Right Ventricle Function in Patients with Acute Coronary Syndrome and Concomitant Undiagnosed Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is frequently undiagnosed in patients with ischemic heart disease. Nowadays, it is still unknown whether undiagnosed concomitant COPD is related to early structural changes of the heart, as detectable by trans-thoracic echocardiography (TTE). Starting from the study population of the Screening for COPD in ACS Patients (SCAP) trial, we sought to investigate potential differences in echocardiographic parameters in patients with acute coronary syndromes (ACS), with or without undiagnosed concomitant COPD. Overall, 137 patients were included. Undiagnosed COPD was detected by spirometry in 39 (29%) patients. TTE was performed at inclusion (before hospital discharge) and after six months. Several echocardiographic parameters including fractional area change (FAC) and RV strain (RVS), were measured. Patients with undiagnosed COPD, as compared to those without COPD, showed lower FAC and reduced RVS both at inclusion (37 ± 6% vs. 44 ± 9%, p < 0.001; −15 ± −4 vs. −20 ± −5, p < 0.001, respectively) and after six months (38 ± 7% vs. 45 ± 9%, p < 0.001; −16 ± −4 vs. −20 ± −5, p < 0.001, respectively). After multivariate analysis undiagnosed COPD was independently associated with lower FAC and reduced RVS at baseline and at TTE after six months. Early impairment of RV function can be detected in ACS patients with concomitant undiagnosed COPD. If these alterations may be changed by an early diagnosis and an early treatment, should be evaluated in future studies. Clinical trial registration: NCT02324660.

Keywords:

• Strain
• fractional area change
• right ventricle
• undiagnosed COPD
• acute coronary syndrome

Introduction

Chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD) frequently coexist in the same patient. These diseases share common risk factors (age, smoking habit) and underlying pathophysiological mechanisms (chronic inflammatory status, increased arterial stiffness, increased platelet reactivity, endothelial dysfunction) (1). However, despite the clinical relevance of these comorbid conditions, COPD is frequently undiagnosed in patients with IHD (2,3). This is true for both out- and in-hospital patients with a significant impact both on short and long-term prognosis (4). Previous studies show that COPD, even if mild, is related to signs of dysfunction of the right ventricle (RV) detectable by trans-thoracic echocardiography (TTE) (5). Among them, strain of the right ventricle (RVS) is significantly reduced in patients with COPD even without pulmonary hypertension (PH) (5). Whether these or other abnormalities in echocardiographic parameters of the RV function are present also in patients with undiagnosed COPD is still unknown. The identification of such a marker can represent a helpful clinical tool for early diagnosis and management of comorbidity with potential impact on the short and long-term prognosis of the patients. For this purpose, we performed a sub-analysis of the Screening for COPD in acute coronary syndrome (ACS) Patients (SCAP) trials (3) aimed to evaluate the differences in echocardiographic parameters of patients admitted to hospital because of an acute coronary syndrome with or without concomitant (undiagnosed at the time of hospitalization) COPD.

Materials and methods

This is a pre-specified sub-analysis of the SCAP trial (3). In brief, the SCAP trial is a prospective, single-center, investigator-driven study enrolling consecutive ACS patients with a smoking habit history admitted to our University Hospital (Azienda Ospedaliera Universitaria di Ferrara, Ferrara, Italy) between December 2014 and August 2015. The main study showed that a screening procedure, which included peak expiratory flow (PEF) rate and a respiratory health status questionnaire (RHSQ), administered before hospital discharge, discriminated ACS patients at negligible risk of undiagnosed COPD. The current sub-study investigates the echocardiographic parameters in the study population, which was stratified according to the presence or not of undiagnosed COPD. All patients signed the written informed consent. The study was approved by the Local Ethic Committee (Comitato Etico Unico della Provincia di Ferrara). The study protocol was registered at clinicaltrial.gov with identifier: NCT02324660.

Study population

The main inclusion and exclusion criteria, as well as the complete study flow chart, are reported elsewhere (3,6). In short, we included smokers or former smokers (≥10 pack/years) hospitalized with a clinical diagnosis of ACS, as defined by current European guidelines (7). Exclusion criteria included previous diagnosis of COPD and/or asthma, known pulmonary diseases other than COPD, ongoing pneumonia, ongoing heart failure, documented or suspicion of malignant disease, life expectancy <1 year, recent thoracic trauma.

