Search the GCU Library and find one new health care article that uses quantitative research. (article attached-heart disease)

Do not use an article from a previous assignment, or that appears in the Topic Materials or textbook.

Complete an article analysis and ethics evaluation of the research using the “Article Analysis and Evaluation of Research Ethics” template. (attached-article analysis)

While APA style is not required for the body of this assignment, solid academic writing is expected, and documentation of sources should be presented using APA formatting guidelines, which can be found in the APA Style Guide, located in the Student Success Center.

This assignment uses a rubric (attached rubric) 

Please review the rubric prior to beginning the assignment to become familiar with the expectations for successful completion. 

Rubic_Print_Format

N/A N/A

5.0%

5.0%

5.0%

5.0%

5.0%

N/A N/A

5.0%

Hypothesis is generally defined. There are some minor inaccuracies.

5.0%

5.0%

5.0%

5.0%

5.0%

5.0%

5.0%

5.0%

10.0%

5.0%

Course Code

Class Code

Assignment Title

Total Points

HLT-362V

HLT-362V-O501

Article Analysis and Evaluation of Research Ethics

140.0

Criteria

Percentage

1: Unsatisfactory (0.00%)

2: Less Than Satisfactory (65.00%)

3: Satisfactory (75.00%)

4: Good (85.00%)

5: Excellent (100.00%)

Comments

Points Earned

Content

100.0%

Article (Quantitative, APA Citation and Permalink)

5.0%

The article presented does not use quantitative research.

N/A

The article presented is based on quantitative research.

Article Citation and Permalink

Article citation and permalink are omitted.

Article citation and permalink are presented. There are significant errors. Page numbers are not indicated to cite information, or the page numbers are incorrect.

Article citation and permalink are presented. Article citation is presented in APA format, but there are errors. Page numbers to cite information are missing, or incorrect, in some areas.

Article citation and permalink are presented. Article citation is presented in APA format. Page numbers are used in to cite information. There are minor errors.

Article citation and permalink are presented. Article citation is accurately presented in APA format. Page numbers are accurate and used in all areas when citing information.

Broad Topic Area/Title

Broad topic area and title are omitted.

Broad topic area and title are referenced but are incomplete.

Broad topic area and title are summarized. There are inaccuracies.

Broad topic area and title are presented.

Hypothesis is generally defined. There are some minor inaccuracies.

Broad topic area and title are fully presented and accurate.

Problem Statement

Problem statement is omitted or incorrect.

Problem statement is referenced but is incomplete.

Problem statement is partially presented. There are inaccuracies.

Problem statement is summarized. There are some minor inaccuracies.

Problem statement is accurate and clearly summarized.

Purpose Statement

Purpose statement is omitted or incorrect.

Purpose statement is referenced but is incomplete.

Purpose statement is partially presented. There are inaccuracies.

Purpose statement is summarized. There are some minor inaccuracies.

Purpose statement is accurate and clearly summarized.

Research Questions

Research questions are omitted or incorrect.

Research questions are partially presented.

Research questions are presented and accurate.

Define Hypothesis (Or state the correct hypothesis based upon variables used.)

Definition of hypothesis is omitted. The definition of the hypothesis is incorrect.

Hypothesis is summarized. There are major inaccuracies or omissions.

Hypothesis is defined. Hypothesis is generally defined. There are some minor inaccuracies.

Hypothesis is accurate and clearly defined

Identify Variables and Type of Data for Variables

Variable type and data for variable are omitted.

Variable type and data for variable are presented. There are major inaccuracies or omissions.

Variable type and data for variable are presented. There are inaccuracies.

Variable type and data for variable are presented. Minor detail is needed for accuracy.

Variable type and data for variable are presented and accurate.

Population of Interest for Study

Population of interest for the study is omitted.

Population of interest for the study is presented. There are major inaccuracies or omissions.

Population of interest for the study is presented. There are inaccuracies.

Population of interest for the study is presented. Minor detail is needed for accuracy.

Population of interest for the study is presented and accurate.

Sample

Sample is omitted.

Sample is presented. There are major inaccuracies or omissions.

Sample is presented. There are inaccuracies.

Sample is presented. Minor detail is needed for accuracy. Page citation for sample information is provided.

Sample is presented and accurate. Page citation for sample information is provided.

Sampling Method

Sampling method is omitted.

Sampling method is presented. There are major inaccuracies or omissions.

Sampling method is presented. There are inaccuracies. Page citation for sample information is omitted.

Sampling method is presented. Minor detail is needed for accuracy.

Sampling method is presented and accurate.

Identify Data Collection

How data were collected is not identified.

How data were collected is presented but is incorrect.

How data were collected is partially presented. There are inaccuracies or omissions.

How data were collected is identified. There are minor inaccuracies

How data were collected is fully identified and accurate.

Summary of Data Collection Approach

The means of data collection are omitted.

The means of data collection are referenced. There are major inaccuracies or omissions.

The means of data collection are presented. There are inaccuracies. Page citation for sample information is omitted.

The means of data collection are summarized. Minor detail is needed for accuracy. Page citation for sample information is provided.

The means of data collection are thoroughly summarized and accurate. Page citation for sample information is provided.

Data Analysis

Data analysis is omitted.

Data analysis is incomplete. Not all types of statistical tests used for the variables are indicated. The types of statistical tests listed are incorrect or unrelated to the variables indicated.

Data analysis is summarized. Types of statistical tests used for the variables are indicated. There are inaccuracies or omissions.

Data analysis is generally discussed. Types of statistical tests used for the variables are indicated. There minor inaccuracies.

Data analysis is discussed. Types of statistical tests used for the variables are all indicated and accurate.

Summary Results of Study

Summary of the results of the study is omitted or incorrect.

The results of the study are partially presented. There are major inaccuracies or omissions. More information is needed.

The results of study are summarized. There are some inaccuracies. Some information or rationale is needed for support.

The results of study are summarized. Minor detail or information is needed for accuracy or clarity.

The results of study are well summarized. The summary is accurate and clearly represents the results of the study.

Summary Assumptions and Limitations

10.0%

Identification of assumptions and limitations by the author is omitted. Summary of potential assumptions and limitations not listed by the author is omitted or not relevant to the study.

Some assumptions and limitations from the article are identified. Other potential assumptions and limitations not listed by the author are partially presented. Significant information is needed.

Most assumptions and limitations from the article are identified. Other potential assumptions and limitations not listed by the author are summarized. There are some inaccuracies. More information or rationale is needed for support.

Assumptions and limitations from the article are identified and accurate. Potential assumptions and limitations not listed by the author are summarized. Some information or rationale is needed for support.

Assumptions and limitations from the article are identified and accurate. Potential assumptions and limitations not listed by the author are summarized. Strong rationale is provided to support summary.

