Introduction
Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous disease involving a combination of risk factors and comorbidities.[ 1,2 ] A previous study showed that 91% of patients with HFpEF show signs of epicardial coronary artery disease (CAD), coronary microvascular dysfunction (CMD), or both.[ 3 ] Despite this prevalence, these conditions, which may serve as therapeutic targets, are often unrecognized in patients with HFpEF. It has been increasingly recognized that right ventricular (RV) dysfunction (RVD) is common and a major contributor to poor prognosis in HFpEF. RVD is present in at least one-fifth and potentially up to 30–50% of patients with HFpEF. In addition, 55% of patients with HFpEF died with clinical signs of right HF. However, the underlying pathways that lead to RVD in HFpEF are unclear.[ 4 ] The presence and severity of coronary atherosclerosis are significantly associated with subclinical RVD.[ 5 ] CAD is associated with more advanced impairment of RV function, RV filling, and diastolic or systolic dysfunction in HFpEF. Especially in patients with pulmonary hypertension (PH), CAD can exacerbate the mismatch between perfusion and demand.[ 4,6 ] Thus, in acute HFpEF patients with CAD, RV function and afterload from the pulmonary vascular system may serve as powerful prognostic factors. The relationship between RV function and the pulmonary vascular system is known as "RV-arterial coupling" and can be expressed as a ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP). TAPSE/PASP is a superior surrogate of the gold-standard for RV-arterial coupling (invasive pressure-volume loop-derived end-systolic/arterial elastance [Ees/Ea] ratio) compared to other surrogates in HFpEF.[ 4,7,8 ]
Identification of acute HFpEF/CAD patients at risk is critical. Previously, the prognostic value of TAPSE/PASP in patients with pulmonary arterial hypertension (PAH), group 2 PH, pre-/post-capillary PH, HFpEF, or HF with reduced ejection fraction (HFrEF) was described.[ 9–11 ] However, few studies have described the prognostic value of TAPSE/PASP in acute HFpEF patients with CAD. Accordingly, we investigated the prognostic value of RV-arterial uncoupling in acute HFpEF patients with CAD, and the association of revascularization with outcomes.
Methods
Ethical approval This protocol was approved by the Ethics Committee of the Clinical School of Thoracic, Tianjin Medical University (2020YS-043-01). Before undergoing any study-related procedure, patients who participated in the trial signed written informed consent.
Study population Our study was a prospective, single-center, observational study involving 352 consecutive patients admitted to the Heart Failure and Intensive Care Unit in Clinical School of Thoracic, Tianjin Medical University, between March 2019 and February 2022 with a diagnosis of acute HFpEF with CAD. Patients were considered eligible when: (1) there was evidence of coronary disease on coronary angiography results (at least one vessel with ≥75% luminal stenosis) or history of myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG); (2) left ventricular ejection fraction (LVEF) ≥50%; (3) HFpEF defined as HFA–PEFF score ≥5 points, based on the HFA–PEFF diagnostic algorithm[ 2 ] ; and (4) acute HF diagnosed according to the European Society of Cardiology Guidelines.[ 12 ] Patients with the following conditions were excluded: (1) primary valvular heart disease, constrictive pericarditis, hypertrophic cardiomyopathy, restrictive cardiomyopathies, chronic obstructive pulmonary disease (COPD), PAH, chronic thromboembolic pulmonary hypertension (CTEPH); (2) acute coronary syndrome (ACS) or any coronary revascularization within 4 weeks prior to admission; (3) chronic kidney disease (CKD) stage 5; (4) a history of hematological diseases or malignancies; (5) age <18 years; (6) life span <6 months; and (7) a history of heart transplantation. Patients who died in the hospital were excluded.
Echocardiography An experienced echocardiographer who was blinded to the data performed comprehensive echocardiographic examinations according to American Society of Echocardiography guidelines. Left atrium anterior-posterior dimension (LAD) was assessed via 2D measures. Left ventricular (LV) internal dimension diastole (LVIDD) measurement was performed at end-diastole via 2D-guided linear measurements. LV volumes were calculated according to the modified biplane Simpson's rule by using apical 2- and 4-chamber views. LV volume measurements at end-diastole and end-systole were used to calculate LVEF. Stroke volume (SV) was calculated using LV end-diastolic volume and LV end-systolic volume. Cardiac output (CO) was calculated using SV and heart rate. Right atrium (RA) and right ventricle transverse diameter (RVTD) at the base were estimated via conventional two-dimensional echocardiography using a right-heart apical four-chamber view. RV systolic function was assessed based on TAPSE, tricuspid lateral annular systolic velocity (s′), and fractional area change (FAC). Right atrial pressure based on the diameter of the inferior vena cava (IVC) and its collapsibility during inspiration, from the subcostal view, was as follows: 3 mmHg (IVC <2.1 cm that collapsed >50%), 15 mmHg (IVC >2.1 cm that collapsed <50%), and 8 mmHg (range, 5–10 mmHg) (IVC and collapse did not fit in this paradigm). Peak tricuspid regurgitation (TR) velocity was measured, and PASP was estimated to be 4× (peak TR velocity)2 + RA pressure. The TAPSE/PASP ratio was considered a non-invasive surrogate of RV-arterial coupling. Early diastolic mitral inflow velocity (E), early diastolic septal mitral annular tissue velocity (eʹ), and the ratio of E/e′ were evaluated using pulse wave Doppler and tissue Doppler imaging. Interventricular septum (IVS) thickness and LV posterior wall thickness (PWT) were measured using a linear method at end-diastole. LV mass (LVM) and relative wall thickness (RWT) were calculated as follows[ 13 ] :
LVM = 0.8 × (1.04 × [(IVS + LVIDD + PWT)3 − LVIDD3 ] + 0.6 grams
RWT = (2 × PWT)/(LVIDD)
To evaluate LV morphology, the LV mass index (LVMI) normalized to body surface area (LVM divided by body surface area and RWT) was calculated.
