Left ventricular dysfunction in COPD without pulmonary hypertension

Janne M Hilde; Jonny Hisdal; Ingunn Skjørten; Viggo Hansteen; Morten N Melsom; Ole J Grøtta; Milada C Småstuen; Ingebjørg Seljeflot; Harald Arnesen; Sjur Humerfelt; Kjetil Steine

doi:10.1371/journal.pone.0235075

. 2020 Jul 16;15(7):e0235075. doi: 10.1371/journal.pone.0235075

Left ventricular dysfunction in COPD without pulmonary hypertension

Janne M Hilde ^1,², Jonny Hisdal ^1,³, Ingunn Skjørten ^2,⁴, Viggo Hansteen ¹, Morten N Melsom ⁴, Ole J Grøtta ⁵, Milada C Småstuen ⁶, Ingebjørg Seljeflot ^2,⁷, Harald Arnesen ^2,⁷, Sjur Humerfelt ⁴, Kjetil Steine ^2,^8,^*

Editor: Vincenzo Lionetti⁹

PMCID: PMC7365599 PMID: 32673327

Abstract

Objectives

We aimed to assess prevalence of left ventricular (LV) systolic and diastolic function in stable cohort of COPD patients, where LV disease had been thoroughly excluded in advance.

Methods

100 COPD outpatients in GOLD II-IV and 34 controls were included. Patients were divided by invasive mean pulmonary artery pressure (mPAP) in COPD-PH (≥25 mmHg) and COPD-non-PH (<25 mmHg), which was subdivided in mPAP ≤20 mmHg and 21–24 mmHg. LV myocardial performance index (LV MPI) and strain by tissue Doppler imaging (TDI) were used for evaluation of LV global and systolic function, respectively. LV MPI ≥0.51 and strain ≤-15.8% were considered abnormal. LV diastolic function was assessed by the ratio between peak early (E) and late (A) velocity, early TDI E´, E/E´, isovolumic relaxation time, and left atrium volume.

Results

LV MPI ≥0.51 was found in 64.9% and 88.5% and LV strain ≤-15.8% in 62.2.% and 76.9% in the COPD-non-PH and COPD-PH patients, respectively. Similarly, LV MPI and LV strain were impaired even in patients with mPAP <20 mmHg. In multiple regression analyses, residual volume and stroke volume were best associated to LV MPI and LV strain, respectively. Except for isovolumic relaxation time, standard diastolic echo indices as E/A, E´, E/E´ and left atrium volume did not change from normal individuals to COPD-non-PH.

Conclusions

Subclinical LV systolic dysfunction was a frequent finding in this cohort of COPD patients, even in those with normal pulmonary artery pressure. Evidence of LV diastolic dysfunction was hardly present as measured by conventional echo indices.

Introduction

In patients with chronic obstructive pulmonary disease (COPD), and in particular in those with severe emphysema, pulmonary hypertension and right ventricular (RV) enlargement, the left ventricle is compressed. However, for the majority of these patients, the left ventricular (LV) ejection fraction is within normal limits [1]. The majority of COPD patients with such findings shows a leftward ventricular septum deviation, most marked at end systole and early diastole, associated with a distortion of LV geometry and reduction of early diastolic filling [1, 2]. This mechanism is thought to be the most likely cause for the decreased LV size, stroke volume and thus under filling of the left ventricle [1–3]. Moreover, Barr RG et al. demonstrated in a population based study of 2816 participants that increasing extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling and reduced stroke volume without changes in LV ejection fraction [4]. However, LV ejection fraction by two-dimensional echocardiography can be normal despite LV dysfunction [5]. Because of this and the symptom similarity between heart failure and COPD, there is a need for more sensitive diagnostic tools to unmask if LV systolic subclinical impairment is present in COPD patients. Moreover, there is only a few existing studies on COPD and LV function recruiting mostly severe COPD, having small number of participants, and they are also deficient with respect to invasive pressure data [6–8].

Tissue Doppler imaging (TDI) is a more sensitive tool to detect subclinical systolic LV dysfunction. The present group has previously demonstrated reduced RV function by TDI, even in COPD patients without pulmonary hypertension [9]. To the best of our knowledge, there are only two small studies on COPD and LV function using TDI [10, 11]. However, none of these two studies had measured pulmonary pressure by right heart catheterization.

The aim of the present study was therefore to characterize LV function and investigate the prevalence of subclinical LV dysfunction by these novel imaging techniques in a patient population of stable COPD patients with and without pulmonary hypertension and without known LV disease. We hypothesized that even in such a cohort, geometric alterations in structure induces LV systolic and diastolic dysfunction in the majority of the patients.

Methods

Study population

Hundred outpatients with stable COPD of different severity and free of clinical cardiovascular disease, were consecutively included from 2006 to 2010 (Table 1). Baseline characteristics of the study population have previously been described in details [9]. The diagnosis of COPD was based on a history of cigarette smoking with at least 10 pack-years and spirometry irreversible airway obstruction according to current guidelines [12]. Spirometry, body plethysmography, diffusion capacity for carbon monoxide, and arterial blood gases were performed according to guidelines. Prediction equations for forced expiratory volume in the first second, forced expiratory capacity and static lung volumes were used [13, 14]. Patients were classified according to the criteria of the Global Initiative for Chronic Obstructive Lung Disease [12]. All patients had optimal bronchodilator therapy.

Table 1. Clinical characteristic of controls and patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with pulmonary hypertension (COPD-PH).

Variables (unit)	Controls (n = 34)	COPD-non-PH (n = 74)	COPD-PH (n = 26)
Demographics
Age (years)	63±7	64±6	62±8
Body mass index (kg/m²)	25±3	24±4	25±7
Body surface area (m²)	1.9 ±0.2	1.8±0.2	1.8±0.3
Systolic blood pressure (mmHg)	120±17	139±22^*	140±18^*
Diastolic blood pressure (mmHg)	76±12	69±11^*	68±13^*
Heart rate (bpm)	68±10	69±13	79±15^*^†
Pack-years of smoking	8±9	40±19^*	39±20^*
Categorical variables	n or n/%	n or n/%	n or n/%
Sex Female/Male (n)	19/15	36/38	15/11
Hypertension (n/%)	3/9	22/30	11/42^*^†
Diabetes (n/%)	0/0	5/7	4/15
GOLD stages I/II/III/IV(n)	0	2/35/23/14	0/2/8/16
Smoking habits0^‡ (n)	2/13/19	51/23/0^*	18/8/0^*
Pulmonary function and art. blood gases
FEV₁% predicted	98±10	47±16^*	32±12^*^†
FVC % predicted	105±11	77±20^*	61±16^*^†
FEV₁/FVC (%)	76±4	50±11^*	43±13^*^†
Total lung capacity % predicted	100±15	122±20^*	133±25^*
Residual volume % predicted	119±16	191±59^*	241±60^*^†
DLCO % predicted	100±15	58±20^*	36±20^*^†
PaO₂ (kPa)	-	9.9±1.2	8.2±1.6^†
PaCO₂ (kPa)	-	5.3±0.6	5.7±0.8
Biomarkers	Geometric mean	Geometric mean	Geometric mean
NT pro-BNP (pmol/l)		9.8 (9.1,10.5)	10.0 (9.1,10.8)
CRP (mg/L)	0.78(0.40, 2.04)	3.97(2.11,7.64) ^*	4.10(1.29, 5.07) ^*
White blood cell (x10⁹/L)	5.60 (4.58, 6.28)	7.30 (6.0, 8.85)^*	7.90 (6.30, 9.60)^*
IL-6 (pg/mL)	1.81 (1.16, 2.75)	3.50 (2.17, 5.74)^*	3.71(2.33, 6.53)^*
TNF α (pg/mL)	1.30 (1.05, 1.47)	1.33 (1.10, 1.57)	1.32 (1.11, 1.60)

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Values are mean±SD. CRP: C-reactive protein, DLCO: Diffusion capacity for carbon monoxide of the lungs, FEV₁: Forced expiratory volume in the first second, FVC: Forced vital capacity, GOLD: Global Initiative for Chronic Obstructive Lung Disease, IL: Interleukin, PaO₂: Arterial oxygen tension; PaCO₂: Arterial carbon dioxide tension, TNF: Tumor necrosis factor.

