypertrophy) predicted hemodynamic and 𝑃II correspond with hemodynamic improvement after
improvement [32]. The aforementioned studies analyzed treatment. Of these changes a decrease of 𝑅 wave amplitude
only a few selected ECG criteria and each of them showed in 𝑉1 is associated with better survival.
different results. In the present paper we focused on a set
of ECG parameters indicating RV overload which were Conflicts of Interest
recommended for clinical use in the AHA/ACCF/HRS guide-
lines [10]. We showed that among them only 𝑅𝑉1 , 𝑃II , and The authors declare no competing financial interests.
Δ max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 are vulnerable to signifi-
cant changes when hemodynamics of pulmonary circulation
improves. We showed that among them only 𝑅𝑉1 , 𝑃II , and Supplementary Materials
Δ max 𝑅𝑉1,2 + max 𝑆I,aVL − 𝑆𝑉1 differentiated patients with In supplementary Table S1 we showed how the following ECG
and without hemodynamics improvement as presented in parameters changed after PAH specific treatment in patients
Table 3. with and without significant hemodynamic improvement:
In previous studies on the association between ECG qR𝑉1 , RSR𝑉1 , 𝑆 > 𝑅 in I, 𝑆 > 𝑅 in II, 𝑆 > 𝑅 in III, 𝑆I
changes and hemodynamics in PAH both patients with and 𝑄III , 𝑅 : 𝑆𝑉1 > 𝑅 : 𝑆𝑉3,4 , and negative 𝑇-wave 𝑉1
and without RBBB were enrolled. RBBB, however, changes through 𝑉3 . In supplementary Tables S2–S5 we compared
several patterns in ECG and therefore we supposed that patients with and without hemodynamic improvement with
it also could modulate the response of ECG to changing respect to changes in several ECG parameters after PAH
hemodynamics. When analyzing patients with RBBB and specific treatment separately for a subgroup with and without
without RBBB separately we found that our data refer only RBBB. Table S1: changes of qualitative electrocardiographic
to the group without RBBB and consequently that changes in parameters after PAH specific treatment in the whole sam-
the AHA/ACCF/HRS markers of RV overload are not useful ple. Table S2: changes of quantitative electrocardiographic
to monitor hemodynamics in PAH patients with RBBB. parameters after PAH specific treatment in patients without
In our previous study [2] we showed that 𝑅𝑉1 and 𝑃II were right bundle branch block. Table S3: changes of qualitative
directly related to right ventricular hypertrophy; therefore electrocardiographic parameters after PAH specific treatment
we think that changes of these parameters during treatment in patients without right bundle branch block. Table S4:
reflect reverse RV remodeling in patients with significant changes of quantitative electrocardiographic parameters after
improvement of hemodynamics. The pharmacological effec- PAH specific treatment in patients with right bundle branch
tiveness on reversal of RV hypertrophy in pulmonary hyper- block. Table S5: changes of qualitative electrocardiographic
tension has been shown in animal models [33–35] and in parameters after PAH specific treatment in patients with right
humans treated with pharmacological [36–39] and surgical bundle branch block. (Supplementary Materials)
treatment [30].

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