Clinical data Basic demographic data, clinical characteristics, laboratory testing and coronary angiography results, and information regarding past medical history, comorbidities, and medications were collected at admission. Hypertension, diabetes, and CKD were defined according to the current guidelines. Residual SYNTAX score (rSS) was calculated according to coronary angiography results.[ 14 ] Complete revascularization was defined as rSS = 0; incomplete revascularization was defined as intervention on ≥1 significant stenoses, but with rSS >0; no revascularization was defined as no intervention. The HFA–PEFF scoring system was applied, which considers functional, morphological, and biomarker domains for HFpEF diagnosis. This scoring system is recommended by the Heart Failure Association of the European Society of Cardiology. Within each domain in this scoring system, major and minor criteria are scored by 2 and 1 points, respectively. HFpEF was defined as HFA–PEFF score ≥5. In our center, not all parameters per domain in the scoring system were checked, such as LV global circumferential strain and left atrium volume index. Major and minor criteria were as follows: (1) functional major criterion: septal e′ <7 cm/s or TR peak velocity >2.8 m/s (PASP >35 mmHg), functional minor criterion: average E/e′ ratio 9–14; (2) morphological major criterion: LVMI ≥149 g/m2 in men and ≥122 g/m2 in women and RWT >0.42, morphological minor criterion: LVMI ≥115 g/m2 in men and ≥95 g/m2 in women or RWT >0.42 or LV end-diastolic wall thickness ≥12 mm; (3) biomarker major criterion: N-terminal pro-B-type natriuretic peptide (NT-proBNP) >220 pg/mL or BNP >80 pg/mL (sinus rhythm), NT-proBNP >660 pg/mL or BNP >240 pg/mL (atrial fibrillation), biomarker minor criterion: NT-proBNP 125–220 pg/mL or BNP 35–80 pg/mL (sinus rhythm), NT-proBNP 375–660 pg/mL or BNP 105–240 pg/mL (atrial fibrillation).
Follow-up and endpoints The primary endpoint was a composite of all-cause death, recurrent ischemic events, and HF hospitalizations. Secondary endpoints were individual clinical events described above. Recurrent ischemic events were defined as ACS after discharge. Patients were followed up by phone. The follow-up period was from the day of first admission until the first occurrence of any endpoint or the end of the study.
Statistical analysis Statistical analyses were performed using SPSS 22.0 (SPSS Inc., Armonk, NY, USA) and GraphPad Prism 9.2.0 (GraphPad Software Inc., San Diego, CA, USA). Continuous data were assessed for normal distribution via the Kolmogorov–Smirnov test. Continuous variables were expressed as the mean ± standard deviation or median (interquartile range [IQR]) and compared via Student's t -test or Wilcoxon rank-sum test as appropriate. Categorical variables were expressed as number with percentage and compared via the chi-squared test. To determine the optimal TAPSE/PASP cutoff value with maximum sensitivity and specificity for predicting the primary endpoint, the area under the curve (AUC) for the receiver operating characteristic curve (ROC) with a 95% confidence interval (CI) were applied. Patients were divided into two groups based on the TAPSE/PASP cutoff value. Kaplan–Meier curves and log-rank statistics were used for assessing the differences in endpoints between two groups. A univariate Cox proportional hazards model was used for identifying risk factors. A multivariate Cox proportional hazards model was used to assess the independent prognostic power of TAPSE/PASP for each endpoint event, and hazard ratios (HRs) were expressed with 95% CIs. Covariates of statistical significance at univariate analysis were entered into the multivariate Cox proportional hazards model. A two-sided P -value <0.05 was considered statistically significant.