* Significantly different from controls (p<0.01),

^† significantly different from COPD-non-PH (p<0.01).

^‡ Former, current and never smoker, respectively.

Caucasians, 40–75 years, with spirometry confirmed COPD in Global Initiative for Chronic Obstructive Lung Disease stages I-IV, all current or former smokers were included. They had to be free of COPD exacerbations the last two months prior to inclusion. All participants underwent pre-inclusion screening, including resting ECG and a dynamic exercise test on bicycle ergometer. Patients with history of congenital, rheumatic, valvular and ischemic heart disease, treated arterial hypertension with blood pressure >160/90 mmHg, arrhythmias (including atrial fibrillation), other acute or chronic pulmonary disease, malignancy, hyper-and hypothyroidism, systemic inflammatory diseases and renal failure, were excluded. Patients using beta-blockers, Warfarin or Clopidogrel were also excluded. Subjects were classified as having diabetes when being under treatment for insulin-dependent or non-insulin dependent diabetes or having fasting blood glucose >7 mmol/L. Use of lipid lowering medication was present in 9.8% of COPD patients.

The COPD patients were compared to an age and gender matched control group (n = 34) and evaluated healthy by clinical, biochemical and imaging investigations. The study complies with the Declaration of Helsinki, and was approved by Regional committee for medical and health research ethics south-east and performed at Oslo university hospital-Aker. Written informed consent was obtained from all the subjects.

Blood collections

Venous blood samples were collected in fasting condition between 08.00 and 10.00 a.m. and centrifuged at 2500 x g for 15 min. Serum and EDTA plasma were stored at -80 °C for subsequent analyses in batch. Routine analyses were performed by conventional methods. Inflammatory markers were determined by ELISA from R&D Systems Europe, (Abingdon, Oxon, UK), except for CRP which was analyzed by ELISA from DRG Instruments (GmbH, Germany). Serum was used for all. Arterial blood gases from radial artery in resting condition was collected and analyzed immediately.

Echocardiography

All study patients underwent a comprehensive Doppler echocardiographic examination prior to and within 120 minutes of right-heart catheterization [9].

LV internal dimension, septal and posterior wall thickness, and LV mass were measured in end-diastole using the parasternal long-axis view [15, 16]. LV MPI and isovolumic relaxation time were measured by pulsed wave TDI and four-chamber view at the basis of the septal and lateral mitral leaflet and averaged. LV myocardial strain was measured by post-processing at the basal third of the septal and lateral LV walls of the apical four-chamber TDI loop and averaged. An LV MPI ≥0.51, LV Strain ≤15.8%, isovolumic relaxation time ≥87 ms and isovolumic relaxation time adjusted for heart rate ≥99 ms (mean+three standard deviations of the controls for all four) were considered abnormal. Isovolumic relaxation time was adjusted for heart rate by dividing the observed Isovolumic relaxation time with the RR interval in seconds.

The mitral inflow measurements included peak early filling (E) and late diastolic filling (A) velocity and the E/A ratio by pulsed Doppler [17]. Early diastolic pulsed TDI (E´) peak velocity was measured at similar locations as LV MPI and averaged, and E/E´ was calculated as surrogate for LV filling pressure [17]. LV ejection fraction and volumes were calculated by the biplane method (modified Simpson’s rule) using apical four and two chamber views [15]. Indexed left atrial volume was calculated using the four and two chamber views at end-systole [15]. Right atrium volume was measured by single-plane area-length algorithm from four-chamber view [18]. RV parameters were obtained as previously reported [9].

Real-time three dimensional echo was used to acquire full-volumetric data sets of LV and RV from four ECG-triggered sub-volumes. Post-processing analysis (RV-Function, TomTec Imaging system GmbH, Unterschleissheim, Germany) was performed with semi-automatic software with predefined LV and RV views for endocardial contours delineation.

Cardiac magnetic resonance imaging

COPD patients (n = 100) were scanned using a 1.5-T Siemens Advanto (Siemens Medical Systems, Erlangen, Germany) with a phased-array body-coil, and acquisition of two- and four-chamber localizers was performed as previously described [9]. All CMR data were processed by a blinded observer (OJG).

Hemodynamic measurements

Right heart catheterization was performed at rest with the patient supine as previously described [9]. Electrocardiogram and heart rate were recorded continuously, and cardiac output was determined by thermodilution technique. Pulmonary vascular resistance and LV filling resistance were calculated [9]. Results were stratified according to presence or absence of PH; COPD-PH if mPAP ≥25 (n = 26) and COPD-non-PH if mPAP<25 mmHg (n = 74) by right heart catheterization. Furthermore, patients with mPAP <25mmHg were subdivided into ≤20mmHg (n = 53) and 21-24mmHg (n = 21).

Statistical analyses

Continuous variables were described as mean and standard deviation and categorical variables as counts and (%). Crude differences between controls and COPD subgroups and between two COPD subgroups were assessed using analysis of variance with Bonferroni correction and two-independent samples t-test. Pairs of categorical variables were compared using Chi-squared test. Possible associations between LV global function by LV MPI and LV systolic function by strain versus functional echo and invasive indices for RV function and volumes, lung function and hyperinflation indices and standard risk factor for LV disease were evaluated using linear regression models. Variables that reached p<0.1 in univariate analyses were entered into multiple regression models. P-values <0.05 were considered statistically significant. All analyses were performed using SPSS 21 and SigmaPlot v.12.

Results

Demographic and clinical data

Clinical data including biomarkers and hemodynamics in controls and patients are summarized in Tables 1 and 2, respectively. Heart rate was higher in the COPD-PH patients vs. controls and vs. COPD-non-PH. All results, also including LV global, systolic and diastolic function, LV size and mass and left atrial size, are summarized in Table 3.

Table 2. Right heart catheterization values in patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with pulmonary hypertension (COPD-PH).

Variables (unit)	COPD-non-PH (n = 74)	COPD-PH (n = 26)
Mean pulmonary artery pressure (mmHg)	18±3	29±4^*
Mean pulmonary wedge pressure (mmHg)	8±4	11±3^*
Mean right atrial pressure (mmHg)	5±3	7±3^*
Pulmonary vascular resistance (WU)	2.0±0.9	3.4±1.5^*
Systemic vascular resistance (WU)	16±4	18±4
Systemic arterial compliance (ml/mmHg)	1.1±0.4	1.0±0.4
Cardiac index (l/min/m²)	2.9±0.4	3.1±0.6^*
Stroke volume indexed (ml/m²/beat)	39±7	37±6
Heart rate (beats/min)	73±12	83±14^*
Left ventricular filling resistance (mmHg/L/min)	1.6±0.7	2.0±0.6^*

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Values are mean±SD (standard deviation).

* Significantly different from COPD-non-PH.

Table 3. Echocardiographic measurements of LV global, systolic and diastolic function, and dimensions of the LV, left atrium and right atrium in healthy controls, patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with pulmonary hypertension (COPD-PH).