Summary of Ethical Considerations

Summary of ethical considerations is omitted.

Ethical considerations related to sampling, collecting data, analyzing data, and publishing results are incomplete. There are major inaccuracies or omissions. Significant information and rationale are needed to support summary.

Ethical considerations related to sampling, collecting data, analyzing data, and publishing results are presented. There are some inaccuracies. Some information and rationale are needed to support summary.

Ethical considerations related to sampling, collecting data, analyzing data, and publishing results are summarized. The ethical considerations summarized are reasonable. Some rationale or evidence are needed to support summary.

Ethical considerations related to sampling, collecting data, analyzing data, and publishing results are clearly summarized. The ethical considerations summarized are reasonable. Strong rationale and support are provided.

Mechanics of Writing (includes spelling, punctuation, grammar, and language use)

Surface errors are pervasive enough that they impede communication of meaning. Inappropriate word choice or sentence construction is employed.

Frequent and repetitive mechanical errors distract the reader. Inconsistencies in language choice (register) or word choice are present. Sentence structure is correct but not varied.

Some mechanical errors or typos are present, but they are not overly distracting to the reader. Correct and varied sentence structure and audience-appropriate language are employed.

Prose is largely free of mechanical errors, although a few may be present. The writer uses a variety of effective sentence structures and figures of speech.

The writer is clearly in command of standard, written, academic English.

Total Weightage

100%

Article Analysis and Evaluation of Research Ethics

Article Citation and Permalink
(APA format)

Article 1

Point

Description

Broad Topic Area/Title

Problem Statement
(What is the problem research is addressing?)

Purpose Statement
(What is the purpose of the study?)

Research Questions
(What questions does the research seek to answer?)

Define Hypothesis
(Or state the correct hypothesis based upon variables used)

Identify Dependent and Independent Variables and Type of Data for the Variables

Population of Interest for Study

Sample

Sampling Method

Identify Data Collection
Identify how data were collected

Summarize Data Collection Approach

Discuss Data Analysis
Include what types of statistical tests were used for the variables.

Summarize Results of Study

Summary of Assumptions and Limitations
Identify the assumptions and limitations from the article.
Report other potential assumptions and limitations of your review not listed by the author.

Ethical Considerations

Evaluate the article and identify potential ethical considerations that may have occurred when sampling, collecting data, analyzing data, or publishing results. Summarize your findings below in 250-500 words. Provide rationale and support for your evaluation.

© 2019. Grand Canyon University. All Rights Reserved.

3

European Journal of Heart Failure (2017) 19, 88 – 97 RESEARCH ARTICL

E

doi:10.1002/ejhf.675

Determinants and prognostic implications
of the negative diastolic pulmonary pressure
gradient in patients with pulmonary
hypertension due to left heart disease
Anikó Ilona Nagy1*, Ashwin Venkateshvaran2,3, Béla Merkely1, Lars H. Lund4,5, and
Aristomenis Manouras4,5

1Heart and Vascular Center, Semmelweis University, Budapest, Hungary; 2School for Technology and Health, Royal Institute of Technology, Stockholm, Sweden; 3Sri Sathya Sai
Institute of Higher Medical Sciences, Bangalore, India; 4Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden; and 5Department of Medicine, Karolinska
Institutet, Stockholm, Sweden

Received 19 March 2016; revised 14 August 2016; accepted 8 September 2016 ; online publish-ahead-of-print 17 October 2016

Aims The diastolic pulmonary pressure gradient (DPG) has recently been introduced as a specific marker of combined
pre-capillary pulmonary hypertension (Cpc-PH) in left heart disease (LHD). However, its diagnostic and prognostic
superiority compared with traditional haemodynamic indices has been challenged lately. Current recommendations
explicitly denote that in the normal heart, DPG values are greater than zero, with DPG ≥7 mmHg indicating Cpc-PH.
However, clinicians are perplexed by the frequent observation of DPG <0 mmHg (DPGNEG), as its physiological explanation and clinical impact are unclear to date. We hypothesized that large V-waves in the pulmonary artery wedge pressure (PAWP) curve yielding asymmetric pressure transmission might account for DPGNEG and undertook this study to clarify the physiological and prognostic implications of DPGNEG.

…………………………………………………..

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Methods
and results

Right heart catheterization and echocardiography were performed in 316 patients with LHD due to primary
myocardial dysfunction or valvular disease. A total of 256 patients had PH-LHD, of whom 48% demonstrated DPGNEG.
The V-wave amplitude inversely correlated with DPG (r = −0.45, P < 0.001) in patients with low pulmonary vascular resistance (PVR), but not in those with elevated PVR (P > 0.05). Patients with large V-waves had negative and lower
DPG than those without augmented V-waves (P < 0.001) despite similar PVR (P >0.05). Positive, but normal DPG
(0 – 6 mmHg) carried a worse 2-year prognosis for death and/or heart transplantation than DPGNEG (hazard ratio
2.97; P < 0.05).

…………………………………………………………………………………………………………………………………………………

Conclusion Our results advocate against DPGNEG constituting a measurement error. We propose that DPGNEG can partially be
ascribed to large V-waves and carries a better prognosis than DPG within the normal positive range.

…………………………………………………………………………………………….

Keywords Diastolic pressure gradient • Pulmonary hypertension • V-wave

Introduction
Pulmonary hypertension (PH) is a common complication of left
heart disease (LHD). In isolated post-capillary PH, the pul-
monary arterial pressure (PAP) elevation is governed solely by
the upstream-transmitted left atrial pressure (LAP). Long-standing

*Corresponding author. Semmelweis University, Heart and Vascular Center, 68 Városmajor utca, Budapest, H-1122, Hungary. Tel: +36 20 8259738, Fax: +36 1 4586818, Email:
anychophora@gmail.com

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.. post-capillary PH may, however, lead to pathological alterations of

the pre-capillary vasculature, contributing to further PAP increase,
a state denoted as combined post- and pre-capillary PH (Cpc-PH).
Although this latter condition is clearly associated with worse
prognosis,1,2 the optimal method to distinguish these two cohorts
haemodynamically remains controversial.