Results
Prognostic value of RV-arterial uncoupling We evaluated the prognostic value of RV-arterial uncoupling for acute HFpEF patients with CAD by the TAPSE/PASP threshold, which accurately predicted the primary endpoint. ROC analysis for the TAPSE/PASP ratio demonstrated the optimal cutoff value for predicting the primary endpoint in patients with a sensitivity of 61.4% and specificity of 76.6% for the TAPSE/PASP threshold of 0.43. This value was chosen according to the Youden index, and the largest AUC of 0.731 (95% CI, 0.666–0.796; P <0.001) [Figure 1 ].
Figure 1: ROC curve analysis for predicting the primary endpoint with TAPSE/PASP threshold in acute HFpEF patients with CAD. The dot represents TAPSE/PASP = 0.43. AUC: Area under the curve; CAD: Coronary artery disease; HFpEF: Heart failure with preserved ejection fraction; ROC: Receiver operating characteristic; TAPSE/PASP: Tricuspid annular plane systolic excursion to pulmonary artery systolic pressure.
Population characteristics A total of 352 patients were prospectively enrolled. Among them, 37 were diagnosed with ACS, 31 refused coronary angiography, and 29 did not undergo PASP estimation. The remaining 255 patients were divided into two groups according to the TAPSE/PASP threshold (RV-arterial coupling group, TAPSE/PASP >0.43, n = 152; and RV-arterial uncoupling group, TAPSE/PASP ≤0.43, n = 103). Only patients discharged alive following hospitalization were included. Five patients were excluded because of death during the hospital stay (n = 4) or contrast-induced nephropathy (n = 1). In the RV-arterial uncoupling group, two patients died in the hospital of acute HF with TAPSE/PASP ratios of 0.31 and 0.25. In the RV-arterial coupling group, two patients died in the hospital of hematencephalon and acute MI with TAPSE/PASP ratios of 0.45 and 0.47, respectively. Thus, the final cohort comprised 250 patients [Figure 2 ].
Figure 2: Flowchart of the study. ACS: Acute coronary syndrome; CAD: Coronary artery disease; HFpEF: Heart failure with preserved ejection fraction; PASP: Pulmonary artery systolic pressure; RV: Right ventricular.
Table 1 shows demographic and clinical characteristics according to the presence of RV-arterial uncoupling (TAPSE/PASP ≤0.43). The median age was 66 years, and 63.6% (159/250) of patients were male. Additionally, 82 patients (32.8%), 59 (23.6%), and 19 (7.6%) had a history of MI, PCI, and CABG, respectively. Complete, incomplete, and no revascularization were performed in 116 patients (46.4%), 109 (43.6%), and 25 (10.0%) of the 250 acute HFpEF patients with CAD before discharge, respectively.
Table 1 -
Baseline characteristics of acute HFpEF patients with CAD by TAPSE/PASP threshold.
Characteristics
All patients
(n = 250)
TAPSE/PASP ≤0.43
(n = 100)
TAPSE/PASP >0.43
(n = 150)
Statistics
value
P- value
Age (years)
66 (56–73)
70 (57–73)
65 (55–70)
–2.838*
0.005
Sex, male
159 (63.6)
67 (67.0)
92 (61.3)
0.832
†
0.362
BMI (kg/m2 )
24.2 ± 4.1
23.4 ± 3.9
24.8 ± 4.1
–2.799‡
0.006
Smoking ever
117 (46.8)
48 (48.0)
69 (46.0)
0.096
†
0.756
Heart rate (beats/min)
84 (70–98)
84 (70–98)
80 (66–96)
–1.635*
0.102
SBP (mmHg)
136 ± 22
132 ± 22
139 ± 21
–2.832‡
0.005
DBP (mmHg)
79 ± 13
80 ± 13
78 ± 13
0.907‡
0.366
Comorbidities
Hypertension
143 (57.2)
64 (64.0)
79 (52.7)
3.148
†
0.076
Diabetes
96 (38.4)
41 (41.0)
55 (36.7)
0.476
†
0.490
Dyslipidemia
99 (39.6)
37 (37.0)
62 (41.3)
0.471
†
0.493
Stroke
70 (28.0)
16 (16.0)
54 (36.0)
11.905
†
0.001
Atrial fibrillation
81 (32.4)
38 (38.0)
43 (28.7)
2.386
†
0.122
CKD
76 (30.5)
36 (36.0)
40 (26.8)
2.365
†
0.124
CAD
Previous MI
82 (32.8)
34 (34.0)
48 (32.0)
0.109
†
0.741