Variable (unit)	Controls (n = 34)	COPD-non-PH (n = 74)	COPD-PH (n = 26)
Global LV function
MPI septal (no unit)	0.37±0.08	0.54±0.11^*	0.63±0.16^* ^†
MPI lateral (no unit)	0.36±0.06	0.56±0.12^*	0.60±0.10^* ^†
MPI (no unit)	0.36±0.05	0.55±0.10^*	0.62±0.10^* ^†
Isovolumic contraction time (ms)	59±11	76±12^*	72±13^* ^†
Isovolumic relaxation time (ms)	49±13	83±15^*	89±17^* ^†
Ejection time (ms)	299±20	291±33^*	265±31^* ^†
Isovolumic relaxation time, HR adjusted	54±15	95±23^*	115±25^* ^†
LV systolic function
Strain septal (%)	-21.9±2.2	-15.8±2.0^*	-13.8±1.3^*^†
Strain lateral (%)	-22.5±2.4	-15.7±2.1^*	-15.0±2.9^* ^†
Strain (%)	-22.2±1.9	-15.8±1.9^*	-14.4±1.7^* ^†
LV diastolic function
Transmitral peak early (E) velocity (m/s)	0.66±0.14	0.70±0.16	0.73±0.15
Transmitral late (A) velocity (m/s)	0.67±0.14	0.68±0.19	0.72±0.21
Transmitral E/A ratio (no unit)	1.07±0.29	1.04±0.25	1.03±0.26
E´ (cm/s)	8.9±2.3	8.3±2.0	7.4±1.7^*
E/E´ ratio (no unit)	7.7±1.5	8.6±2.1	10.3±2.2^*^†
LV, left and right atrial dimensions
LV diastolic diameter (cm)	5.1±0.6	4.8±0.7	4.5±0.6^*
LV interventricular septum dimension (cm	0.8±0.1	0.9±0.1	0.9±0.2
LV posterior wall dimension (cm)	0.8±0.1	0.9±0.1	0.9±0.1
LV Mass (g/m²)	78±19	79±22	70±17
Relative wall thickness (no unit)	0.33±0.06	0.38±0.07^*	0.38±0.07^*
Left atrium volume (ml/ m²)	21±4	24±5^*	21±4 ^†
Right atrium volume (ml/m²)	14±3	21±6^*	22±8^*
Ratio of left/right atrium volumes	1.6±0.5	1.3±0.5^*	1.1±0.3^* ^†

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Values are mean±SD. E´: average of peak early mitral velocities from at the root of septal and lateral mitral leaflet, respectively, HR: heart rate, Isovolumic contraction and relaxation time and ejection time: average of measurements from the root of septal and lateral mitral leaflet, respectively, LV: left ventricular, MPI septal and MPI lateral: myocardial performance index measured at the root of septal and lateral mitral leaflet, respectively, MPI: average of MPI septal and lateral, strain septal and lateral: strain measured at basal third of LV septal and lateral wall, respectively, strain: average of strain septal and lateral, TDI: Tissue Doppler imaging.

* Significantly different from controls,

^† significantly different from COPD-non-PH.

LV systolic function

Both LV MPI and LV strain were significantly different between controls, COPD-non-PH and COPD-PH (p<0.01 for all) (Table 3 and Fig 1). LV MPI ≥0.51 was found in 64.9% and 88.5% and LV strain ≤-15.8 in 62.2.% and 76.9% in the COPD-non-PH and COPD-PH patients, respectively. When patients with diabetes and/or hypertension (n = 37) were excluded, this was not significantly changed. Even those with mPAP below 20 mmHg showed LV MPI and LV strain significantly impaired compared to controls (Table 4).

Table 4. LV function by LV MPI and LV strain, key respiratory and invasive hemodynamic indices of COPD patients with no pulmonary hypertension divided in two groups, mean pulmonary pressure ≤20 mmHg (normal) and 21–24 mmHg (borderline).

	Controls (n = 34)	COPD (n = 53)	COPD (n = 21)
Global (MPI) and LV systolic function	(n = 34)	mPAP≤20 mmHg	mPAP 21–24
MPI septal (no unit)	0.36±0.08	0.55±0.12^*	0.52±0.10^*
MPI lateral (no unit)	0.37±0.06	0.56±0.12^*	0.58±0.11^*
MPI (no unit)	0.36±0.06	0.55±0.09^*	0.55±0.08^*
Strain septal (%)	-21.9±2.2	-15.8±2.1^*	-15.7±1.7^*
Strain lateral (%)	-22.5±2.4	-15.7±2.1^*	-15.7±2.1^*
Strain (%)	-22.2±1.9	-15.8±1.9^*	-15.7±1.8^*
Hemodynamic/respiratory variables
Mean pulmonary pressure (mmHg) ^z		16.7±2.5	22.6±1.2^†
Pulmonary vascular resistance (Wu) ^z		1.8±0.7	2.4±1.0^†
Cardiac output (l/min) ^z		5.1±1.0	5.2±0.9
Pulmonary artery wedge pressure (mmHg) ^z		7.7±3.5	9.9±3.5 ^†
PaO₂ (kPa)		10.0±1.3	9.5±1.0
Residual volume% predicted	119±16	182.5±52.2^*	212.9±69.1^†
FEV₁% predicted	98±10	50.8±15.6^*	38.1±14.1^†

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PaO₂: Arterial oxygen tension, FEV₁: Forced expiratory volume in the first second, MPI: average of MPI septal and lateral, Strain: average of strain septal and lateral,

* Significantly different from controls (p<0.01),

^† Significantly different from COPD with mPAP≤20 mmHg (p<0.05) ^z Performed by right heart catheterization.

LV and RV ejection fraction by CMR correlated significantly, r = 0.66 (p<0.001), and there were significant correlations between LV MPI vs RV MPI and tricuspid annular plane systolic excursion of r = 0.70 and r = 0.59, respectively and between LV strain vs. RV MPI and tricuspid annular plane systolic excursion of r = 0.56 and r = 0.60 (p<0.001 for all), respectively. Fig 2 displays significant correlations between stroke volume by right heart catheterization and residual volume % predicted, LV MPI and LV strain. There was no significant correlation between the LV/RV ratio by CMR and LV MPI and strain.

Fig 2 — Panel A, B, C and D display significant associations between invasive stroke volume and residual volume (% predicted), LV MPI (myocardial performance index), LV strain and IVRT HR-adjusted (heart rate adjusted isovolumic relaxation time), respectively. Grey circles are COPD patients without pulmonary hypertension (COPD-non-PH) and black circles COPD patients with pulmonary hypertension (COPD-PH).

Two separate multiple regression models were fitted, and backward stepwise approach was used. In the final model with LV MPI as dependent variable, residual volume % predicted (p<0.01), invasive stroke volume (p<0.001), RV ejection fraction by CMR (p<0.01) and log transformed CRP (p<0.05) were all independently associated with LV MPI, and this model explained 55% of the variation in LV MPI. The initial model was also adjusted for systolic blood pressure, pack-years, heart rate, interleukin 6, forced expiratory volume in the first second, forced expiratory volume in the first second/forced vital capacity, arterial oxygen tension and mPAP, which were all statistically significant (p<0.01 for all) in univariate analyses. Similarly, with LV strain as dependent variable: Residual volume % predicted (p<0.01), invasive stroke volume (p<0.001), mPAP (p<0.05), and forced expiratory volume in the first second/forced vital capacity (p<0.05), explained 57% of the variation in LV strain. In addition to the above first six listed independent variables, the initial model was also adjusted for RV ejection fraction, arterial oxygen tension and log transformed CRP. All nine variables, except for heart rate and arterial oxygen tension, were statistically significantly associated with LV strain in univariate analyses (p<0.05 for all). In addition, we included sex and age in both models (both not statistically significant in crude analyses).