Definition of undiagnosed COPD

Two months after discharge, all patients underwent spirometry to determine the presence of COPD (1). Briefly, COPD was diagnosed in the presence of: (i) exposure to risk factors for the disease (all patients enrolled in the study were current former smokers); (ii) presence of chronic respiratory symptoms (mainly shortness of breath, cough and sputum) and (iii) post-bronchodilator fixed ratio forced expiratory volume at first second (FEV1)/forced vital capacity (FVC) < 0.7 (1,3). The fixed ratio FEV1/FVC < 0.7 is known to be age-biased, possibly causing 10-25% over diagnosis in the elderly (8). For this reason, the patients were also grouped according to the presence or absence of airflow limitation, which was defined using the 5th percentile of normal distribution of FEV1/vital capacity (VC) as lower limit of normality according to ERS/ATS recommendation (8–10). A spirometry was performed by two expert pulmonologists and revised by an independent reviewer blinded to patients’ clinical conditions and outcomes. Spirometry was performed according to standardized procedures (9,10).

Trans-thoracic echocardiography

Baseline TTE was performed in all patients at the time of the enrollment, which occurred at hospital discharge. A second TTE was repeated at the six-month follow-up visit. The baseline TTE was available in all patients, but for four patients the follow-up was not feasible (n = 1 died, n = 1 admitted to hospital for heart failure, n = 2 refused). TTE was performed by expert cardiologists (ET, EG) blinded to the results of the spirometry. Images have been reviewed and analyzed by two blinded independent reviewers (RP, AF). TTEs have been performed with GE Vivid 7 and E9 (GE Healthcare, Horten, Norway) with 3.5 MHz or M5S transducers. All patients underwent a comprehensive TTE, taking into consideration both left and RV function with the acquisition of standard 2D images, color, pulsed and continuous wave Doppler images. Two cardiac cycles have been recorded for every image and then stored in cine-loop format with a frame rate between 50 and 70 Hz. The post-processing analyses have been performed with EchoPAC software Version 201 (GE Healthcare, Horten, Norway). Whenever possible, all measurements have been indexed for the body surface area (BSA) of the patients. The following parameters have been recorded:

Left heart: (i) Left ventricle (LV) end-systolic and end-diastolic volume in four chamber view (4CV) and two chamber view (2CV) (11). (ii) Ejection fraction (EF) calculated by the modified biplane Simpson method (11). (iii) End-systolic left atrium area in 4CV and 2CV and left atrium length in 4CV with calculation of left atrial volume indexed for BSA (11). (iv) LV diastolic function was assessed with measurement of trans-mitral Doppler flow of peak velocity during the early filling (E wave), atrial contraction (A wave) and estimation of deceleration time (dT), then with the assessment of tissue Doppler images on mitral annulus for the estimation of the peak velocity of early filling (derived as mean value between septal and lateral é). Eventually, the ratio between E and é was calculated (12). (v) Global longitudinal strain (GLS) of the LV (13): the GLS was calculated from the apical views (2CV, 4CV and long axis view (LAX)). For each view, three sample points were based at the endocardium at the level of the septal and lateral mitral annulus and at the apex of the LV for the creation of the region of interest (ROI). Once the ROI was positioned over the entire myocardium, minimal adjustment of the ROI position was performed to obtain optimal tracking (13). GLS was calculated by the software as the average of the peak systolic strain in the three apical views.

Right heart: (i) End-diastolic basal diameter of the RV assessed in 4CV (8). (ii) End-diastolic thickness of the RV assessed in parasternal LAX (14). (iii) End-systolic area and length of the right atrium in 4CV with subsequent calculation of atrium volume indexed for BSA (11). (iv) End-systolic and end-diastolic area of the RV in 4CV, with calculation of fractional area change (FAC) (11). (v) Tricuspid annular plane systolic excursion (TAPSE) calculated by m-mode at the junction of the tricuspid valve and RV free wall in the apical 4CV. (vi) Systolic pulmonary arterial pressure (sPAP) calculated by the addition of estimated right atrial pressure and the calculated RV pressure obtained by the modified Bernoulli formula (4 × (peak tricuspid regurgitation velocity)²). (vii) Pulmonary acceleration time measurement (ACT). (viii) Mean pulmonary arterial pressure (mPAP) calculated by the formula: mPAP = (79 − 0.45 (ACT)) (15). (ix) Strain of the free wall of the right ventricle (RVS) (16) was calculated by the apical 4CV. The sample points for ROI creations were positioned at the basal and apical RV endocardium. The RVS was the average of the peak systolic strain of the three segments of the free wall of the RV.