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

Negative DPG in pulmonary hypertension 89

Traditionally, pulmonary vascular resistance (PVR) and transpul-
monary gradient (TPG) have been employed for discerning
Cpc-PH, both metrics bearing an established prognostic value in
PH due to LHD (PH-LHD).3,4 However, as both these markers
are influenced by LAP and stroke volume,5 their specificity has
been questioned. In recent times, the diastolic pulmonary pres-
sure gradient (DPG), considered less affected by heart failure
(HF)-induced haemodynamic changes,5 has been introduced as a
more reliable Cpc-PH index. Based on the above rationale and
study results demonstrating prognostic superiority of the DPG,6,7

the Fifth World Symposium on PH proposed that a DPG ≥7
mmHg alone should define Cpc-PH.5 However, the failure of
two recent large-scale studies to confirm the prognostic value of
DPG8,9 raised concerns regarding its use in PH-LHD.8,10 Despite
the significant prevalence of negative DPG values (DPGNEG),
reportedly varying between 10% and 50%,8,11 the physiological
background and the potential prognostic implications of DPGNEG
have not yet been investigated; rather, DPGNEG has arbitrarily been
considered to represent a measurement error.12 We hypothesized
that prominent V-waves in the pulmonary artery wedge pressure
(PAWP) recordings might account for the DPGNEG by causing
‘asymmetrical’ pressure transmission through the pulmonary
capillaries, i.e. a backward LAP wave reflection characterized by
disproportionate phasic pressure changes. We therefore under-
took the present study in order to (i) investigate the impact
of V-waves on the DPG and particularly on the occurrence
of DPGNEG; (ii) elucidate the influence of PAWP as compared
with direct LAP measurements on the DPG; and (iii) assess the
prognostic significance of DPGNEG compared with positive but
normal DPG.

Methods
Study population
The study population consisted of 316 patients. A total of 192 patients
were enrolled prospectively; 86 consecutive patients with PH due to
heart failure (HF) (denoted as PH-LHD in the following) referred for
right heart catheterization (RHC) for HF assessment between January
and December 2014 were enrolled prospectively at Karolinska Uni-
versity Hospital, while 106 consecutive patients with severe rheumatic
mitral valve stenosis (denoted as MS in the following) referred for per-
cutaneous transvenous mitral commissurotomy (PTMC) between Jan-
uary and June 2012 were enrolled again prospectively at the Sri Sathya
Sai Institute (Bangalore, India). In addition, 124 consecutive patients
with PH-LHD referred for RHC at the Karolinska University Hospital
were studied retrospectively. In all PH-LHD cases, medical treatment
had been titrated and haemodynamic stabilization achieved at the time
of examination. None of the patients included in the study presented
with acute coronary syndrome or had undergone cardiac surgery
within 1 year before enrolment. In the case of the MS cohort, sub-
jects with >1 grade mitral regurgitation, aortic valve disease, ischaemic
heart disease, AF, or hypertension were not included in the study.
In the PH-LHD cohort, no specific exclusion criteria were applied,
apart from the fact that patients with pressure tracings of inadequate
quality (i.e. that would not have allowed reliable and reproducible
identification of waveforms) were not included. A flowchart describ-
ing patient enrolment and haemodynamic grouping is provided in the .

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. Supplementary material online, Figure S1. Follow-up data were col-

lected from the Karolinska University Hospital database that is updated
centrally; patients were followed until death, cardiac transplantation,
or the end of the study period (mean time: 15.6 months). The prog-
nostic value of DPGNEG vs. positive but normal DPG was assessed. The
study was approved by the local ethics committee (registration number
2013/1991-32). All prospectively enrolled subjects provided written
informed consent. All subjects underwent transthoracic echocardiog-
raphy and RHC.

Catheterization
Right heart catheterization was performed using a 6 F balloon-tipped
fluid-filled Swan – Ganz catheter (Edwards Lifesciences, Irvine, CA,
USA) through jugular or femoral vein access. Mean right atrial pressure
(RAPM), diastolic (PAPD), mean pulmonary artery pressure (PAPM),
mean pulmonary artery wedge pressure (PAWPM), and right ventric-
ular systolic pressure (RVSP) were recorded under fluoroscopy after
calibration with the zero level set at the mid-thoracic line. All pressure
tracings were stored in a connected haemodynamic recorder and anal-
ysed offline with commercially available software (Xper Information
Management, Philips Medical Systems, The Netherlands). Importantly,
in order to ensure the uniformity of data acquisition and the standard-
ization of the study, the same investigator (A.M.) participated in RH

C

for all MS and the majority of PH-LHD patients and performed the
analysis of all waveforms at both sites. From the PAWP recordings,
the peak V- and A-wave and the PAWPM were obtained. All pressure
measurements were averaged from a minimum of five heart cycles
at end-expiration. Cardiac output (CO) was measured using Fick’s
principle. The oxygen consumption was measured breath by breath
by a dedicated gas analysis system. In 15 cases, thermodilution was
employed.

The PVR, TPG, and DPG were calculated as: PVR = (PAPM –
PAWPM)/CO; TPG = PAPM – PAWPM; and DPG = PAPD – PAWPM,
respectively. The difference between TPG and DPG (ΔPG), which
equals PAPM – PAPD, was analysed in order to investigate diagnos-
tic discrepancies by the two measures. The right ventricular stroke
work index was calculated as RVSWi = (PAPM – RAPM) × SVi × 0.0136,
where SVi denotes the stroke volume index measured as: CO/heart
rate (HR)/body surface area. In MS patients, measurements were per-
formed prior to PTMC. For full details of methods, please see the
Supplementary material online.

Simultaneous left atrial pressure
and pulmonary artery wedge pressure
assessment
In 51 MS patients, simultaneous, beat-to-beat, LAP and PAWP tracings
were obtained concurrently with RHC. Interatrial septal puncture was
performed with an 8 F Mullins’ sheath, dilator and a Brockenbrough
needle. The LAP was measured directly through the Mullins’ sheath
used during valvuloplasty. Both transducers were zeroed after careful
calibration, pressures were recorded during a 10 sec period and stored
for offline analysis.

Statistical analysis
The IBM SPSS statistics version 23.0 was used. Normality was
tested by the Kolmogorov – Smirnov test. Continuous variables were

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

90 A.I. Nagy et al.

expressed as mean ± SD or median and interquartile range. Cat-
egorical variables were expressed as absolute values and percent-
age. Comparisons of groups were performed with Mann – Whitney
rank-sum test. Correlations were tested by the Pearson’s two-tailed
test. All tests were performed at 95% confidence intervals (CIs).
A P-value of <0.05 was considered statistically significant. Receiver operator characteristic (ROC) curve analysis was performed. Sur- vival was analysed in 127 PH-LHD patients (115 retrospective, 12 prospective) with Kaplan – Meier non-parametric test and compared using a log-rank test.† Univariate and multiple Cox proportional haz- ards regression models were used to examine the effects of the DPG on patients’ survival. Age-, creatinine-, and sex-adjusted sur- vival curve estimates of the DPG were derived from stratified Cox models.