LV diastolic function

There was a small, but statistically significant increase of E/E´ from controls to COPD-non-PH (p<0.01), and to COPD-PH (p<0.01), driven by the reduced E´. The E/A ratio and left atrial volume did not differ between the three groups (Table 3). However, isovolumic relaxation time by TDI, without and with adjustment for heart rate, was significantly increased in both patient groups compared to controls and between COPD-PH and COPD-non-PH (Table 3). Isovolumic relaxation time ≥87ms was found in 42% and 58% of the COPD-non-PH and COPD-PH patients, respectively. When adjusted for heart rate <99, this was changed to 36% and 64%, respectively. There were significant, but weak correlations between invasive stroke volume and heart rate adjusted isovolumic relaxation time, r = - 0.46 (p<0.01), left atrial volume, r = 0.32 (p<0.01) and the E/A ratio, r = 0.21 (p<0.05), however not to E, E´ and E/E´.

LV and RV volumes

Table 5 shows LV and RV volumes and ejection fraction by CMR, two- and three dimensional echo. End diastolic LV/RV volume ratio was significantly lower, driven by RV volume, in both COPD-groups compared to controls; controls: 1.03, COPD-non-PH: 0.88, and COPD-PH: 0.78 (p<0.01 for all). Similar to the results with three-dimensional echo, the LV/RV ratio of end diastolic volumes by CMR decreased from 0.88 in COPD-non-PH to 0.81 in COPD-PH (p<0.01). LV ejection fraction by CMR <50% was found in 19%, although mild, 45±5%.

Table 5. Left and right ventricle volumes and ejections fractions in healthy controls, patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with (COPD-PH) pulmonary hypertension.

Variables (unit)	Controls (n = 34)	COPD-non-PH (n = 68)	COPD-PH (n = 20)
Left ventricle CMR
End-diastolic volume (ml/m²)		75±15	70±12
End-systolic volume (ml/m²)		34±12	35±13
Stroke volume index (ml/beat/m²)		42±9	39±9
Myocardial Mass (g/m²)		41±15	43±21
Ejection fraction (%)		56±7	56±10
Right ventricle CMR
E End-diastolic volume (ml/m²)		88±26	95±25
End-systolic volume (ml/m²)		45±14	52±16
Stroke volume index (ml/beat/m²)		43±14	43±13
Ejection fraction (%)		49±6	45±9
Left ventricle 3DE		COPD-non-PH (n = 74)	COPD-PH (n = 26)
End-diastolic volume (ml/m²)	59±10	61±12	57±11
End-systolic volume (ml/m²)	23±5	26±7^*	25±7
Stroke volume index (ml/beat/m²)	36±6	35±7	33±7
Ejection fraction (%)	62±5	58±5^*	58±5^*
Right ventricle 3DE
End-diastolic volume (ml/m²)	57±7	71±15^*	74±15^*
End-systolic volume (ml/m²)	24±5	35±9^*	40±11^*
Stroke volume index (ml/beat/m²)	34±4	35±7	34±7
Ejection fraction (%)	58±4	50±5^*	46±6^*^y
Left ventricle 2DE
End-diastolic volume (ml/m²)	55±9	54±11	50±12
End-systolic volume (ml/m²)	22±5	23±6	22±7
Stroke volume index (ml/beat/m²)	33±5	31±6	29±6^*
Ejection fraction (%)	61±5	57±4^*	58±5^*

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Values are mean±SD. CMR: Magnetic resonance imaging, 3DE and 2D: Three and two dimensional echocardiography, respectively,

*significantly different from controls,

^ysignificantly different from COPD-non-PH.

Discussion

The present study has demonstrated subclinical impairment of LV global and systolic function by TDI in a stable cohort of COPD patients without cardiovascular disease compared to controls. These findings were present in COPD patients with and without pulmonary hypertension, even in those with mPAP below 20 mmHg.

LV systolic function

LV systolic and global function, however, as measured by TDI strain and LV MPI, respectively, were both able to differentiate between controls and the COPD subgroups. Moreover, the impairment of LV function by these two echo indices was similar on the LV lateral wall as that of the interventricular septum. The results also demonstrated that LV systolic dysfunction was highly prevalent, as the majority of our patients demonstrated LV MPI and strain above and below the predefined cut-off of ≥0.51and <-15.8%, respectively. The proportion of patients with LV dysfunction remained high, even when those with cardiovascular risk factors (diabetes and hypertension) were excluded. Moreover, traditional method as 2D and novel 3D ejection fraction were also reduced in COPD with and without PH as compared to normal individuals. The difference, however, was small and probably not of clinical significance, but emphasizes the findings of LV strain and MPI. In addition, LV ejection fraction by CMR was also found mildly reduced in 19%.

Freixa et al. showed a prevalence of LV dysfunction of 13.3%, and Macchia et al. 13.8% [19, 20]. In the study by Frexia et al., however, there was more than 60% self-reported LV disease, and in the study by Macchia et al., patients with LV disease were not excluded. These two studies reflect the main difference between the present study and other studies on COPD, namely the thorough exclusion of clinical LV disease, the absence of LV ejection fraction <50% prior to inclusion, the use of more sensitive TDI echo tools and invasive hemodynamic data in the present study. We consider this to emphasize that our findings most likely are caused by the COPD disease itself and not by other left heart diseases. Although a recent study reported similar prevalence of coronary artery disease in COPD as in an age and gender matched group without pulmonary disease, we cannot exclude that some of our COPD patients had silent coronary heart disease [21].

Several studies have shown that the main reason for the reduction of LV function in advanced COPD patients is the right side of the heart due to impaired RV function, dysfunctional interventricular septum due to increased pulmonary pressure, oversized right heart, and thus under-filling of the left ventricle [1–4, 6, 22]. The present multiple regression analyses confirm the connection between impaired LV function by the two novel indices and the hyperinflated lungs, reduced stroke volume, and impaired RV function, and that this underscores the notion of under-filling as the main mechanism for the subclinical reduction in LV function.

The present study has demonstrated that even those with mPAP below 20 mmHg, showed increased LV MPI and reduced strain, and that the LV systolic impairment by these two indices was similar between the LV interventricular septum and the LV lateral wall. We consider this to reflect that the abovementioned systemic under-filling has a more negative and systemic impact on LV function than that of the interventricular septum. The not existing association between the LV/RV ratio by CMR and the two TDI indices for LV function underscores this notion. Nevertheless, our results of early impairment of LV systolic function in COPD are in line and extend the large and non-invasive study by Barr et al. showing a gradual impairment of LV systolic function from normal lung structure to severe air flow obstruction [4].

It has been speculated, since there is substantial loss of pulmonary vascular bed even in smokers and mild COPD, that this may lead to a small increase in pulmonary vascular resistance and reduced compliance leading to an increase of RV load and reduction of RV function and thus under-filling of the left side [3, 4, 23]. It has also been suggested that the systemic inflammatory state in patients with COPD may cause LV functional changes [24], and that smoking may have a negative direct impact on LV function [25]. However, we could not show any reliable association to inflammation parameters or to pack-years, respectively.

Our patients had a low-grade state of inflammation by higher circulating levels of inflammatory biomarkers compared to healthy controls. There were, however, no differences between COPD-non-PH and COPD-PH, which confirms COPD as a pro inflammatory disease [24, 26]. However, only crp remained as an independent variable in the multiple regression analyses to predict LV function, in contrast to a previous study, showing that IL-6 was higher in COPD-PH than COPD-non-PH, and a correlation with severity of pulmonary hypertension [26].