Statistical analysis

Continuous data were tested for normal distribution with the Kolmogorov-Smirnov test. Normally distributed values were presented as mean ± SD and compared by t test. Otherwise, median [interquartile range] and Mann-Whitney U were used. Overtime changes of echocardiographic parameters were assessed with t-test for matched pairs or Wilcoxon signed-rank test, as appropriate. Categorical variables were summarized in terms of counts and percentages and were compared by using the two-sided Fisher’s exact test. Intraclass correlation coefficients were used to measure the inter-rater agreement between independent reviewers. Univariate logistic regression was used to test the relationship between all variables listed in Table 1 and TTE parameters of the RV. The role of undiagnosed COPD on RV echocardiographic parameters was assessed with multivariate logistic regression after correction for potential confounding factors (age, pack/years, inferior location) and expressed as OR and 95% confidence interval. Finally, the inter-rater agreement between operators was tested with Bland-Altman scatter-plot analysis and intraclass correlation coefficients. A 2-sided value of p < 0.05 was considered significant. All analyses were performed with SPSS version 21 (IBM, Italy).

Table 1. Baseline characteristics of the study population.

	Undiagnosed COPD (according GOLD document)		Airflow limitation (according to ATS-ERS recommendation)
	No (n = 98)	Yes (n = 39)	No (n = 94)	Yes (n = 43)	P1	P2
Age, (years)	63 ± 11	69 ± 8	65 ± 9	68 ± 7	<0.01	0.03
Male sex, no. (%)	83 (85)	32 (82)	79 (81)	36 (83)	0.8	0.9
BMI, (Kg/m2)	28 ± 4	27 ± 4	28 ± 4	27 ± 4	0.2	0.3
Diabetes, no. (%)	21 (21)	11 (28)	20 (21)	12 (28)	0.5	0.4
Hypertension, no. (%)	67 (68)	25 (64)	64 (68)	28 (65)	0.7	0.7
Hyperlipidemia, no. (%)	55 (56)	17 (44)	52 (56)	20 (47)	0.2	0.3
Current smoker, no. (%)	44 (45)	17 (44)	42 (45)	19 (44)	0.9	0.9
Previous smoker, no. (%)	54 (55)	22 (56)	52 (55)	24 (55)	0.8	0.9
Pack/years	28 [15–45]	40 [16–60]	26 [13–43]	40 [16–60]	<0.01	<0.01
Prior MI, no. (%)	16 (16)	8 (21)	16 (17)	8 (18)	0.3	0.8
Prior PCI, no. (%)	18 (18)	6 (15)	18 (19)	6(14)	0.8	0.5
Prior CABG, no. (%)	5 (5)	2 (5)	6 (6)	1 (2)	0.9	0.3
Clinical presentation, no. (%)
STEMI	40 (41)	19 (49)	40 (43)	19 (44)	0.6	0.7
NSTEMI	34 (35)	14 (36)	31 (33)	17 (40)
Unstable angina	24 (24)	6 (15)	23 (24)	7 (16)
Angiographic data
Multivessel PCI	15 (15)	7 (18)	14 (15)	8 (19)	0.6	0.6
Target vessel of PCI
LAD	53 (54)	21 (54)	53 (56)	22 (52)	0.8	0.9
LCx	25 (25)	10 (25)	26 (28)	9 (21)
RCA	32 (32)	14 (35)	32 (30)	14 (32)
LM	3 (3)	1 (2)	3 (3)	1 (2)
Cardiovascular therapy, no. (%)
Aspirin	97 (99)	39 (100)	93 (99)	43 (100)	0.9	0.9
P2Y12 inhibitor	98 (100)	39 (100)	94 (100)	43 (100)	0.9	0.9
Beta-blocker	84 (86)	35 (90)	81 (86)	38 (89)	0.8	0.7
ACE inhibitor/ARB antagonist	88 (90)	37 (95)	86 (91)	39 (91)	0.5	0.9
Statin	96 (98)	37 (95)	92 (98)	41 (95)	0.3	0.4
RSHQ	18[15–21]	22[18–24]	17[14–20]	23[19–25]	<0.01	<0.01
Lung function data
VC (L)	3.9 ± 0.8	3.4 ± 0.7	3.9 ± 0.8	3.5 ± 0.7	<0.01	0.02
VC (% predicted)	102 ± 19	97 ± 22	102 ± 19	98 ± 21	0.2	0.3
FVC (L)	3.8 ± 0.8	3.3 ± 0.7	3.8 ± 0.9	3.3 ± 0.7	<0.01	<0.01
FVC (% predicted)	102 ± 19	97 ± 20	102 ± 19	97 ± 20	0.1	0.1
FEV1 (L)	2.9 ± 0.7	2.1 ± 0.5	2.8 ± 0.7	2.1 ± 0.5	<0.01	<0.01
FEV1 (% predicted)	98 ± 16	78 ± 15	98 ± 16	80 ± 15	<0.01	<0.01
Post-bronchodilator FEV1 (L)	2.8 ± 0.6	2.2 ± 0.5	2.8 ± 0.6	2.3 ± 0.5	<0.01	<0.01
Post-bronchodilator FEV1 (% predicted)	100 ± 19	83 ± 15	100 ± 18	82 ± 16	<0.01	<0.01
Post-bronchodilator FEV1/FVC (%)	76 ± 6	65 ± 5	75 ± 7	66 ± 7	<0.01	<0.01
FEV1/VC % predicted	86 ± 5	77 ± 7	90 ± 1.8	78 ± 7	<0.01	<0.01