Results
Study population
Of the 316 patients enrolled, 269 (84.5%) demonstrated PH (PAPM
≥25 mmHg). Of these, 256 (MS: 37%) had PH-LHD (PAPM ≥25
mmHg and PAWPM > 15 mmHg). Demographics are presented in
Table 1. Due to the different underlying pathology, the MS and
PH-LHD groups were analysed separately. MS patients had higher
PAPM, A- and V-waves, and RVSWi compared with the PH-LH

D

group. However, DPG did not differ between the two groups
(Table 2).

V-wave influence on the diastolic
pulmonary pressure gradient
To evaluate the effect of V-waves on the DPG, we subgrouped the
cohort based on the presence of large V-waves, defined as the
V-wave exceeding the PAWPM by the arbitrary limit of >10 mmHg
as previous investigators have performed.13 In the 69 cases (45%)
with large V-waves (43 MS and 26 PH-LHD patients), the DPG
was on average negative and lower (P < 0.05) compared with those with smaller V-waves, despite similar levels of TPG, PVR, PAP, and cardiac index (P > 0.05, for all comparisons; Table 3; Supplementary
material online, Figure S2).

A significant inverse correlation between the V-wave and DPG
was evident in patients with PVR <3 Wood Units (WU) (r = −0.45, P < 0.001), both in the MS (r = −0.34, P = 0.03) and in the PH-LHD group (r = −0.46, P < 0.001). A weaker, yet statistically significant inverse correlation (r = −0.36; P = 0.01) between the V-wave and DPG was found in patients with a PVR of 3 – 7 WU. However, this relationship disappeared at higher PVR values (P > 0.05; Figure 1A).
Conversely, no association between the V-wave and TPG was
observed (P > 0.05; Figure 1B). The modest overall correlation
between the V-wave and DPG might be ascribed to the diver-
gent association of V-waves with PAPD at higher PAPM and PVR
(Figure 1D), whereas the association between V-waves and PAWPM
was essentially unaltered throughout the examined PAPM and PVR
range (Figure 1C).

†Correction added on November 23, 2016, after first online publication:
the patient count given in this sentence was corrected. ..

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.. Importantly, in patients with PVR <3 WU, the V-wave showed the strongest correlation with the ΔPG (r = 0.45, P < 0.001 for the whole cohort, r = 0.36, P = 0.005 for PH-LHD; r = 0.6, P = 0.003 for the MS group, Figure 1E), with a weaker yet significant association of both the absolute and relative V-wave value with ΔPG (r = 0.26 and r = 0.19, respectively; P < 0.05). Conversely, neither the A-wave nor the CO correlated with ΔPG (P > 0.05, in all cases).

The puzzling finding of normal DPG with concomitantly ele-
vated TPG (>12 mmHg) is not unusual. Indeed, in our study 59
patients (23%, MS: 29%), TPG and DPG demonstrated incongru-
ent diagnostics (TPG >12 mmHg, DPG <7 mmHg). Furthermore, DPGNEG with concomitantly elevated TPG (>12 mmHg) occa-
sionally occurs. In our study, we decided to quantify this discrep-
ancy by calculating ΔPG (ΔPG = TPG – DPG). The ΔPG value
that leads to discrepant Cpc-PH diagnostics between TPG and
DPGNEG is 12 mmHg. In order to examine whether the V-wave
amplitude impacted on this discrepancy, we employed ROC analy-
sis in patients with PVR <3 WU. The association between ΔPG and V-wave amplitude is presented in Figure 1E. At an optimal cut-off limit of 30.5 mmHg, V-wave yielded a sensitivity of 85% and a specificity of 70% [area under the curve (AUC) 0.80, 95% CI 0.72 – 0.88; P < 0.001) for the identification of ΔPG >12 mmHg
(Supplementary material online, Figure S3). For the whole cohort of
patients with PVR <7 WU, the corresponding figures were: AUC 0.73, P < 0.003; 95% CI 0.61 – 0.84 at an optimal cut-off limit of the V-wave of 31.5 mmHg.

In an attempt to investigate potential non-invasive and clinical
determinants of the V-wave amplitude, left atrial end-systolic
volume index, LV mass index, internal LV dimensions, as well as
the available clinical variables were tested. None of the tested
variables, however, was associated with the V-wave (P > 0.05 in all
cases).

Negative diastolic pulmonary pressure
gradient values
In total, 123 patients (48%) demonstrated DPGNEG (median −3
mmHg; interquartile range −5 to −2 mmHg) with higher preva-
lence in the MS compared with the PH-LHD group (55% vs. 44%,
P < 0.05). MS patients had significantly higher V-waves (P < 0.001, Table 2). When the whole study population was considered, patients with DPGNEG showed significantly larger V-waves and lower PAPM, RAPM, PVR, and TPG values, whereas the PAWPM and cardiac index levels were comparable with those with positive DPG (Table 4).

Assuming that pre-capillary changes differ between positive DPG
and DPGNEG patients, we compared the two groups within a
pre-defined PVR range (3 – 7 WU) in order to ensure a compar-
atively equivalent degree of pre-capillary alterations between the
two groups. Patients with DPGNEG demonstrated higher V-waves
in both the MS and PH-LHD groups, and a less prominent right
heart dilatation along with better RV function (P < 0.001) as com- pared with the positive DPG cohort, despite similar PAPM (P > 0.05,
Table 4; Supplementary material online, Table S1). Interestingly, the
V-wave amplitude was similar in MS and PH-LHD patients in the
DPGNEG group.

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

Negative DPG in pulmonary hypertension 91

Table 1 Demographic and echocardiographic data of the study population

All patients (n = 256) MS (n = 94) PH-LHD (n = 162) P-value PH-LHD R (n = 124)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Demographics
Age 50 ± 19 31 ± 9 61 ± 15 <0.001 61 ± 15 Female (%) 51% 72% 39% <0.001 40% BSA (m2) 1.8 ± 0.3 1.4 ± 0.2 2.0 ± 0.2 <0.001 1.9 ± 0.2 HT (%) 0% 85% 51% DM (%) 0% 60% 45% Aetiology of HF

IHD (n, %) 0% 36 (22%) 32 (26%)
Idiopathic 68 (42%) 48 (39%)
Myocarditis 21 (13%) 6 (5%)
Other 37 (23%) 38 (31)

AF (n, %) 53 (21%) 0 53 (33%) 43 (35%)
Functional class

NYHA II – IIIa 60 (64%) 84 (52%) <0.001 70 (56%) NYHA IIIb 34 (36%) 49 (30%) <0.001 29 (23%) NYHA IV – 29 (18%) 25 (20%)

Medication
Diuretics 100% 81% 78%
ACE inhibitor 85% 81%
Beta-blocker 100% 98% 93%
CCA 25% 18%
MRA 31% 34%