LV diastolic function

The main echo indices for the diagnosis of LV diastolic dysfunction are the size of the left atrium, E´, E/A, and E/E´ ratios [17]. Our COPD-PH patients showed higher E/E´ ratio and lower E´; however, only on a group level. In particular, only eight patients had E/E´ above 13, and none had a pulmonary wedge pressure above 15 mmHg by right heart catheterization or a left atrium > 34 ml/ m² [17]. Although we could show a marked increase of isovolumic relaxation time in our patients (Table 3), indicating impairment of early diastolic LV relaxation, there was not a consistent link between LV diastolic dysfunction and COPD based on standard echo indices. Moreover, left atrial and LV size were functionally undersized compared to the right side, which probably, in concert with the impaired RV function and the significant associations between stroke volume and left atrium volume, reflects under-filling of the left side (Table 3). Although under-filling probably is not the only mechanism for the reduced size of the left side, this may have masked LV diastolic dysfunction as assessed by standard echo indices in several of our patients. To the best of our knowledge, we could not find any study showing LV diastolic dysfunction in the majority of the COPD patients as measured by standard echo indices, only small group differences [6, 10, 27]. This in contrast to what is expected in this group of patients [24]. LV isovolumic relaxation time by TDI, in particular heart rate adjusted, seems to be the best method to evaluate LV diastolic dysfunction in patients with stable COPD disease, which is consistent with two other studies [6, 10]. Its association to pulmonary pressure is also important for the mechanistic understanding of this echo index.

Limitations

The study participants were not routinely screened invasively with coronary angiograms, and silent coronary artery disease could therefore be overlooked. Although a thorough screening process and testing with echocardiography, resting ECG and exercise testing were performed to unmask ischemic heart disease, we cannot entirely exclude neither macro nor microvascular disease in our patients.

We included medically treated hypertension, diabetes and smokers, known risk factors for cardiovascular disease, and hence, confounders in the evaluation of LV function and structure. However, restricting the analyses to participants with or without systemic hypertension, and to the presence or absence of diabetes, gave similar results.

We did not perform CMR in the controls. The absence of CMR data in this group limits a definite assessment of the role of COPD in the pathogenesis of cardiac disorders in relation to hyperinflation and LV mass.

The present study reports upper normal limits for LV MPI, LV Strain, isovolumic relaxation time and isovolumic relaxation time adjusted for heart rate. Determining accurate thresholds from continuous variable have many pitfalls as pointed out by Giannoni m and co-workers [28]. Although we made three times standard deviation of the mean from the controls to avoid false positive results, it does not necessarily provide our study with the correct upper normal limits.

Conclusion

LV systolic dysfunction by LV MPI and strain, was highly prevalent even in COPD patients without pulmonary hypertension. LV diastolic dysfunction when measured with conventional methods, was hardly present. Isovolumic relaxation time by TDI, however, seems to be a consistent echo index to reveal LV diastolic dysfunction in this stable cohort of COPD.

Supporting information

S1 Datafile

(DAT)

Click here for additional data file.^{(53.5KB, dat)}

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

JMH: Eastern Norway Regional Health Authority, 2303 Hamar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0235075.r001

Decision Letter 0

Vincenzo Lionetti

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

31 Mar 2020

PONE-D-20-04365

Left ventricular dysfunction in COPD without pulmonary hypertension

PLOS ONE

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Reviewer #1: In the paper of Steine and coworkers the prevalence of left ventricular (LV) systolic and diastolic

function in a stable cohort of COPD patients (n=100) with and without pulmonary hypertension (PH) was thoroughly evaluated by using both advanced echocardiography and cardiac MRI. Authors found that subclinical LV systolic dysfunction, as expressed by altered LV myocardial performance index (MPI ≥0.51) and LV strain (≤15.8%.) was a frequent finding in this cohort of COPD patients, even in those with normal pulmonary artery pressure. On the contrary, LV diastolic dysfunction was hardly documented in COPD patients.

The authors should be commended for the great effort in collecting several instrumental (including MRI and right heart catheterization) and biohumoral data and for the solid methodological approach used in a relatively large cohort of patients. However, I have the following concerns:

1) The hypothesis behind the study seems week. The reason why it would be clinically important to screen with that attention to details COPD patients to identify signs of subclinical myocardial damage should be better highlighted and explained. This is of key importance to understand the clinical repercussions of the study. Authors conclude “LV MPI and strain are two simple echo indices of LV global and systolic function, respectively, that should be implemented in the examination of patients with COPD. Since most COPD patients have subclinical LV dysfunction, this should be taken into consideration when the COPD patients´ dyspnea is considered by the clinicians.” However, the symptoms or the functional capacity (I mean 6MWT or better a cardiopulmonary exercise testing) have not been performed and thus it is unknown whether the decrease in MPI or LV strain at rest would actually contribute (and to which extent) to the symptoms and/or outcome of COPD patients.

2) A resting ECG or a dynamic exercise test have poor sensitivity to exclude comorbid coronary artery disease. This may be a major limitation of the study also considering that the great majority of patients were smokers or ex-smokers with a relevant exposition to smoking. Therefore, it is likely that a high percentage of patients do have macrovascular or microvascular coronary artery disease and thus the subclinical LV systolic dysfunction has to be related to smoking or CAD (not recognized by a simple ECG stress testing).

3) Authors should justify the choice of using TDI strain analysis only on the basal third of the septal and lateral LV walls, instead of considering the whole ventricle. What if some apical spearing was present? Considering a tomtec workstation why do not use speckle-tracking on the whole ventricle?

4) Please discuss also the potential importance of left atrial strain especially considering the strong association with symptoms (Cameli Int J Cardiol. 2019;286:87-91)

5) Surprisingly, no data on late gadolinium enhancement or T1-mapping is provided relative to cardiac MRI analysis. To use only cardiac MRI to obtain LV ejection fraction or LV RV ratio is a serious underuse of a much powerful technique. Is there any macro or microscopic fibrosis at MRI. Please report at least the LGE data.

6) Even more surprisingly authors have not assessed two biomarkers that can easily disclose a subclinical myocardial involvement, even more sensitive than echo and cardiac MRI, i.e. natriuretic peptides and high sensitivity troponins. This is a major limitation and seems not logical in such a complex study design including cardiac MRI and right heart catheterization. Do you have those data?

7) Again in the results the order and meaning of the several correlations provided seems mainly explorative and not supported by an overall hypothesis.

8) Please avoid comments in the results and leave them to the discussion (i.e. which explains the significant difference in cardiac index”).

9) Patients using beta-blokers, Warfarin or clopidogrel were also excluded. What about aspirin (are there any patients with CAD)? What about other drugs used in hypertension such as ACE-inhibitors, ARBs, MRA that can have an impact on myocardial performance?

10) Please show a CONSORT diagram to make the reader (and reviewers) aware of any potential selection bias. In a population of smokers as the one presented is very unusual to not find some atherosclerotic disease, either on carotid artery or coronary artery and so on. How many patients with CAD were excluded from the original population?

11) Finally, please specify the way the cutpoint of ≥0.51and <-15.8% were “pre”-defined, since this is of key relevance in defining the epidemiology of subtle LV dysfunction in your population. Please be aware and discuss the need to use cutpoints defined in similar population of the one under study and the problem of losing power or clinical information when dicothomizing a continous variable (please refer to Giannoni, PLoS One 2014;9:e81699.).