COPD: chronic obstructive pulmonary disease. BMI: body mass index. MI: myocardial infarction. PCI: percutaneous coronary intervention. CABG: coronary artery bypass graft. STEMI: ST-segment elevation myocardial infarction. NSTEMI non ST-segment elevation myocardial infarction. UA: unstable angina. LAD: left anterior descending. LCx: left circumflex. RCA: right coronary artery. LM: left main. ACE: Angiotensin converting enzyme. ARB: angiotensin 2 receptor. RSHQ: Respiratory Health Status Questionnaire. PEF: Peak expiratory flow. P1: comparison between patients with or without COPD [1]; P2: comparison between patients with or without airflow limitation [8].

Results

Overall, 137 patients were included in the study. Baseline clinical characteristics are detailed in Table 1. COPD, based on clinical findings, was diagnosed in 39 (29%) patients (3). As previously reported, the large majority of patients had mild (59%) to moderate (38%) airflow limitation (3). Lung function parameters have been previously detailed (3) and reported also in Table 1. Only age and pack/years significantly differed between patients with vs. without concomitant undiagnosed COPD. Similar results were obtained when the study population was grouped based on the presence (n = 43) or absence (n = 94) of airflow limitation (irrespective of the clinical diagnosis of COPD and defined according to ERS/ATS recommendation (8)) (Table 1).

Baseline trans-thoracic echocardiography

When comparing parameters of the LV, no difference was found in patients admitted for ACS with or without concomitant undiagnosed COPD (Table 2). Conversely, patients with concomitant undiagnosed COPD had significantly lower FAC (38 ± 6% vs. 44 ± 9%, p < 0.001) as well as significantly reduced RVS (−15 ± −4 vs. −20 ± −5, p < 0.001), compared to patients without COPD (Table 2). Interestingly, the inferior location of MI did not influence the results. Indeed, RVS and FAC did not differ between patients with inferior location of myocardial infarction vs those without inferior location (RVS −19 ± −6 vs. −19 ± −5, p = 0.1 and FAC 42 ± 9% vs. 42 ± 9%, p = 0.3). After correction for potential confounding factors (age, pack/years and inferior location of MI), undiagnosed concomitant COPD was independently associated with reduced FAC (OR 1.12; 95% CI 1.04–1.20; p = 0.002) and reduced RVS (OR 1.11; 95% CI 1-1.23, p = 0.042). Similar results were obtained when the study population was grouped according to the presence (n = 43) or absence (n = 94) of airflow limitation (irrespective of the clinical diagnosis of COPD) (Table 3). A reduced FAC (OR 1.07; 95% CI 1.00–1.14; p = 0.03) and reduced RVS (OR 1.27; 95% CI 1.10–1.46, p = 0.001) were independently related to airflow limitation.

Table 2. Baseline and six-month trans-thoracic echocardiography (TTE) in patient with or without COPD [1].