Echo data
EF ≤45% 69 (27%) 5 (5%) 62 (38%) <0.001 55 (44%) LVEDD (mm) 44 ± 7 52 ± 13 <0.001 54 ± 14 LVESD (mm) 29 ± 0.4 41 ± 15 <0.001 43 ± 16 LVMi (g/m2) 64 ± 18 105 ± 50 <0.001 114 ± 55 LA-ESVi (mL/m2) 68 ± 19 50 ± 21 <0.001 58 ±

2

0

MVA (cm2) 0.8 ± 0.2
MVG (mmHg) 19 ± 9
RVEDD (mm) 36 ± 5 40 ± 8 <0.001 41 ± 7 TAPSE (mm) 18 ± 3 14 ± 5 <0.001 14 ± 4

MR grade
Mild 163 (63%) 64 (68%) 99 (61%) <0.001 82 (66%) Moderate 23 (9%) – 23 (14%) 14 (11%) Severe 17 (6%) – 17 (10.5%) 11 (9%)

AS grade
Moderate 3 (1%) – 3 (2%) 4 (3%)

AR grade
Mild 32 (13%) – 32 (20%) 31 (25%)
Moderate 3 (1%) – 3 (2%) 6 (5%)

Data are expressed as mean ± SD or number (%).
P-values indicate the difference between the two prospective cohorts, i.e. MS and LHD.
AR, aortic valve regurgitation; AS, aortic valve stenosis; BSA, body surface area; CCA, calcium channel blocker; DM, diabetes mellitus; IHD, ischaemic heart disease; MS,
mitral valve stenosis; PH-LHD, pulmonary hypertension due to left heart disease; PH-LHD R, retrospective arm of the PH-LHD group; HT, hypertension; LA-ESVi, left atrial
end-systolic volume index; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; LVMi, LV mass index; MRA, mineralocorticoid receptor
antagonist; MVA, mitral valve area; MVG, mitral valve mean diastolic gradient; RVEDD, right ventricular end-diastolic diameter; TAPSE, tricuspid annular plane systolic excursion;
MR, mitral valve regurgitation.

Determinants of the diastolic pulmonary
pressure gradient
Left atrial pressure vs. pulmonary artery wedge pressure
in diastolic pulmonary pressure gradient assessment

In the 51 MS patients with simultaneous PAWP and LAP recordings,

the DPG was calculated from PAWP (DPGPAWP) and LAP (DPGLAP)

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. separately. DPGPAWP was negative in 28 cases while DPGLAP was

negative in 22 cases, due to a slightly yet not significantly lower
(mean bias: −2 mmHg) LAP (24.1 ± 8.0 mmHg) as compared
with PAWP (26.0 ± 8.1 mmHg; P > 0.05). However, in only three
cases with negative DPGPAWP was the corresponding DPGLAP
positive, while in one case reclassification occurred in the opposite
direction.

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

92 A.I. Nagy et al.

Table 2 Haemodynamics of the entire cohort

All patients (n = 256) MS (n = 94) PH-LHD (n = 162) P-value
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

PAPM (mmHg) 35 (29 to 44) (256) 38 (30 to 50) (94) 34 (29 to 43) (162) 0.024
PAPD (mmHg) 24 (20 to 31) (255) 27 (19 to 36) (94) 23 (20 to 29) (161) 0.026
RVSP (mmHg) 24 (21 to 29) (256) 59 (47 to 83) (94) 40 (49 to 63) (162) <0.001 PAWPM (mmHg) 24 (21 to 29) (256) 25 (23 to 32) (94) 23 (20 to 27) (162) 0.026 A-wave (mmHg) 26 (22 to 32) (229) 31 (26 to 37) (91) 24 (21 to 28) (138) <0.001 V-wave (mmHg) 31 (27 to 37) (235) 35 (31 to 44) (94) 28 (25 to 33) (141) <0.001 CI (L/min/m2) 1.9 (1.6 to 2.4) (256) 1.7 (1.4 to 2.1) (94) 2 (1.7 to 2.5) (162) <0.001 RAPM (mmHg) 10 (6 to 15) (255) 6 (3.8 to 8) (94) 12 (9 to 17) (161) <0.001 RVSWi (g/m2/beat) 9 (6.6 to 13) (255) 10.4 (7.8 to 14.8) (94) 8.2 (6 to 12.2) (161) <0.001 AV (mL/L) 54 (45 to 65) (241) 50 (42 to 57) (94) 57 (45 to 17) (147) <0.001 DPG (mmHg) 0 (−3 to 4) (255) −1 (−4 to 5) (94) 0 (−3 to 3) (161) 0.327 DPG <7 −1 (−4 to 1) (83%) −2 (−5 to 0) (79%) −1 (−3 to 1) (85%) DPG ≥7 13 (9 to 15) (17%) 14 (10 to 18) (21%) 12 (9 to 14) (14%) TPG (mmHg) 10 (7 to 18) (256) 9 (6 to 21) (94) 11 (7 to 16) (162) 0.72

TPG ≤12 8 (5.5 to 9) (61%) 7 (5 to 9) (62%) 8 (6 to 10) (61%)
TPG >12 20 (16 to 27) (39%) 25 (18 to 34) (38%) 19 (15 to 23) (39%)

PVR (WU) 3 (1.8 to 5.2) (256) 4 (2.5 to 8.8) (94) 2.6 (1.7 to 4.5) (162) <0.001 PVR <3 1.8 (1.4 to 2.5) (51%) 1.9 (1.3 to 2.6) (36%) 1.8 (1. 3 to 2.4) (59%) PVR ≥3 5.3 (3.8 to 7.8) (49%) 7.1 (4.1 to 11.6) (64%) 4.8 (3.8 to 6.1) (41%)

Values are expressed as the median and interquartile range.
P-values report the statistical difference between MS and PH-LHD.
AV, arteriovenous difference of oxygen saturation; CI, cardiac index; DPG, diastolic pulmonary pressure gradient; MS, mitral valve stenosis; PAPM and PAPD, mean and diastolic
pulmonary artery pressure, respectively; PAWPM , mean pulmonary artery wedge pressure; PH-LHD, pulmonary hypertension due to left heart disease; PVR, pulmonary
vascular resistance; RAPM, mean right atrial pressure; RVSP, right ventricular systolic pressure; RVSWi, right ventricular stroke work index; TPG, transpulmonary pressure
gradient; V- and A-wave, the maximal amplitude of the V- and A-wave of the PAWP waveform, respectively; WU, Wood Units.