12) In the discussion, I do not understand why authors attribute the loss in MPI and LV strain to underfilling also in patients with completely normal pulmonary artery pressure. Why should those patients have a problem of the underfilling? Are there actually any significant differences in pulmonary vascular resistances in your population? From the data you showed patients with COPD and normal pulmonary pressure have slightly higher LV systolic volumes as compared to controls (underfilling?) Is there any relationship between PVR and MPI or LV strain? Please avoid overstatement and keep the discussion closer to the data you have. The problem of inflammation in this respect seems more promising and supported by data.

13) Please give more relevance also in the results and the discussion to the decrease observed in 2D and 3D LVEF and RVEF, do not focus only on MPI and LV strain, this seems a biased way of presenting your data.

have shown that mild COPD and subclinical LV dysfunction often coexist, the combination of these two is associated with an increased risk for long-term all-cause mortality. Also authors have mentioned about using preoperative ‘integrated cardiopulmonary risk index’ by performing standard preoperative spirometry and echocardiography.

Current study confirms abovementioned findings about coexisting of COPD and subclinical LV dysfunction, but also adds mechanisms for the reduced LV systolic function in COPD patients without pulmonary hypertension. Researchers have found that LV MPI and strain are two simple echo indices of LV global and systolic function in these patients and based on this they recommend to implement it in the examination of patients with COPD. In the light of the above; this study may be helpful in COPD management and can be used as simplified COPD management tool.

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PLoS One. 2020 Jul 16;15(7):e0235075. doi: 10.1371/journal.pone.0235075.r002

Author response to Decision Letter 0

14 May 2020

Answers to Reviewer #1 concerning the article

Left ventricular dysfunction in COPD without pulmonary hypertension

Answer:

Hypothesis: We agree with the comment from the reviewer that the hypothesis should be more highlighted and explained more thoroughly, in particular why it is important to discover subclinical LV systolic dysfunction. To overcome this request, we had to change the introduction substantially by adding new sentences and making deletions not only to be within similar number of words as the first edition, but also in the sense of highlighting the novel content better. The reviewer can in that regard study page four and five in the attached and revised article, where the novel sentences are marked in red and deletions will be found.

We agree with the reviewer that 6MWT and in particular cardiopulmonary exercise testing (CPET) are good functional tests in COPD patients and had fit in the article. Both tests have been performed as parts of a larger study including two PhDs and eight articles. These results are, however, not implemented in the present study partly because it has been presented before (1) and partly because the overall scope of this article had become too large.

Answer: We thank you for this comment. Cazolla M. et al found in a population-based retrospective study that COPD had 14% increased risk for ischemic events vs. 7% in the general population (2). On the other hand, Hong Y and co-workers studied more than 26.000 coronary angiograms retrospectively and found that odds ratio of having CAD was 0.83 for patients with COPD compared to those without COPD (3). The sensitivity of exercise testing ranges between 60 and 70%, while specificity has been reported between 85 and 90%(4). In addition to the regular dynamic exercise test, all our patients went through a cardiopulmonary exercise test (1), and all who could not perform a bicycle exercise test or perform a six minutes walking test, were excluded from the study. Although we cannot exclude that some of our patients had macrovascular coronary disease, and that these patients may have had a negative influence on LV systolic function, we do not believe this to have any important impact on our finding of subclinical LV dysfunction. We have, however, rephrased the second sentence in the Limitation subchapter, see below and on page 14, second paragraph:

When it comes to microvascular coronary artery disease, we do agree that this might be a possible and theoretical explanation for the subclinical LV dysfunction in COPD. We could not, however, find any study that has demonstrated such a direct connection in COPD. One study, however could show increased retinopathy in COPD (5). More interesting is the HFPEF paradigm introduced by Paulus WJ and Tschope C, who claim that patients with overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and hypertension induce a systemic proinflammatory state that causes coronary microvascular endothelial inflammation

which reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and in the end protein kinase G (PKG) activity in cardiomyocytes favoring hypertrophy development and increases resting tension (6) It is tempting to argue that such a mechanism also could be responsible for LV systolic subclinical dysfunction as presented in the present study. On the other hand, our COPD patient could hardly show any LV diastolic dysfunction that often precedes HFPEF.

Page 14, second paragraph: Although a thorough screening process and clinically relevant non-invasive testing with echocardiography, resting ECG and exercise testing were performed to unmask ischemic heart disease, we cannot entirely exclude neither macro nor microvascular disease in our patients.

Answer: We chose LV basal TDI strain of two reasons: The TDI strain findings of the basal part of the left ventricle is a summation of the systolic function or strain of the whole left ventricle. If the TDI strain is reduced further down towards the apex in the left ventricle, the basal strain or systolic deformation would also be reduced. A similar principle is used for systolic LV basal velocity and mitral annular plane systolic excursion (MAPSE) with M-mode

The second reason is a consequence of only performing strain measurement at the LV base: It is for the sake of simplicity, because we considered it for important to have reliable measurements that were easy to use. If apical spearing had been present as by amyloidosis, the LV basal strain would have been reduced as well. However, such patients would have been excluded in any case by the echo examination before inclusion.

Two-dimensional speckle tracing was not invented when this study was performed. In this respect we want to underline the following: It is well known that patients with COPD in most cases have reduced acoustic conditions. When two-dimensional speckle tracking is used, there will be a problem to achieve two-dimensional loops of good enough quality and thus impossible to measure strain on quite few of these patients. In the the ACE 1950 study, a community study including 3706 individuals of both sexes in their mid-sixties, we could measure LV two-dimensional strain in only 67% of the participants (7)

4) Please discuss also the potential importance of left atrial strain especially considering the strong association with symptoms (Cameli Int J Cardiol. 2019;286:87-91)

Answer: The study by Cameli M and co-workers have demonstrated a strong and negative correlation between quality of life (The Minnesota Living with Heart Failure Questionaire (MLHFQ)) and left atrial reservoir strain (8). The physical basis for this connection is that atrial stretch receptors are stimulated by increased filling pressure in patients with heart failure. This information is then translated by vagal afferent nerves to medulla and the limbic system where the perception of dyspnoea occurs. As mentioned in this paper, the size of the left atrium is well established as a prognostic factor, the larger size the worse prognosis. The paper by Cameli M et al. have thus given us a mechanism or connection (impaired reservoir atrial function) between experienced dyspnoea and quality of life in patients with heart failure.

It is tempting to see the paper by Cameli M et al in light of the present study, since dyspnoea is a main symptom in COPD. As mentioned on page 13, paragraph four, we could not show any clear evidences, neither by echo nor by right heart catheterisation (pulmonary wedge pressure) that our COPD patients had increased LV filling pressure. Although it should have been very interesting to perform left atrial reservoir strain on our patients to find if their dyspnoea partly is related to left atrial strain (or right atrium), it is to be expected that dyspnoea in COPD mainly is caused by the lungs.

Answer: We agree that late gadolinium enhancement (LGE) data and measurements of fibrosis had been interesting in this respect, in particular in view of possible mechanism for the subclinical LV dysfunction. The MRI examinations were performed 11 years ago, and the protocol was then set up merely for evaluation of volumes. No contrast was administered, and hence no LGE data are available. T1-mapping, as it is understood today, was not available when our original recordings were performed.

Answer: We have measured natriuretic peptides. They were originally within our paper in JACC from 2013, but were taken out according to space problems in that article, and because they were within normal references (9). NT pro-BNP were 9.8 (9.1,10.5) pmol/l in those without pulmonary hypertension and 10.0 (9.1,10.8) in those with pulmonary hypertension. NT pro-BNP was thus normal in both groups, and there was not any clinically important correlation to LV dysfunction. This is now added in table 1 on page 20. Since the present article is about LV dysfunction, NT pro-BNP is the most relevant of the two. As high sensitive troponin (Hs tnt) is more interesting concerning prognostic implication, it is our plan to perform the analysis based on biobank samples by use of high sensitive assay. This will, however, be quite another study.