	Baseline TTE parameters in patients with concomitant Undiagnosed COPD			6-month TTE parameters in patients with concomitant Undiagnosed COPD
Left heart	No (n = 98)	Yes (n = 39)	p	No (n = 95)	Yes (n = 38)	p	p1	p2
biEDV, ml	114 ± 37	114 ± 33	0.9	101 ± 22	114 ± 29	0.7	0.9	0.8
biESV, ml	54 ± 3	57 ± 5	0.6	54 ± 27	57 ± 26	0.9	0.9	0.5
EF, %	54 ± 12	51 ± 10	0.3	52 ± 8	56 ± 9	0.7	0.8	0.7
LV GLS	−13 ± −4	−13 ± −4	0.3	−15 ± −4	−15 ± −4	0.3	<0.001	0.005
LAVol i, ml/m^2	23 ± 10	27 ± 12	0.08	24 ± 13	27 ± 15	0.2	0.5	0.8
E wave, cm/s	75 ± 24	76 ± 26	0.9	67 ± 12	69 ± 15	0.1	0.1	0.9
A wave, cm/s	74 [58–83]	71 [60–83]	0.4	80 [35–130]	85 [52–105]	0.4	0.9	0.7
E/A	1 [0.8–1.4]	1.1 [0.7–1.5]	0.2	0.9 [0.5–2.2]	0.9 [0.5–1.7]	0.3	0.6	0.7
dT, ms	208 [168–247]	217 [174–282]	0.8	263 [179–325]	235 [160–334]	0.5	0.1	0.6
e’, cm/s	6 ± 2	5 ± 1	0.3	7 ± 2	7 ± 2	0.6	0.3	0.2
E/e’	12 [7–22]	15 [8–25]	0.3	9[7–17]	7[6–15]	0.1	0.2	0.2
Right heart
FAC, %	44 ± 9	37 ± 6	<0.001	45 ± 9	38 ± 7	<0.001	0.2	0.3
Basal dmt, cm	3.6 ± 0.6	3.6 ± 0.7	0.8	3.4 ± 0.7	3.7 ± 0.7	0.7	0.4	0.5
TAPSE, cm	2.0 ± 0.4	2.0 ± 0.4	0.8	2.2 ± 0.3	1.9 ± 0.7	0.2	0.2	0.4
RV thickness, cm	0.4 ± 0.1	0.5 ± 0.1	0.3	0.4 ± 0.1	0.5 ± 0.2	0.6	0.1	0.2
RA Vol i, ml/m^2	21 ± 9	23 ± 8	0.3	22 ± 10	27 ± 8	0.01	0.5	0.03
mPAP, mmHg	30 ± 9	26 ± 11	0.3	28 ± 11	25 ± 13	0.9	0.6	0.7
sPAP, mmHg	35 ± 11	36 ± 13	0.7	27 ± 12	35 ± 14	0.001	0.03	0.7
ACT, ms	110 ± 23	119 ± 25	0.3	118 ± 25	111 ± 30	0.7	0.6	0.7
RVS	−20 ± −5	−15 ± −4	<0.001	−20 ± −5	−16 ± −5	<0.001	0.6	0.3

p1: for the comparison between baseline vs. 6-month in patients without undiagnosed COPD.

p2: for the comparison between baseline vs. 6-month in patients with undiagnosed COPD.

TTE: trans-thoracic echocardiography. COPD: chronic obstructive pulmonary disease.

biEDV: biplane end-diastolic volume; biESV: biplane end-systolic volume; EF: ejection fraction; LV GLS: left ventricle global longitudinal strain; LAVol i: left atrium volume indexed for BSA; dt: deceleration time; FAC: fractional area change; Basal dmt: basal diameter; TAPSE: tricuspid annular plane systolic escursion; RV: right ventricle; RA Vol i: right atrium volume indexed for BSA; mPAP: mean pulmonary arterial pressure; sPAP: systolic pulmonary arterial pressure; ACT: acceleration time; RVS: strain of the free wall of the right ventricle.

Table 3. Baseline and six-month trans-thoracic echocardiography (TTE) in patients with or without airflow limitation [8].