Table 3 Haemodynamics stratified according to V-wave amplitude

Small V-waves n = 166 (51 MS) Large V-waves n = 69 (43 MS) P-value
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

PAPM (mmHg) 34 (29 to 44) 35 (30 to 45) 0.36
PAPD (mmHg) 24 (20 to 30) 23 (19 to 32) 0.77
PAWPM (mm Hg) 23 (20 to 27) 25 (22 to 31) 0.001
V-wave (mmHg) 28 (25 to 32) 39 (34 to 46) <0.001 V-waveabs (mmHg) 5 (3 to 7) 13 (11 to 17) <0.001 PVR (WU) 2.9 (1.9 to 5.6) 3.1 (1.7 to 5.2) 0.73 TPG (mmHg) 11 (7 to 19) 9 (7 to 15) 0.39 DPG (mmHg) 0 (−2 to 5) −2 (−4 to 1) 0.002 CI (L/min/m2) 1.9 (1.6 to 2.4) 1.8 (1.6 to 2.5) 0.26

Values are expressed as the median and interquartile range.
Small V-wave signifies a difference between maximal amplitude of the V-wave of the PAWP waveform (PAWPv) and the mean pulmonary artery wedge pressure (PAWPM ), i.e.
V-waveabs of <10 mmHg. Large V-wave signifies a V-waveabs ≥10 mmHg. CI, cardiac index; DPG, diastolic pulmonary pressure gradient; MS, mitral valve stenosis; PAPM and PAPD , pulmonary artery mean and diastolic pressure, respectively; PAWPM , mean pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; TPG, transpulmonary pressure gradient; WU, Wood Units.

Heart rhythm

When the analysis was confined to the 192 patients with HR < 85 b.p.m., 52% demonstrated DPGNEG. Similarly, when only the 53 patients in AF were considered, DPGNEG was measured in 50%.

Alternative pulmonary artery wedge pressure
measurements

As detailed in the Supplementary material online (Table S2), when
the DPG was calculated using the PAWP value measured at the .

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.. z-point of the PAWP curve, instead of using PAWPM in patients
with DPGNEG, this resulted in significantly higher DPG values. Still,
the prevalence of DPGNEG was not significantly reduced.

Prognostic value of the diastolic
pulmonary pressure gradient
Two-year outcome for the combined endpoint of death or cardiac
transplantation was significantly better for PH-LHD patients with

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

Negative DPG in pulmonary hypertension 93

10

DeltaPG [mmHg]

2015

50

V
-w

a
ve

[
m

m
H

g
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60

50

40

30

20

10

PH-LHD; r= 0.36

MS; r=0.60

806040

200

P
A

W
P

M

[m

m
H
g
]

r = 0.88; p < 0.001

r = 0.76; p < 0.001

PVR < 3 WU PVR ≥ 3 WU

V-wave [mmHg]

PVR < 3 WU PVR ≥ 3 WU 806040200 P A

P
D
[
m

m
H
g
]
60
50
40
30
20
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60
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40
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r = 0.55; p < 0.001

r = 0.46; p < 0.001

V-wave [mmHg]
806040200

T
P

G
[
m

m
H
g
]
50
40
30
20
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-10

r = – 0.14; p: NS

r = 0.12; p: NS

V-wave [mmHg]
PVR < 3 WU PVR ≥ 3 WU

806040
V-wave [mmHg]

200

D
P

G
[
m
m
H
g
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20
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r = – 0.45; p < 0.001

r = – 0.1; p = NS

PVR < 3 WU PVR ≥ 3 WU

A B

C
E
D

Figure 1 (A) Correlation between the diastolic pulmonary pressure gradient (DPG) and V-wave amplitude in patients with low (<3 WU) and high (≥ 3 WU) pulmonary vascular resistance (PVR). (B) Correlation between the transpulmonary pressure gradient (TPG) and V-wave amplitude in patients with low (<3 WU) and high (≥3 WU) PVR. (C) Correlation between mean pulmonary artery wedge pressure (PAWPM) and V-wave amplitude in patients with low (<3 WU) and high (≥3 WU) PVR. (D) Correlation between diastolic pulmonary artery pressure (PAPD) and V-wave amplitude in patients with low (<3 WU) and high (≥3 WU) PVR. (E) Correlation between V-wave amplitude and ΔPG in patients with mitral valve stenosis (MS) and pulmonary hypertension due to left heart disease (PH-LHD). WU, Wood Units.

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

94 A.I. Nagy et al.

Table 4 Comparison of negative and positive diastolic pulmonary pressure gradient groups within the entire study
population and in patients with a predefined pulmonary vascular resistance range of 3 – 7 Wood Units

All patients PVR 3 – 7 WU
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

DPG <0 (n) DPG ≥0 (n) DPG <0 (n) DPG ≥0 (n) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

MS patients (n) 52 (42%) 42 (32%) 18 (64%) 11 (19%)
PAPM (mmHg) 31 (28 to 37) (123) 41 (33 to 49) (132) (P < 0.001) 38 (30 to 43) (28) 40 (34 to 45) (57) (P = 0.128) PAPD (mmHg) 20 (17 to 26) (123) 28 (23 to 35) (132) (P < 0.001) 23 (18 to 30) (28) 27 (24 to 31) (57) (P = 0.013) V-wave (mmHg) 33 (28 to 39) (112) 29 (25 to 36) (123) (P < 0.001) 37 (32 to 42) (26) 28 (24 to 33) (52) (P < 0.001) PAWPM (mmHg) 24 (21 to 29) (123) 24 (20 to 28) (132) (P = 0.06) 25 (21 to 32) (28) 24 (20 to 28) (57) (P = 0.071) RVSP (mmHg) 49 (41 to 59) (123) 62 (47 to 78) (132) (P < 0.001) 51 (46 to 32) (28) 61(47 to 71) (56) (P = 0.67) RAPM (mmHg) 9 (5 to 13.5) (123) 11 (7 to 15) (132) (P = 0.004) 7.5 (4 to 10) (28) 11 (7 to 15) (57) (P = 0.005) PVR (WU) 2.2 (1.4 to 3.0) (123) 4.7 (2.6 to 7.6) (132) (P < 0.001) 4 (3.4 to 4.8) (28) 4.7 (3.7 to 5.6) (57) (P = 0.09) DPG (mmHg) −3 (−5 to −2) (123) 3 (1 to 9) (132) (P < 0.001) −2.5 (−4 to −1) (28) 3.0 (1 to 5) (57) (P < 0.001) TPG (mmHg) 7 (5 to 9) (123) 16 (11 to 24) (132) (P < 0.001) 9 (8 to 14) (28) 15 (12 to 21) (57) (P < 0.001) CI (L/min/m2) 1.9 (1.6 to 2.5) (123) 1.9 (1.6 to 2.3) (132) (P = 0.392) 1.7 (1.3 to 1.9) (28) 1.8 (1.6 to 2.2) (57) (P = 0.034) RVSWi (g/m2/beat) 8.2 (6.4 to 11) (123) 10.5 (6.8 to 15) (P = 0.004) 8.4 (6 to 12.6) (28) 10.3 (6.3 to 14) (57) (P = 0.24) A – V (mL/L) 49 (42 to 59) (115) 58 (48 to 69 (126) (P < 0.001) 49 (41 to 63) (28) 62 (49 to 71) (53) (P = 0.04) TAPSE (mm) 17 (12 to 19) (123) 15 (12 to 18) (132) (P = 0.025) 18 (15 to 21) (28) 14 (11 to 17) (57) (P = 0.004) RA area (cm2) 18 (12 to 24) (123) 22 (15 to 27) (132) (P = 0.002) 12 (10 to 24) (28) 23 (18 to 29) (57) (P < 0.001) RVEDD (mm) 36 (33 to 41) (123) 38 (34 to 46) (132) (P < 0.003) 34 (33 to 43) (28) 40 (36 to 48) (57) (P = 0.005)