7) Again in the results the order and meaning of the several correlations provided seems mainly explorative and not supported by an overall hypothesis.

Answer: We partly agree to this, and it has been discussed thoroughly among the authors. Our conclusion is that these correlations are connected and belongs to the context of the article. We agree, however that they, rated one by one, not necessarily support the overall hypothesis, but they explain associations and possible mechanisms which again are important for the final result, namely the substantial subclinical systolic LV dysfunction in patients with COPD.

8) Please avoid comments in the results and leave them to the discussion (i.e. which explains the significant difference in cardiac index”).

Answer: We have done as recommended, and taken out the sentence as pointed out by the reviewer. See page nine, first paragraph.

Answer: Patients on aspirin were only excluded if this were due to coronary artery disease, and they were, of course, thoroughly interviewed and examined with regards to CAD. As written on page six, first paragraph: ”Patients with history of congenital, rheumatic, valvular and ischemic heart disease, treated arterial hypertension with blood pressure >160/90 mmHg,….were also excluded.” This means that patients with well controlled hypertension who were on ACE-inhibitors (16 participants), ARBs (0 participants.) or MRA (0 participants.) were included. We do not consider these drugs to have negative impact on LV systolic function. Rather the other way around, since they are used in the treatment of LV dysfunction. If systemic blood pressure is not good enough controlled, this may have a negative impact on LV function. Moreover, excluding 37 participants with diabetes and/or hypertension did not change the prevalence of LV systolic dysfunction by LV MPI and LV strain (See page nine, second paragraph) As can be seen from table 1, a major part of the COPD patients were normotensive. Regarding patients with CAD, see point 2 above.

Answer: As the overall intention with the present study was to find out if the COPD disease itself had a negative impact on LV function, it was important to exclude any other cause than COPD that could damage LV function. These potential selection bias have now been outlined in point 2) with the given changes in the manuscript page 14, second paragraph, and point 9).

In addition, there was in advance performed a thorough screening process, where approximately 1300 patients with COPD were screened by one of the authors (Ingunn Skjorten) very thoroughly. Those with the slightest symptoms of CAD, were excluded in this part of the process. Unfortunately, we do not have any exact number how many that were excluded according to this reason. We have therefore not included a CONSORT diagram. Those participants who came through this needle`s eye were then exposed to exercise bicycle test. None of these patients experienced horizontal or downwards sloping of the ST segment ≥ 1 mm. However, four got chest pain, of whom two had normal CT angiograms, one normal coronary angiogram and one had a borderline stenosis which was not dilated.

Answer: We are thankful for making us aware of the problems of making threshold for a given continuous variable. As we have written in the method section on page seven, second paragraph: “mean+three standard deviations of the controls for all four were considered abnormal” were considered as the threshold or upper normal limit in our population. Although we considered by this to be well within the limit for not generating false positive results, since mean + 2SD is mostly used, we acknowledge, after studying the paper by Giannoni A and co-workers, that even then it is difficult to achieve reliable thresholds with continuous variables, which are highly depended on the mean of the different studies (9). According to this recognition, we have added Gianonni A et al as reference no 28 in the article and underlined this in the limitation section on page 15, paragraph three in the Limitation section by adding:

Page 15, paragraph three: “The present study reports upper normal limits for LV MPI, LV Strain, isovolumic relaxation time and isovolumic relaxation time adjusted for heart rate. Determining thresholds from continuous variable have many pitfalls as pointed out by Giannoni A and co-workers (28). Although we made three times standard deviation of the mean from the controls to avoid least possible false positive results, it does not necessarily provide our study with the correct upper normal limits.

Answer: This part requires are little more space:

First: “patients with completely normal pulmonary artery pressure.” Our no PH (no pulmonary hypertension) had 18±3 and those with PH had 29±4 mmHg in mean pulmonary pressure (mPAP) (Normal mPAP is 14±3 mmHg,) which reflect resting state. We have, however, in another invasive study, in the same patients by right heart catheterisation, demonstrated that even those with no PH have a pathological rise in their pulmonary pressure when they exercise (10).

Second: “Are there actually any significant differences in pulmonary vascular resistances in your population?” Again: According to the existing upper normal limits at that time (2012), PVR was elevated at rest in all patients with PH and in 50 patients (69%) in no-PH group (10).

Third: Under-filling: Our data show that left atrial and LV size were undersized compared to the right side. We consider this, together with the impaired RV function and the significant associations between stroke volume and left atrium volume (decreasing SV and decreasing left atrium), is a reflection of under-filling of the left side. This is well illustrated in figure 2B and 2C where a gradual reduction of stroke volume is accompanied with a decrease in MPI and strain. Under-filling of the left side in similar patients has also been emphasized by others (See ref 1-3 in the article) However, we acknowledge that we have presented this more or less as the only explanation, which we regret. We have thus modified this by adding the sentence below on page 14, first paragraph. We are grateful to the reviewer who has made us aware of this.

Page 14, paragraph one: Although under-filling probably is not the only mechanism for the reduced size of the left side,

Answer: We agree with the reviewer that the findings regarding 2D and 3D EF are too little focused in the article, and we have therefore added a supplement in the discussion part on page 11, third paragraph (See below). However, the right heart function in general including RVEF, has been thoroughly featured in our previous JACC paper, which is also referred to several times (11). Thus, we do not find it correct to go deeper into this topic in the present paper.

Page 11, third paragraph: Moreover, traditional method as 2D and novel 3D ejection fraction were also reduced in COPD with and without PH as compared to normal individuals. The difference, however, was small and probably not of clinical significance, but emphasizes the findings of LV strain and MPI. In addition, LV ejection fraction by CMR was also found mildly reduced in 19%.

References

1. Ingunn Skjørten , Janne Mykland Hilde, Morten Nissen Melsom, Viggo Hansteen, Kjetil Steine, Sjur Humerfelt Pulmonary Artery Pressure and PaO2 in Chronic Obstructive Pulmonary Disease. Respir Med. 2013;107:1271-9.

2. Cazzola M. Bettoncelli G. Sessa E. Cricelli C. Biscione G. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration. 2010; 80: 112-119 

3. Hong Y, Graham MM, Southern D, McMurtry MS. The Association between Chronic Obstructive Pulmonary Disease and Coronary Artery Disease in Patients Undergoing Coronary Angiography.COPD. 2019;16:66-71.

4. Fuller T, Movahed A. Current review of exercise testing: application and interpretation. Clin Cardiol.1987;10:189-200.

5. Chew SK, Colville D, Canty P, Hutchinson A, Wong A, Luong V, Wong TY, McDonald C, Savige J. Kidney Hypertensive/Microvascular Disease and COPD: a Case Control Study. Blood Press Res. 2016;41:29-39.

6. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62:263-71.

7. Aagaard EN, Kvisvik B, Pervez MO, Lyngbakken MN, Berge T, Enger S, Orstad EB, Smith P, Omland T, Tveit A, Røsjø H, Steine K.Left ventricular mechanical dispersion in a general population: Data from the Akershus Cardiac Examination 1950 study. Eur Heart J Cardiovasc Imaging. 2020;21:183-190.