	Baseline TTE parameters In patients with Airflow limitation			6-month TTE parameters In patients with Airflow limitation
Left heart	No (n = 94)	Yes (n = 43)	p	No (n = 91)	Yes (n = 42)	p	p1	p2
biEDV, ml	112 ± 37	115 ± 32	0.7	114 ± 37	113 ± 39	0.8	0.8	0.7
biESV, ml	54 ± 27	57 ± 26	0.6	54 ± 3	53 ± 28	0.9	0.5	0.9
EF, %	53 ± 11	52 ± 10	0.6	54 ± 12	54 ± 12	0.6	0.8	0.9
LV GLS	−13 ± −3	−12 ± −4	0.3	−13 ± −4	−15 ± −3	0.3	0.002	0.001
LAVol i, ml/m^2	23 ± 10	27 ± 11	0.1	23 ± 10	29 ± 10	0.3	0.1	0.06
E wave, cm/s	74 ± 24	77 ± 23	0.5	75 ± 24	75 ± 21	0.1	0.2	0.9
A wave, cm/s	79 [59–90]	78 [59–90]	0.5	77 [55–86]	74 [60–85]	0.9	0.9	0.8
E/A	0.6 [0.8–1.2]	0.9 [0.7–1.1]	0.2	1 [0.8–1.4]	0.8 [0.7–1.2]	0.5	0.5	0.8
dT, ms	219 [172–280]	207 [160–263]	0.5	206 [164–232]	251 [192–300]	0.07	0.4	0.6
é, cm/s	6 ± 2	5 ± 9	0.2	6 ± 2	8 ± 2	0.6	0.3	0.2
E/é	9 [7–17]	7 [6–15]	0.4	12 [7–22]	1 [7–22]	0.3	0.2	0.3
Right heart
FAC, %	43 ± 13	36 ± 6	0.007	45 ± 9	41 ± 8	0.03	0.21	0.3
Basal dmt, cm	3.4 ± 0.7	3.7 ± 0.7	0.8	3.4 ± 0.6	3.6 ± 0.6	0.2	0.4	0.5
TAPSE, cm	2.0 ± 0.4	2.1 ± 0.4	0.6	2.1 ± 0.4	2.1 ± 0.4	0.9	0.3	0.9
RV thickness, cm	0.4 ± 0.1	0.5 ± 0.2	0.8	0.4 ± 0.2	0.4 ± 0.1	0.9	0.1	0.3
RA Vol i, ml/m^2	20 ± 9	21 ± 9	0.6	24 ± 9	26 ± 9	0.1	0.5	0.004
mPAP, mmHg	29 ± 10	25 ± 11	0.3	27 ± 10	28 ± 11	0.7	0.4	0.3
sPAP, mmHg	34 ± 10	38 ± 12	0.04	26 ± 16	29 ± 15	0.4	0.05	0.1
ACT, ms	110 ± 22	120 ± 24	0.3	115 ± 23	116 ± 26	0.8	0.4	0.4
RVS	−19 ± −5	−16 ± −3	0.01	−20 ± −5	−15 ± −4	0.006	0.4	0.1

p1: for the comparison between baseline vs. 6-month in patients without undiagnosed COPD.

p2: for the comparison between baseline vs. 6-month in patients with undiagnosed COPD.

TTE: trans-thoracic echocardiography. COPD: chronic obstructive pulmonary disease.

biEDV: biplane end-diastolic volume; biESV: biplane end-systolic volume; EF: ejection fraction; LV GLS: left ventricle global longitudinal strain; LAVol i: left atrium volume indexed for BSA; dt: deceleration time; FAC: fractional area change; Basal dmt: basal diameter; TAPSE: tricuspid annular plane systolic escursion; RV: right ventricle; RA Vol i: right atrium volume indexed for BSA; mPAP: mean pulmonary arterial pressure; sPAP: systolic pulmonary arterial pressure; ACT: acceleration time; RVS: strain of the free wall of the right ventricle.

Six-month trans-thoracic echocardiography

At the control assessment performed 6 months after discharged, we did not find any significant difference in the LV parameters between patients with and without COPD (Table 2). Significant differences were observed in the parameters of the RV (Table 2). FAC was significantly lower (37 ± 7% vs. 46 ± 9%, p < 0.001) and RVS significantly reduced (−16 ± −4 vs. −20 ± −5, p < 0.001) in patients with concomitant COPD compared to those without COPD (Table 2). Furthermore, in patients with concomitant COPD compared to patients without concomitant COPD, we found significantly higher RA atrium volume (27 ± 8 ml/m² vs. 22 ± 10 ml/m², p = 0.01), as well as significantly higher level of sPAP (35 ± 14 mmHg vs. 27 ± 12 mmHg, p = 0.001) (Table 2). These findings were not related to inferior location of MI. After multivariate logistic regression undiagnosed COPD was confirmed to be independently associated with a reduced FAC (OR 1.12; 95% CI 1.02–1.24, p = 0.013) and reduced RVS (OR 1.20; 95% CI 1.01–1.42, p = 0.024). Similar results were obtained after stratification for the presence of airflow limitation (irrespective of the clinical diagnosis of COPD) (Table 3) confirming the relationship between reduced FAC (OR 1.07; 95% CI 1.00–1.16; p = 0.04) and reduced RVS (OR 1.14; 95% CI 1.00–1.28; p = 0.04) and presence of airflow limitation (Table 3).