Previous PCI
59 (23.6)
19 (19.0)
40 (26.7)
1.956
†
0.162
Previous CABG
19 (7.6)
14 (14.0)
5 (3.3)
9.721
†
0.002
Revascularization
Complete revascularization
116 (46.4)
37 (37.0)
79 (52.7)
5.921
†
0.015
Incomplete revascularization
109 (43.6)
45 (45.0)
64 (42.7)
0.133
†
0.716
No revascularization
25 (10.0)
18 (18.0)
7 (4.7)
11.852
†
<0.001
Laboratories
eGFR (mL∙min–1 ∙1.73 m–2 )
62.0 ± 33.0
61.0 ± 32.9
62.6 ± 33.2
–0.376‡
0.707
Serumuric acid (μmol/L)
396.3 (319.5–519.6)
408.5 (332.1–534.2)
389.6 (313.6–515.3)
–1.185*
0.236
BUN (mmol/L)
8.3 (5.9–14.0)
8.2 (5.9–16.0)
8.4 (5.9–11.5)
–0.275*
0.783
NT-proBNP (pg/mL)
2620 (1458–6318)
6290 (2320–11,309)
1780 (1165–3350)
–7.307*
<0.001
cTnI (ng/mL)
0.027 (0.015–0.106)
0.032 (0.017–0.128)
0.023 (0.015–0.073)
–2.302*
0.021
Hemoglobin (g/L)
124 ± 24
124 ± 21
124 ± 26
–0.068‡
0.946
Hematocrit (%)
37.7 ± 7.5
37.8 ± 6.6
37.6 ± 8.1
0.217‡
0.829
TC (mmol/L)
4.1 (3.5–4.8)
4.3 (3.5–5.2)
4.0 (3.5–4.7)
–1.167*
0.243
TG (mmol/L)
1.3 (1.0–1.9)
1.1 (0.9–1.9)
1.4 (1.1–2.0)
–2.598*
0.009
LDL-C (mmol/L)
2.1 (1.7–2.8)
2.4 (1.6–3.0)
2.0 (1.7–2.7)
–0.995*
0.320
FBG (mmol/L)
5.7 (5.1–6.7)
5.6 (4.8–6.5)
5.7 (5.2–6.9)
–1.135*
0.256
HbA1c (%)
6.2 (5.9–7.4)
6.2 (5.9–7.7)
6.3 (5.9–7.3)
–0.516*
0.606
Serum albumin (g/L)
38.0 ± 4.6
37.3 ± 3.9
38.4 ± 5.0
–1.945‡
0.053
Echocardiography
LVIDD (cm)
5.3 ± 0.7
5.4 ± 0.7
5.3 ± 0.7
1.341‡
0.181
IVS (cm)
1.0 (0.9–1.1)
1.0 (0.9–1.1)
1.0 (0.9–1.1)
–1.730*
0.084
LVPW (cm)
0.9 (0.9–1.0)
0.9 (0.8–1.0)
0.9 (0.9–1.0)
–1.390*
0.164
Septal e′ (cm/s)
4.3 ± 1.3
4.1 ± 1.2
4.4 ± 1.3
–1.667‡
0.097
E/e′
21.7 (16.5–30.3)
24.9 (18.2–36.0)
18.4 (15.9–25.0)
–4.755*
<0.001
TR velocity (m/s)
2.7 (2.5–3.0)
3.1 (2.6–3.5)
2.5 (2.3–2.7)
–8.450*
<0.001
PASP (mmHg)
35 (31–43)
45 (37–58)
32 (28–36)
–10.133*
<0.001
LAD (cm)
4.5 ± 0.6
4.7 ± 0.7
4.4 ± 0.6
3.054‡
0.003
RVTD (at the base, mm)
47 ± 8
48 ± 8
44 ± 6
1.459‡
0.154
SV (mL)
75 (64–87)
77 (63–90)
75 (64–85)
–0.966*
0.334
CO (L/min)
5.4 (4.8–6.7)
5.4 (5.0–6.7)
5.3 (4.8–6.6)
–0.835*
0.404
LVEF (%)
59 (52–66)
57 (51–62)
61 (52–67)
–2.327*
0.020
TAPSE (mm)
17 (15–20)
15 (13–17)
19 (16–22)
–7.225*
<0.001
s′ (cm/s)
11.3 ± 3.2
10.3 ± 3.1
12.0 ± 3.1
–4.447‡
<0.001
FAC (%)
40 (32–48)
33 (26–43)
45 (38–49)
–5.889*
<0.001
TAPSE/PASP threshold
0.48 ± 0.16
0.32 ± 0.08
0.58 ± 0.11
–19.501‡
<0.001
IVC (mm)
18 (16–21)
20 (17–23)
17 (16–19)
–4.156*
<0.001
RA diameter (mm)
40 (36–43)
42 (38–44)
38 (35–41)
–4.847*
<0.001
RA pressure (mmHg)
5 (5–10)
8 (5–10)
5 (5–8)
–4.934*
<0.001
Medications
Diuretics
207 (82.8)
89 (89.0)
118 (78.7)
4.499
†
0.034
Beta blocker
159 (63.6)
66 (66.0)
93 (62.0)
0.415
†
0.520
ACEI/ARB/ARNI
137 (54.8)
55 (55.0)
82 (54.7)
0.003
†
0.959
Aldosterone antagonist
199 (79.6)
84 (84.0)
115 (76.7)
1.987
†
0.159
Statins
214 (85.6)
82 (82.0)
132 (88.0)
1.752
†
0.186
Aspirin/clopidogrel
173 (69.2)
69 (69.0)
104 (69.3)
0.003
†
0.955
Anticoagulant
45 (18.0)
19 (19.0)
26 (17.3)
0.113
†
0.737
Nitrates
138 (55.2)
63 (63.0)
75 (50.0)
4.100
†
0.052
Calcium channel blocker
47 (18.8)
14 (14.0)
33 (22.0)
2.515
†
0.113
SGLT-2i
83 (33.2)
35 (35.0)
48 (32.0)
0.243
†
0.622
GLP-1 RA
29 (11.6)
14 (14.0)
15 (10.0)
0.936
†
0.333