8. Matteo Cameli, Carlotta Sciaccaluga, Ferdinando Loiacono, Iana Simova, Marcelo H Miglioranza, Dan Nistor, Francesco Bandera, Michele Emdin, Alberto Giannoni, Marco M Ciccone, Fiorella Devito, Andrea Igoren Guaricci, Stefano Favale, Matteo Lisi, Giulia E Mandoli, Michael Henein, Sergio Mondillo. The Analysis of Left Atrial Function Predicts the Severity of Functional Impairment in Chronic Heart Failure: The FLASH Multicenter Study. Int J cardiol 2019;286:87-91

9. Alberto Giannoni, Resham Baruah, Tora Leong, Michaela B Rehman, Luigi Emilio Pastormerlo, Frank E Harrell, Andrew J S Coats, Darrel P Francis. Do Optimal Prognostic Thresholds in Continuous Physiological Variables Really Exist? Analysis of Origin of Apparent Thresholds, With Systematic Review for Peak Oxygen Consumption, Ejection Fraction and BNP. PLOSone 2014;9:

10. Janne Mykland Hilde, Ingunn Skjørten, Ole Jørgen Grøtta, Viggo Hansteen, Morten Nissen Melsom, Jonny Hisdal, Sjur Humerfelt, Kjetil Steine. Haemodynamic responses to exercise in patients with COPD. Eur Respir J 2013;41:1031–41.

11. Janne Mykland Hilde, Ingunn Skjørten, Ole Jørgen Grøtta, Viggo Hansteen, Morten Nissen Melsom, Jonny Hisdal, Sjur Humerfelt, Kjetil Steine, Right Ventricular Dysfunction and Remodeling in Chronic Obstructive Pulmonary Disease Without Pulmonary Hypertension. Journal of the American College of Cardiology 2013;62:1103-1111.

Answers to Reviewer #2 concerning the article

Left ventricular dysfunction in COPD without pulmonary hypertension

Reviewer #2: I have read with great interest the article regarding LV dysfunction in COPD patients without pulmonary hypertension. The novelty in research paper is slightly dubious. Researches have already studied this problem. For example- Willem-Jan Flu A et al (Co-existence of COPD and left ventricular dysfunction in vascular surgery patients. Respiratory Medicine (2010) 104, 690-696) have shown that mild COPD and subclinical LV dysfunction often coexist, the combination of these two is associated with an increased risk for long-term all-cause mortality. Also authors have mentioned about using preoperative ‘integrated cardiopulmonary risk index’ by performing standard preoperative spirometry and echocardiography. 

Answer: Willem-Jan Flu A and co-workers have studied 1003 patients undergoing prospectively peripheral vascular or endovascular surgery (1). This and the present study are, however, quite different of two main reasons: First, according to a review article by Gersh BJ et al., the prevalence of serious angiographic coronary artery disease ranges from 37% to 78% in patients undergoing operation for peripheral vascular disease (2). The LV dysfunction in the study by Willem-Jan Flu A was therefore probably mainly caused by ischemic heart disease (1). Second, the aim of the present study was to find out if the COPD disease itself has a negative impact on LV function. It was therefore a main issue to exclude patients with coronary heart disease, since this is also present in COPD. This was performed by a systematic examination by one of the authors (IS), where approximately 1300 outpatients COPD were screened and then examined by a bicycle exercise test (JMH) and echo (JMH), and patients with LV EF < 50% were excluded. We cannot therefore agree with reviewer #2 that “The novelty in research paper is slightly dubious”, and we hope that what is written above is elucidating in this concern. We are, however, aware, even after such a thorough selecting process, that a few patients with silent coronary heart disease may have been included in our study. We believe, however, that this has not had any important impact on our result.

Answer: We are thankful for the recognition of our work regarding the usefulness of LV MPI and LV strain in the assessment of LV function in patients with COPD.

References

1. Willem-Jan Flu, Yvette R B M van Gestel, Jan-Peter van Kuijk, Sanne E Hoeks, Ruud Kuiper, Hence J M Verhagen, Jeroen J Bax, Don D Sin, Don Poldermans. Co-existence of COPD and Left Ventricular Dysfunction in Vascular Surgery Patients. Respir med 2010;104:690-96.

2. Gersh BJ, Rihal CS, Rooke TW, Ballard DJ. Evaluation and management of patients with both peripheral vascular and coronary artery disease. J Am Coll Cardiol. 1991;18:203-14.

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PLoS One. doi: 10.1371/journal.pone.0235075.r003

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9 Jun 2020

Left ventricular dysfunction in COPD without pulmonary hypertension

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Reviewer #1: The authors should be awarded for their effort to go through all my previous concerns. I believe that the paper now deserves to be published.

Reviewer #2: The novelty in research paper is slightly dubious. Researches have already studied this problem. For example- Willem-Jan Flu A et al (Co-existence of COPD and left ventricular dysfunction in vascular surgery patients. Respiratory Medicine (2010) 104, 690-696) have shown that mild COPD and subclinical LV dysfunction often coexist, the combination of these two is associated with an increased risk for long-term all-cause mortality. Also authors have mentioned about using preoperative ‘integrated cardiopulmonary risk index’ by performing standard preoperative spirometry and echocardiography. Current study confirms abovementioned findings about coexisting of COPD and subclinical LV dysfunction, but also adds mechanisms for the reduced LV systolic function in COPD patients without pulmonary hypertension. Researchers have found that LV MPI and strain are two simple echo indices of LV global and systolic function in these patients and based on this they recommend to implement it in the examination of patients with COPD. In the light of the above this study may be helpful in COPD management and can be used as simplified COPD management tool. Reviewer suggests accepting the article.

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PLoS One. doi: 10.1371/journal.pone.0235075.r004

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30 Jun 2020

PONE-D-20-04365R1

Left ventricular dysfunction in COPD without pulmonary hypertension

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PERMALINK

Left ventricular dysfunction in COPD without pulmonary hypertension

Janne M Hilde

Jonny Hisdal

Ingunn Skjørten

Viggo Hansteen

Morten N Melsom

Ole J Grøtta

Milada C Småstuen

Ingebjørg Seljeflot

Harald Arnesen

Sjur Humerfelt

Kjetil Steine

Roles

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Methods

Study population

Table 1. Clinical characteristic of controls and patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with pulmonary hypertension (COPD-PH).

Blood collections

Echocardiography

Cardiac magnetic resonance imaging

Hemodynamic measurements

Statistical analyses

Results

Demographic and clinical data

Table 2. Right heart catheterization values in patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with pulmonary hypertension (COPD-PH).

Table 3. Echocardiographic measurements of LV global, systolic and diastolic function, and dimensions of the LV, left atrium and right atrium in healthy controls, patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with pulmonary hypertension (COPD-PH).

LV systolic function

Fig 1. LV myocardial performance index and LV strain in controls, COPD patients with normal and intermediate pulmonary pressure and with pulmonary hypertension.

Table 4. LV function by LV MPI and LV strain, key respiratory and invasive hemodynamic indices of COPD patients with no pulmonary hypertension divided in two groups, mean pulmonary pressure ≤20 mmHg (normal) and 21–24 mmHg (borderline).

Fig 2. Associations between stroke volume and residual volume, LV myocardial performance index, LV strain and heart rate adjusted isovolumic relaxation time.

LV diastolic function

LV and RV volumes

Table 5. Left and right ventricle volumes and ejections fractions in healthy controls, patients with chronic obstructive pulmonary disease without (COPD-non-PH) and with (COPD-PH) pulmonary hypertension.

Discussion

LV systolic function

LV diastolic function

Limitations

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Vincenzo Lionetti

Roles

Transfer Alert

Author response to Decision Letter 0

Decision Letter 1

Vincenzo Lionetti

Roles

Acceptance letter

Vincenzo Lionetti

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

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