Variation overtime of LV and RV parameters

Although LVEF did not change significantly over time, we observed a significant increase in LV GLS in both groups of patients with and without undiagnosed COPD (Tables 2 and 3). On the contrary, both FAC and RVS did not change over time (Tables 2 and 3). It is relevant to note that in patients without COPD we observed a significant improvement of sPAP (35 ± 11 mmHg vs. 27 ± 12 mmHg, p = 0.03) (Tables 2 and 3) that did not occur in patients with concomitant COPD (Tables 2 and 3).

Inter-rater agreement

For inter-rater agreement, the intra-class correlation coefficients for FAC at the baseline was 0.84 (95% CI 0.70–0.94) and 0.85 (95% CI 0.72–0.96) at the follow-up, for RVS it was 0.92 (95% CI 0.82–0.97) and 0.94 (95% CI 0.85–0.98) at baseline and follow-up respectively. Results of Bland-Altman scatterplots are reported in Table 4.

Table 4. Bland-Altman scatterplot analysis, and calculated intraclass correlation coefficients (ICCs).

	FAC baseline	FAC follow-up	RVS baseline	RVS follow-up
Bland-Altman scatterplot values
Mean difference	0.91	0.89	0.3	0.3
Agreement limits (lower, higher)	−4.1 to 6.2	−4 to 5.9	−1.7 to 2.4	−1.5 to 2.2
ICC
ICC	0.84	0.85	0.92	0.94
95% CI	0.70–0.94	0.72–0.96	0.82–0.97	0.85–0.98
p	<0.001	<0.001	<0.001	<0.001

ICC: intraclass correlation coefficients; CI: confidence interval.

Discussion

In this study, we found that in patients hospitalized for acute coronary syndrome (ACS) the presence of concomitant COPD (undiagnosed at the time of hospital admission) is associated with early changes of RV function, as assessed by FAC and RVS. This finding was observed immediately after ACS, before hospital discharge, and it was still present after six months. Similar results were obtained when, to avoid a misclassification of patients due to the use of FEV1/FVC ratio (8), the data have been re-analyzed according to the presence of airflow limitation according to ERS/ATS recommendation (irrespective of the clinical diagnosis of COPD (8)). These data confirm that, in smoker patients admitted to hospital because of ACS, the presence of airflow limitation (even if it is very mild) is associated with early echocardiographic abnormalities of RV function.

Previous studies investigated RVS in patients with established diagnosis of COPD or in patients with severe COPD undergoing lung transplantation (5,17–19). This is the first study assessing RVS in ACS patients with concomitant undiagnosed COPD. We found a significant and early impairment of RVS. In this setting, several factors may contribute to affect RVS, e.g. the inferior location of MI (20), the systolic LV dysfunction and/or the concomitant pulmonary disease. Our study excluded the location of MI as potential confounding factor. We stratified patients according to the presence of inferior location of MI and we did not find significant differences. Similarly, the relationship between RVS and undiagnosed COPD was independent from systolic LV function. Interestingly, we observed a significant improvement in LV GLS from baseline to follow-up. This improvement was present in all patients, independently from the presence of undiagnosed COPD. This finding differs from the data of a previous study in which LV GLS was more impaired in patients with ST-segment elevation MI and concomitant COPD (21). Nevertheless, our study population was significantly different from the previous one. The latter analyzed echocardiographic parameters only during index hospitalization and COPD diagnosis was already established (21), while in our study we enrolled patients with undiagnosed COPD showing mainly mild airflow limitation.

Moreover, sPAP tended to show a different pattern between the study subgroups. In patients with undiagnosed COPD, sPAP was slightly higher at baseline and did not vary significantly after six months. RVS was already found significantly reduced in COPD patients without pulmonary hypertension (5). The early impairment in RVS might reflect the impact of endothelial dysfunction (6,22), increased arterial stiffness and inflammation on right heart function, rather than only hypoxia (and even more in a population with mainly mild to moderate COPD) (5). Thus, it is highly probable that sPAP in patients with undiagnosed COPD is mainly determined by concomitant pulmonary disease, which did not differ between acute and chronic phase (23). On the contrary, in patients without COPD the improvement in LV function (24) (as demonstrated by the increase in LV GLS) is the main factor related to the slight improvement in sPAP. Considering all these data, our study suggests that the impairment of RVS was primarily related to the presence of undiagnosed COPD.