Data are shown as n (%), mean ± standard deviation, or median (IQR). * The statistics were calculated using Wilcoxon rank-sum test. † The statistics were calculated using chi-squared test. ‡ The statistics were calculated using Student's t -test. ACEI: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin receptor blocker; ARNI: Angiotensin receptor neprilysin inhibitor; BMI: Body mass index; BUN: Blood urea nitrogen; CABG: Coronary artery bypass grafting; CAD: Coronary artery disease; CKD: Chronic kidney disease; CO: Cardiac output; cTnI: Cardiac troponin I; DBP: Diastolic blood pressure; E/e′: The ratio of mitral peak velocity of early filling E to the velocity of mitral annulus early diastolic motion e′; eGFR: Estimated glomerular filtration rate; FAC: Fractional area change; FBG: Fasting blood glucose; GLP-1 RA: Glucagon-like peptide-1 receptor agonists; HbA1c: Hemoglobin A1c; IQR: Interquartile range; IVC: Inferior vena cava; IVS: Interventricular septum; LAD: Left atrium anterior-posterior dimension; LDL-C: Low-density lipoprotein cholesterol; LVIDD: Left ventricular internal dimension diastole; LVEF: Left ventricular ejection fraction; LVPW: Left ventricular posterior wall; MI: Myocardial infarction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PASP: Pulmonary artery systolic pressure; PCI: Percutaneous coronary intervention; RA: Right atrium; RVTD: Right ventricle transverse diameter; s′: Tricuspid lateral annular systolic velocity; SBP: Systolic blood pressure; SGLT-2i: Sodium-glucose cotransporter 2 inhibitor; SV: Stroke volume; TAPSE: Tricuspid annular plane systolic excursion; TC: Total cholesterol; TG: Triglyceride; TR: Tricuspid regurgitation.
Patients in the RV-arterial uncoupling group were older, had a lower body mass index and systolic blood pressure, and were more likely to have a history of CABG vs . patients in the coupling group. Revascularization strategies were slightly different between groups; the RV-arterial uncoupling group had a lower rate of complete revascularization (37.0% [37/100] vs . 52.7% [79/150], P = 0.015) and a higher rate of no revascularization (18.0% [18/100] vs . 4.7% [7/150], P <0.001) than the coupling group. Additionally, patients in the RV-arterial uncoupling group had a higher NT-proBNP and cTnI (and were more likely to be on diuretics) than patients in the coupling group.
Echocardiographic characteristics Echocardiographic analysis [Table 1 ] showed that the RV-arterial uncoupling group had a significantly lower TAPSE, s′, FAC, and LVEF; higher TR velocity, RA pressure, IVC, RA diameter (RAD), and PASP than the coupling group. Additionally, LV filling pressures estimated based on E/e′ and LAD, were higher and more dilated in the RV-arterial uncoupling group than the coupling group. However, LVIDD, IVS, LVPW, septal e′, RVTD, SV, and CO were not significantly different between groups.
Prognostic values of RV-arterial uncoupling and revascularization Over a median follow up of 433 (IQR 210, 900) days, 130 (52.0%) patients met the primary endpoint, 33 patients (13.2%) had an all-cause death, 58 (23.2%) had recurrent ischemic events, and 75 (30.0%) experienced recurrent HF hospitalizations. Kaplan–Meier analysis revealed that patients with TAPSE/PASP ≤0.43 had a significantly worse prognosis than patients with TAPSE/PASP >0.43. The RV-arterial uncoupling group had worse event-free survival of primary endpoint (HR, 2.31 [95% CI, 1.58–3.39], P <0.0001) [Figure 3A ] and higher rates of recurrent HF hospitalizations and all-cause death (HR, 2.25 [95% CI, 1.37–3.71], P = 0.0003; and HR, 3.43 [95% CI, 1.61–7.32], P = 0.0002, respectively) [Figures 3B and C ] than the coupling group. No statistically significant association was observed between RV-arterial uncoupling and recurrent ischemic events (log-rank P = 0.215, Figure 3D ).
Figure 3: Kaplan–Meier survival curves for prediction of primary endpoint (A), recurrent HF hospitalization (B), all-cause death (C), and recurrent ischemic events (D). HF: Heart failure; No.: Number; TAPSE/PASP: Tricuspid annular plane systolic excursion to pulmonary artery systolic pressure.