Values are expressed as the median and interquartile range.
A – V, arteriovenous difference in oxygen saturation; CI, cardiac index; DPG, diastolic pulmonary pressure gradient; MS, mitral valve stenosis; PAPM and PAPD , mean and diastolic
pulmonary artery pressure, respectively; PAWPM and V-wave, mean pulmonary artery wedge pressure and the maximal amplitude of the V-wave of the PAWP waveform,
respectively; PVR, pulmonary vascular resistance; RA, right atrial; RAPM , mean right atrial pressure; RVEDD, right ventricular end-diastolic diameter; RVSP, right ventricular
systolic pressure; RVSWi, right ventricular stroke work index; TAPSE, tricuspid annular plane systolic excursion; TPG, transpulmonary pressure gradient; WU, Wood Units.

DPGNEG as compared with those with positive but normal DPG
(0 ≤ DPG <7 mmHg) (Figure 2A). In the DPGNEG group (n = 57), the combined endpoint was documented in 16 cases (10 deaths and 6 transplantations), while in the 0 ≤ DPG <7 mmHg group (n = 53) the corresponding figures were 24 (14 deaths and 10 transplanta- tions). Finally, in the DPG ≥7 mmHg group (n = 17), eight combined endpoint events were recorded (5 deaths and 3 transplantations).

The occurrence of the combined endpoint of death or trans-
plantation was significantly higher for 0 ≤ DPG <7 mmHg both in unadjusted analysis (P < 0.005) and when adjusted for age, creatinine, and ischaemic heart disease (Figure 2B). Conversely, neither TPG (cut-off 12 mmHg) nor PVR (cut-off 3 WU) pro- vided significant prognostic information (P = 0.522 and P = 0.718, respectively). Furthermore, combining DPG and TPG (DPGNEG and TPG ≤12 mmHg vs. 0 ≤ DPG <7 mmHg and TPG >12 mmHg)
also failed to provide prognostic information (P = 0.223).

Discussion
In the present study, we (i) confirm the high prevalence of DPGNEG
in PH-LHD patients; (ii) demonstrate that DPGNEG does not always
represent a measurement error, but instead may be ascribed to high
V-wave amplitude in patients with relatively low resistance in the
pulmonary vascular bed; and (iii) show that DPGNEG is associated
with lower mortality as compared with the corresponding group
of positive yet not elevated DPG.

In healthy subjects and in patients without significant
pre-capillary alterations, PAPD is closely related to LAP, with .

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.. DPG values ranging between 0 and 5 mmHg.5 DPGNEG values

have so far been regarded as a measurement bias, ascribed to
overwedging or inaccurate PAPD recordings.

5 However, the high
DPGNEG prevalence, ranging from 20% in critically ill patients

11,14

to 35%8 and up to 50%15 in PH-LHD patients, calls for a reappraisal
of its pathophysiological origin. DPGNEG was found in 44% of our
PH-LHD cohort, most probably reflecting the higher proportion
of PH (95%) compared with that (45%) reported in a recent study.8

V-wave influence on the diastolic
pulmonary pressure gradient
During systole, the second phase of LA filling occurs, yielding the
most prominent positive deflection of the PAWP waveform desig-
nated as the V-wave. The volume and the rate of blood entering
the left atrium as well as this chamber’s compliance determine
the V-wave amplitude,16,17 which in healthy subjects averages 12
mmHg, ranging between 4 and 19 mmHg, being at most 6 mmHg
higher than LAPM.

18 Importantly, the LA volume – pressure rela-
tionship follows an exponential rather than a linear pattern, so
that at lower LAP a certain volume entering the left atrium yields
minor pressure elevation, whereas at higher LAP an equal inflow-
ing volume results in a greater pressure rise.13,16 Conceivably, large
V-waves arise not only in the presence of severe acute mitral
regurgitation19 but also in conditions such as MS20 and longstanding
LV dysfunction, when LA distensibility is impaired, resulting in an
upward shift of the LA volume – pressure curve. In our study, large
V-waves were present in 20% of the PH-LHD group and in 46% of

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

Negative DPG in pulmonary hypertension 95

Figure 2 (A) Kaplan – Meier analysis for the three diastolic pulmonary pressure gradient (DPG) groups. Group I, DPG <0 mmHg; Group II, 0 ≥ DPG <7 mmHg; Group III, DPG ≥7 mmHg. (B) Hazard ratio for death and/or transplantation for patients with positive normal DPG (0 ≤ DPG <7 mmHg) and negative DPG. Due to few patients in Group III, only the statistical comparison between Group I and II is presented. CI, confidence interval; HTX, heart transplantation; IHD, ischaemic heart disease.

the MS cohort, similar to the findings of Wang and colleagues.20

It should be emphasized that the augmented V-waves in these
two cohorts represent distinct haemodynamic conditions; in MS
it reflects increased LA stiffness due to obstructed mitral valve ori-
fice, whereas in PH-LHD it is mainly secondary to a rise in LV
end-diastolic pressure (LVEDP). It has been shown that the dis-
torted LAP waveform in the presence of large V-waves leads to
overestimation of the LVEDP.21 Furthermore, there is evidence
of retrograde superimposition of prominent V-waves on the PAP
contour.22 Caro and colleagues demonstrated that at high LAP,
the ratio of pulmonary arterial to pulmonary venous compliance
changes, promoting an asymmetrical backward transmission of the
phasic LAP.23 Although studies concomitantly reporting V-wave
amplitude and PAPD are infrequent, the existing data on large
V-waves in the context of increased LA stiffness reveal DPGNEG in
essentially all cases.17 Importantly, we demonstrate that the inverse
correlation between the V-wave and DPG was confined to patients
with relatively low PVR, in accordance with the findings of Falicov
and colleagues.15 Under physiological conditions, at end-diastole,
the pulmonary vascular bed allows pressure equilibration24 which is .