Moreover, even though in a normal range, also FAC was significantly lower in patients with undiagnosed COPD, compared to those without. This data are consistent with the observed impairment of RVS and indirectly confirms that undiagnosed COPD determines early changes in the structure and function of the right heart.

It is relevant to note that the conventional 2D echocardiographic parameters used in the clinical routine for the evaluation of RV function such as TAPSE, the thickness of the RV, or RV areas are not significantly different between patients with and without undiagnosed COPD, considering also that the majority of patients had only mild (59%) or moderate airflow limitation (38%). Das et al. analyzed the relation between pulmonary functional tests and echocardiographic parameters in patients with COPD, showing that FAC is related with the severity of airflow limitation and, by contrast, TAPSE and RV wall thickness did not (25), confirming therefore the findings of our study. Furthermore, we found a slight but significant increase in left atrium volume at early stage in patients with undiagnosed COPD. This finding is consistent with the higher occurrence of atrial arrhythmias in COPD patients (26).

Soriano et al. showed that patients with IHD treated with percutaneous coronary intervention (PCI) and with concomitant undiagnosed COPD have an increase in cardiovascular events and mortality in the follow-up (2). Our study shows early echocardiographic signs of RV function deterioration in patients with ACS and concomitant COPD. Early impairment of the RV, in association with endothelial dysfunction (6,21,27), higher platelet counts (28) and on-treatment platelet reactivity (6,29), can justify the worse clinical outcome of patients with IHD and undiagnosed COPD. These findings provide new data to understand complex mechanisms behind the increased clinical severity and prognosis of patients with concomitant IHD and COPD. Larger studies are needed to confirm these hypotheses and findings.

The major strengths of our study are: (i) peculiarity of the study population with spirometry data, (ii) completeness of TTE parameters, (iii) blinded revision of TTE data and (iv) TTE analysis at two-time points (acute and chronic phases). The latter, in particular, is an important point as it minimizes the link between certain variables (e.g. RVS) and potential confounding factors (e.g. heart failure or stunning due to acute phase of ACS).

We also recognized some limitations. Firstly, the inter-rater agreement was good for FAC and very good for RVS according to Koo et al. guideline for the interpretation of intraclass correlation coefficients (Table 4) (30). Secondly, this is a sub-analysis of a single center study, therefore the results of these data should be considered only as hypothesis generating. The limited number of patients and the adverse events preclude the possibility to assess the relation between echocardiographic parameters and outcome. Moreover, considering the limited amount of patient examined, our data cannot be considered definitive, and other larger studies are necessary to confirm the relation between undiagnosed COPD and reduced right ventricle strain. Thirdly, the echocardiographic data acquisition has been performed only once during hospitalization and once at follow-up precluding the possibility to perform an analysis on test-retest reliability (31). Lastly, one of the main hurdles limiting the applicability of strain in daily clinical practice is the difference in technique used that varies among modalities and vendors (32). There are not globally recognized reference values for RV strain and, thus, this represents another limit to the interpretation of our data.

Conclusion

Early changes of the RV function, as detected by reduced RVS and reduced FAC, is present in patients admitted to hospital for ACS and with concomitant undiagnosed COPD. Further studies are warranted to determine whether these alterations can be reversed/modulated by an early identification and treatment and whether targeting early RVS reduction results in better clinical outcomes in these comorbid patients.

Ethics approval and consent to participate

All patients signed written informed consent. The study was approved by the Local Ethic Committee (Comitato Etico Unico della Provincia di Ferrara).

Declaration of interest

The authors declare that they have no competing interests.

Authors’ contributions

Rita Pavasini is the guarantor of the content of the manuscript, including the data and analysis. Rita Pavasini, Gianluca Campo, Andrea Fiorencis: conception, design, analysis and interpretation of data. Rita Pavasini, Gianluca Campo, Marco Contoli, Simone Biscaglia: data analysis and interpretation. All authors: drafting of the manuscript and revising it critically for important intellectual content. All authors: final approval of the manuscript submitted.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.