Baseline risk factors associated with prognosis were used for adjustment and included hypertension, diabetes, revascularization, estimated glomerular filtration rate (eGFR), NT-proBNP, E/e′, and TAPSE based on univariate Cox analysis. The univariate Cox analysis revealed that TAPSE/PASP ≤0.43 (HR, 2.35 [95% CI, 1.66–3.32], P <0.001), complete revascularization, incomplete revascularization, eGFR, NT-proBNP, E/e′, and TAPSE had significant effects on the primary endpoint [Table 2 ]. After adjusting for baseline risk factors, multivariate Cox analysis revealed TAPSE/PASP ≤0.43 as an independent associated factor for the primary endpoint, rate of all-cause death, and rate of recurrent HF hospitalizations (HR, 2.21 [95% CI, 1.44–3.39], P <0.001; HR, 3.32 [95% CI, 1.30–8.47], P = 0.012; and HR, 1.93 [95% CI, 1.10–3.37], P = 0.021), but not for recurrent ischemic events (HR, 1.48 [95% CI, 0.75–2.90], P = 0.257). Patients who underwent complete or incomplete revascularization displayed significant improvement in the primary endpoint, all-cause deaths, and recurrent HF hospitalizations compared with patients with no revascularization. The full results of the multivariate Cox analysis for predicting the clinical endpoints are described in Table 2 .
Table 2 -
Cox regression model for prognostic factors of primary and secondary endpoints.
Factors
Unadjusted HR (95% CI)
P -value
Adjusted HR (95% CI)
P -value
Composite endpoint
Hypertension
1.36 (0.96–1.94)
0.086
1.00 (0.69–1.45)
0.988
Diabetes
1.39 (0.98–1.96)
0.067
1.15 (0.80–1.65)
0.449
Revascularization
No revascularization
1.00
–
1.00
–
Complete revascularization
0.30 (0.18–0.51)
<0.001
0.33 (0.19–0.58)
<0.001
Incomplete revascularization
0.42 (0.25–0.70)
0.001
0.42 (0.24–0.72)
0.002
eGFR
2.28 (1.61–3.22)
<0.001
2.63 (1.80–3.84)
<0.001
NT-proBNP
1.82 (1.29–2.58)
0.001
1.66 (1.13–2.45)
0.010
E/e′
1.79 (1.26–2.55)
0.001
1.52 (1.05–2.22)
0.028
TAPSE
0.61 (0.43–0.86)
0.004
0.95 (0.65–1.40)
0.803
TAPSE/PASP ≤0.43
2.35 (1.66–3.32)
<0.001
2.21 (1.44–3.39)
<0.001
All-cause death
Hypertension
1.19 (0.60–2.39)
0.616
0.75 (0.37–1.52)
0.418
Diabetes
1.94 (0.98–3.85)
0.057
1.59 (0.78–3.26)
0.205
Revascularization
No revascularization
1.00
–
1.00
–
Complete revascularization
0.15 (0.06–0.35)
<0.001
0.18 (0.07–0.49)
0.001
Incomplete revascularization
0.18 (0.08–0.44)
<0.001
0.19 (0.07–0.49)
0.001
eGFR
3.26 (1.62–6.59)
0.001
5.13 (2.33–11.32)
<0.001
NT-proBNP
1.91 (0.96–3.83)
0.067
1.61 (0.72–3.62)
0.245
E/e′
1.38 (0.69–2.75)
0.357
1.02 (0.48–2.16)
0.964
TAPSE
0.40 (0.20–0.81)
0.010
0.69 (0.31–1.54)
0.359
TAPSE/PASP ≤0.43
3.51 (1.75–7.04)
<0.001
3.32 (1.30–8.47)
0.012
Recurrent ischemic events
Hypertension
1.76 (1.02–3.03)
0.042
1.48 (0.84–2.62)
0.180
Diabetes
2.02 (1.20–3.38)
0.008
1.77 (1.04–3.03)
0.037
Revascularization
No revascularization
1.00
–
1.00
–
Complete revascularization
0.53 (0.20–1.40)
0.200
0.65 (0.24–1.76)
0.397
Incomplete revascularization
0.65 (0.25–1.70)
0.377
0.72 (0.27–1.97)
0.527
eGFR
2.09 (1.24–3.50)
0.005
2.08 (1.18–3.67)
0.011
NT-proBNP
1.41 (0.84–2.36)
0.199
1.45 (0.81–2.59)
0.209
E/e′
1.38 (0.82–2.32)
0.225
1.15 (0.65–2.01)
0.631
TAPSE
0.90 (0.53–1.53)
0.702
1.21 (0.67–2.19)
0.532
TAPSE/PASP ≤0.43
1.41 (0.82–2.44)
0.218
1.48 (0.75–2.90)
0.257
Recurrent HF hospitalizations
Hypertension
1.67 (1.04–2.71)
0.036
1.24 (0.75–2.06)
0.394
Diabetes
1.13 (0.71–1.79)
0.619
0.87 (0.54–1.41)
0.577
Revascularization
No revascularization
1.00
–
1.00
–
Complete revascularization
0.24 (0.12–0.45)
<0.001
0.25 (0.13–0.49)
<0.001
Incomplete revascularization
0.35 (0.18–0.65)
0.001
0.34 (0.17–0.67)
0.002
eGFR
2.48 (1.57–3.92)
<0.001
2.82 (1.71–4.65)
<0.001
NT-proBNP
1.92 (1.21–3.05)
0.005
1.75 (1.06–2.91)
0.030
E/e′
1.97 (1.23–3.17)
0.005
1.69 (1.02–2.78)
0.040
TAPSE
0.57 (0.36–0.90)
0.015
0.91 (0.55–1.50)
0.709
TAPSE/PASP ≤0.43
2.28 (1.44–3.60)
<0.001
1.93 (1.10–3.37)
0.021
CI: confidence interval; E/e′: The ratio of mitral peak velocity of early filling E to the velocity of mitral annulus early diastolic motion e′; eGFR: Estimated glomerular filtration rate; HF: Heart failure; HR: Hazard ratio; NT-proBNP: N-terminal pro-B-type natriuretic peptide; TAPSE: Tricuspid annular plane systolic excursion; TAPSE/PASP: Tricuspid annular plane systolic excursion to pulmonary artery systolic pressure; –: Not applicable.