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. otherwise hindered by the presence of vascular remodelling. Taken

together, our results indicate that in PH-LHD the V-wave ampli-
tude significantly influences the DPG calculation unless significant
pre-capillary remodelling is present. However, with progressive
maladaptive pre-capillary alterations, the V-wave no longer acts as
an important determinant of the DPG, which might be explained by
increased stiffening of the pulmonary arteries and thus dampening
of the backward LAP transmission. Previous investigations suggest
that large V-waves inversely correlate with the ratio between sys-
tolic and diastolic pulmonary inflow velocities.25 In accordance with
previous investigators, LA volume was not associated with V-wave
amplitude.26 As echocardiography plays a key role in the initial PH
assessment in HF, further studies are warranted to address poten-
tial incremental value of this modality.

Methodological considerations
The current findings argue against the notion that DPGNEG
represents merely an inaccurate measurement. First, the PAWP
and PAP waveforms were assessed manually at end-expiration by a

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

96 A.I. Nagy et al.

single investigator, limiting the possibility of erroneous computer-
ized PAPD measurements and preventing potential PAWPM under-
estimation due to pressure averaging throughout the respiratory
cycle.27 Experimental studies have shown that HR impacts on DPG;
at higher HR, DPG rises due to lower LVEDP and a concomi-
tant PAPD elevation.

28 Our results reveal that even when confining
the analysis to patients with normal HR or patients with AF, the
incidence of DPGNEG was unaltered. Finally, our simultaneously
performed PAWP and LAP measurements partly contradict the
opinion that DPG would be a result of erroneous PAWP record-
ings. Direct LAP measurements yielded slightly higher DPG values
as compared with PAWP. In ∼11% cases with negative DPGPAWP,
the corresponding DPGLAP was positive, while in one case reclas-
sification occurred in the opposite direction (4.5%). This finding
points to the fact that due to its low absolute value, even a small
measurement error will affect the DPG value; however, it also
demonstrates that measurement error accounts for only a minority
of DPGNEG cases. Taken together, although the slight discrepancy
between LAP and PAWP might account for a minor portion of the
DPGNEG, our findings suggest that DPGNEG values can for the most
part be ascribed to the augmented V-waves.

Prognostic significance
The prognostic impact of DPGNEG is as yet unknown. It has been
suggested that patients with DPGNEG, instead of being a subclass
of the isolated post-capillary PH (DPG <7 mmHg) group, in fact represent a cohort with worse haemodynamics.8 Our findings contradict this hypothesis. We demonstrate that when compar- ing DPGNEG patients with those with 0 ≤ DPG <7 mmHg, within a pre-defined range of PVR (3 – 7 WU), the DPGNEG cohort is characterized by lower RAP, and higher tricuspid annular plane sys- tolic excursion (TAPSE), reflecting a state of less pronounced right heart loading and remodelling advocating for milder haemodynamic derangements in the DPGNEG group. This, together with the lower event rate in the DPGNEG as compared with the DPG 0 – 7 mmHg cohort further supports the concept that DPGNEG in large part results from high V-waves shifting the DPG towards lower values, and suggests limited pre-capillary changes.

In our study, neither PVR nor TPG was associated with worse
outcome. Furthermore, combining TPG and PVR with DPG
failed to demonstrate significant prognostic value (P = 0.223 and
P = 0.195, respectively). This observation stands in contrast to pre-
vious results and might be partly related to differences in patient
profile. Indeed, as compared with the report by Tampakakis et al.,
the occurrence of ischaemic heart disease was much higher in our
study;8 additionally, our patient cohort comprised older patients
than those studied by Tampakakis et al. or Tedford et al.8,9 Finally,
the follow-up period was shorter in our study. The constellation
of the aforementioned issues as well as the fact that our study
comprised fewer patients might account for this discrepancy.

Limitations
Heterogeneity might be considered as comprising a limitation of
the current study as catheterizations were performed in two .

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. different centres. However, all studies in India were performed in

the presence of A.M. who was responsible for the standardization
of the studies in the two centres; additionally, the same technical
equipment and catheters were used at both sites. Patient char-
acteristics as well as haemodynamics of the two studied cohorts
are also rather divergent, as demonstrated in Table 1 (e.g. patients
with AF, hypertension, or ischaemic heart disease were excluded
from the MS but not the PH-LHD group); however, as the objec-
tive of the present study was not to assess the influence of AF
or other co-morbidities on the DPG, but rather to assess the
effect of V-wave amplitude on DPG measurement, we believe that
despite the patients’ heterogeneity, the haemodynamic essence of
our hypothesis is still addressed. Our cohort comprised patients
with PH-LHD (including both preserved and reduced EF) and MS,
in which respect it is different from previous comparable studies.
Indeed, pre-capillary involvement as defined by DPG ≥7 mmHg
was more frequent in MS patients (20.2%). However, the preva-
lence of Cpc-PH in the PH-LHD group was 13.6% that is com-
parable with previous studies (8 – 16%).6,8,9 Finally, the current
study was performed on haemodynamically stable patients, imply-
ing that our findings might not be valid in a state of decompensated
acute HF.

Conclusion
The present study verifies the recently observed high frequency
of DPGNEG. We propose an applicable physiological explanation
for this haemodynamic finding demonstrating a significant inverse
association of V-wave amplitude in the PAWP waveform with
the DPG in patients with low PVR. Using direct LAP measure-
ments, we show that the occurrence of DPGNEG is clearly not
reflecting methodological inaccuracies; rather it largely represents
the augmented disproportionate phasic LAP transmission. Finally,
DPGNEG in patients with PH-LHD appears to be associated with
milder haemodynamic derangements and better 2-year progno-
sis compared with patients with DPG within the normal positive
range.

Supplementary Information
Additional Supporting Information may be found in the online
version of this article:
Supplementary Methods and Results.
Figure S1. Flowchart demonstrating the patient enrolment pro-
cess and haemodynamic classification.
Figure S2. Representative pressure tracings illustrating the influ-
ence of V-waves on the DPG value.
Figure S3. Receiver operator characteristics (ROC) analysis of
the prognostic ability of the V-wave (PAWPV) for identifying a ΔPG
>12 mmHg in patients with pulmonary vascular resistance (PVR)
<3 Wood Units. Table S1. Comparison of negative and positive DPG groups in MS and LHD patients with a pre-defined PVR range of 3 – 7 WU. Table S2. Alternative PAWP measurements and DPG calculation.

© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

Negative DPG in pulmonary hypertension 97

Acknowledgement
This project was supported by the János Bolyai Scholarship of the
Hungarian Academy of Sciences.
Conflict of interest: none to declare.
Correction added on November 23, 2016, after first online publi-
cation: Acknowledgement section was added.

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© 2016 The Authors
European Journal of Heart Failure © 2016 European Society of Cardiology

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