Discussion
We assessed whether RV-arterial uncoupling based on the TAPSE/PASP ratio can be used for identifying high-risk acute HFpEF patients with CAD. The major precipitating causes of HFpEF included atrial fibrillation, hypertension, and CAD.[ 15 ] In previous studies, HFpEF patients were not classified according to different precipitating causes. The data presented here support the following: (1) RV-arterial uncoupling had a strong association with poor outcomes in acute HFpEF patients with CAD; (2) the optimal cutoff value of TAPSE/PASP for predicting the primary endpoint was 0.43 in acute HFpEF patients with CAD; (3) revascularization had a positive effect on the prognosis and might be a therapeutic target.
Acute HFpEF patients with CAD in our study were mostly male, displayed typical atherosclerotic risk factors, and were mostly treated with anti-ischemic medications. Our cohort showed an optimal TAPSE/PASP threshold of 0.43. The TAPSE/PASP threshold may differ among different study populations. Tello et al [ 16 ] showed that patients of pre-capillary PH with TAPSE/PASP <0.31 had a significantly worse prognosis, including CTEPH. Gorter et al [ 10,17 ] described that TAPSE/PASP <0.36 identified patients with pre-capillary PH and predicted poor outcome in HFpEF, which included 16.5% of patients with COPD, a clinical subtype of pre-capillary PH. However, our cohort excluded patients with COPD or CTEPH, who showed a pre-capillary PH and lower TAPSE/SPAP thresholds, and showed a higher TAPSE/PASP threshold of 0.43. Guazzi et al [ 7 ] calculated the optimal threshold of TAPSE/PASP as 0.36, which had a prognostic value for cardiac mortality in HFrEF and HFpEF. A previous study[ 11 ] found that patients with HFpEF had a higher TAPSE and lower PASP than those with HFrEF (P <0.001). In our study, only HFpEF patients were included, and they might have a higher TAPSE/PASP threshold. Nakagawa et al [ 18 ] reported that a TAPSE/PASP threshold of 0.48 was associated with adverse outcomes in decompensated HFpEF patients. Compared with this study, only 14% of CAD patients were included, and all patients in our study were diagnosed with CAD, which was associated with elevated PASP.[ 19 ] In our study, 7.6% (19/250) of patients had undergone CABG. TAPSE may be considerably reduced after CABG.[ 4 ] Elevated PASP and/or reduced TAPSE potentially explained why the prognostic threshold of TAPSE/PASP showed a relatively lower ratio of 0.43.
As a non-invasive index of RV-arterial uncoupling, the TAPSE/PASP ratio is a powerful independent predictor of poor prognosis in HFpEF.[ 11,20,21 ] CAD is common in HFpEF. In the cohort study by Rush et al ,[ 3 ] 91% of the patients with HFpEF showed signs of epicardial CAD, CMD, or both. Therefore, in HFpEF patients with CAD, the prognostic value of the TAPSE/PASP ratio should be further discussed. CAD is involved in the occurrence of ventricular interdependence, including systolic and diastolic ventricular interdependence,[ 4,19 ] which is one of the mechanisms underlying the development of RVD and RV-arterial uncoupling in HFpEF patients. Twenty to forty percent of RV systolic performance can be attributed to myocardial muscle fibers and the IVS shared with LV.[ 22 ] HFpEF, especially with myocardial ischemia, can result in regional LV contractile dysfunction and reduced RV contraction by systolic ventricular interdependence. Due to LV diastolic dysfunction and LV mechanical dyssynchrony, elevated PASP is common in HFpEF patients with CAD.[ 19 ] However, even a slight increase in PASP may already lead to a leftward septal shift and impaired LV diastolic compliance induced by diastolic ventricular interdependence, which may also contribute to right heart remodeling and dysfunction.[ 4 ] In our study, RV-arterial uncoupling was an independent prognostic factor for HFpEF patients with CAD.
We observed that compared with no revascularization, both complete and incomplete revascularization improved the primary endpoint, all-cause death, and recurrent HF hospitalizations in HFpEF patients with CAD. Previous studies have reported that adverse impact of CAD on HFpEF may be related to the multivessel disease.[ 1 ] This may be why, in our cohort, diabetes could predict recurrent ischemic events independently, because diabetic patients with CAD are usually characterized by multivessel lesions and longer lesions than non-diabetic patients.[ 23 ] Revascularization improved the ventricular function and prevented further damage on the residual viable myocardium from subsequent acute coronary events,[ 1,24 ] which improved survival and prognosis in HFpEF patients with CAD. Although revascularization may affect RV-arterial coupling, complete or incomplete revascularization does not always contribute to the improvement of RV-arterial uncoupling. TAPSE might be considerably reduced after CABG, and RV-arterial uncoupling aggravated accordingly.[ 4 ] RV-arterial uncoupling cannot be explained simply and exclusively by a general feature of myocardial ischemia; therefore, other potential mechanisms must be involved. For example, cytokine release, inflammation or effusion post-surgery, and/or coronary microvascular dysfunction without obstructive CAD may have significant effects on RVD.[ 3 ] These findings suggest that RV-arterial uncoupling and revascularization have a different inherent mechanism for prognosis. The present study showed that TAPSE/PASP was associated with adverse outcomes independent of revascularization.
Unger et al [ 25 ] showed that renal dysfunction was independently associated with worse cardiac mechanics and outcomes (HF, ACS, or death) in HFpEF. Additionally, CKD accelerated CAD via several mechanisms.[ 25,26 ] Similarly, in our cohort, renal dysfunction was a negative prognostic factor, and reduced eGFR predicted recurrent ischemic events in HFpEF patients with CAD. Although renal dysfunction strongly associated with PH and RVD,[ 4 ] our data showed that TAPSE/PASP was associated with adverse outcomes independent of renal dysfunction.
Diastolic mechanical dyssynchrony due to CAD results in elevated LV filling pressure, which is the key characteristic of HFpEF, and can be estimated based on E/e′.[ 27,28 ] Elevated LV filling pressure contributes to RV-arterial uncoupling,[ 15 ] and NT-proBNP is also a prognostic marker for RVD. Previous studies have showed that E/eʹ and NT-proBNP are predictive of death or HF re-hospitalizations in acute HFpEF or ischemic HF patients.[ 28–30 ] Consistent with these results, our findings showed that the RV-arterial uncoupling group had significantly elevated E/e′, NT-proBNP, and IVC compared with the RV-arterial coupling group. Elevated E/eʹ and NT-proBNP were associated with the primary endpoint and recurrent HF hospitalizations. However, TAPSE/PASP had an independent prognostic value even after adjusting for these factors. RV-arterial uncoupling directly contributes to the pathophysiology of HFpEF,[ 21 ] and there has been an increasing emphasis placed upon the identification of specific sub-grouping HFpEF, such as CAD, which had different prognoses and might respond differentially to specific interventions. Accordingly, RV-arterial uncoupling may serve as a key therapeutic target.
This study has several limitations. First, the sampling was subject to selection bias because we excluded patients with partially missing data of coronary angiography and estimated PASP. Second, both revascularization and RV-arterial uncoupling had independent prognostic values. Considering that CAD contributes to RVD and myocardial deformation,[ 31 ] it needs to be investigated whether RV-arterial uncoupling benefits from revascularization and the pathophysiological mechanism involved. Third, the gold-standard measure of RV-arterial coupling is the invasively measured Ees/Ea, based on right heart catheterization and pressure-volume catheterization. TAPSE/PASP is a straight-forward non-invasive estimate of RV-arterial coupling in patients with PH. In future studies, our findings should be validated via direct invasive measurement. Fourth, echocardiography was performed before discharge and not upon admission, and the optimal examination timing for echocardiography was decided by the attending physician, which might lead to potential bias. Fifth, our study was a single-center study with a relatively small sample size, and the median follow-up time was only 433 days. Multi-center studies with more patients and a longer follow-up time are needed for validation.
In conclusion, our findings showed a strong association of RV-arterial uncoupling with adverse outcomes in acute HFpEF patients with CAD. TAPSE/PASP has a significant prognostic value independent of revascularization, eGFR deterioration, diabetes, elevated E/e′, or NT-proBNP.
Funding None.
Conflicts of interest None.
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