Role of Inferior Vena Cava Dynamics for Estimating Right Atrial Pressure in Congenital Heart Disease

Abstract

Background:

Inferior vena cava (IVC) size and collapsibility (IVC dynamics) are used for estimating right atrial pressure (RAP). However, the diagnostic performance of the American Society of Echocardiography (ASE) IVC criteria for estimating RAP in patients with congenital heart disease (CHD) are unknown. The purpose of this study was to assess the role of IVC dynamics for estimating RAP in adults with CHD.

Methods:

Retrospective study of adults with CHD that underwent cardiac catheterization and echocardiogram at Mayo Clinic (2003–2019). IVC diameter was measured at inspiration (IVC_min) and end-expiration (IVC_max), and IVC collapsibility index (IVC_CI) was calculated.

Results:

Based on 918 patients, we observed a good correlation between IVC_max and invasive RAP (r=0.56, p<0.001); IVC_min and RAP (r=0.58, p<0.001); and IVC_CI (r=−0.72, p<0.001). There was excellent correlation between invasive RAP and estimated RAP using IVC_CI (r=0.80, p<0.001). We observed that IVC_CI <60% had superior diagnostic performance as compared to ASE criteria (IVC_max >2.1 cm, area under the curve [AUC] difference 0.15, p<0.001; IVC_CI <50%, AUC difference 0.09, p=0.008; combination of IVC_max >2.1 cm and IVC_CI <50%, AUC difference 0.06, p=0.02). Estimated RAP >10 mmHg based on IVC_CI had comparable prognostic performance as invasive RAP, but superior prognostic performance as the ASE criteria.

Conclusions:

IVC_CI <60% was the best criterion to identify patients with elevated RAP. IVC_CI was comparable to invasively measured RAP in its relation to prognosis. Further studies are required to determine whether the use of IVC_CI in clinical decision making will improve clinical outcomes in this population.

INTRODUCTION

Right atrial pressure (RAP) is a composite metric of right heart function, and reflects right ventricular (RV) diastolic function, RA compliance, and volume status.¹ RAP is a well-established prognostic metric, and it is routinely used to guide clinical decision making in patients with pulmonary arterial hypertension and other forms of acquired heart failure.^1–3 However, the assessment of RAP requires right heart catheterization (RHC), and hence is not ideal for routine hemodynamic monitoring in the ambulatory clinical setting. Transthoracic echocardiography is the main diagnostic tests for hemodynamics assessment, and the American Society of Echocardiography (ASE) endorses the use of inferior vena cava (IVC) size and respiratory collapsibility (IVC dynamics) for the estimation of RAP.⁴

Several studies have shown that estimated RAP using IVC dynamics correlates with invasively measured RAP and can predict clinical outcomes during follow-up.^5–7 As a result, IVC dynamics (size and collapsibility) are routinely used for risk stratification and prognostication.^{1, 8, 9} However, the cut-off points for defining normal versus abnormal IVC dynamics (and in turn, normal versus abnormal RAP) were derived from studies conducted in patients with acquired heart disease.^5–7 Since patients with congenital heart disease (CHD) differ significantly from those with acquired heart disease (in terms of population demographics and disease pathophysiology), it is unclear how well the current ASE criteria for normal versus anormal IVC dynamics correlate with invasively measured RAP in patients with CHD. The purpose of this study was to assess the diagnostic and prognostic role of IVC dynamics (size and collapsibility) for estimating RAP in adults with CHD.

METHODS

The authors declare that all supporting data are available within the article. The Mayo Clinic Institutional Review Board approved the study.

Study Population

This is a retrospective cohort study of adults (age ≥18 years) with CHD that underwent RHC and transthoracic echocardiogram at Mayo Clinic from January 1, 2003 and December 31, 2019. The patients were identified through the Mayo Adult Congenital Heart Disease (MACHD) registry. We excluded patients with Fontan palliation and patients without transthoracic echocardiogram performed within 7 days from the time of RHC. The patients that met the study inclusion criteria were divided into 2 groups (derivation cohort and validation cohort) using a random assignment based on the last digit of their research identification number (even vs odd numbers). The purpose of separating the cohort into derivation and validation samples was to test the ability of IVC dynamics derived from one cohort to correctly identify patients with elevated RAP in a different cohort.

Study Objectives

The ASE partitioned RAP into 3 categories: normal (mean RAP 3 mmHg, range 0–5 mmHg), intermediate (mean 8 mmHg, range 5–10 mmHg), and high RAP (mean 15 mmHg, range 10–20 mmHg). Based on the ASE criteria, an IVC diameter that was >2.1 cm and collapsed <50% with a sniff was suggestive of high RAP (range 10–20 mmHg). Accordingly, we defined high RAP as RAP >10 mmHg for the purpose of this study, to capture the patients in the top RAP category based on the ASE partitions.

The study objectives were to: (1) assess the correlation between IVC dynamics and invasively measured RAP using the derivation cohort; (2) Compare the discriminatory ability of IVC dynamics (using the cut-off points obtained from the derivation cohort) to that of the ASE criteria to correctly identify patients with increased RAP (RAP >10 mmHg) in the validation cohort; (3) Compare the prognostic power of estimated RAP derived from IVC noninvasively to invasively measured RAP to predict cardiovascular events during follow-up using the combined cohort. Prognostic power was defined as the ability to correctly identify patients at risk for cardiovascular event.

Echocardiography

Comprehensive echocardiogram was performed according to contemporary guidelines,^{4, 10} and offline image analyses and measurements were performed by two experienced research sonographers (J.W and K.T). The IVC was assessed in a standard fashion in the supine position from the subcostal long-axis window using 2-dimensional echocardiography, and the length of the imaging clip was adjusted to cover at least 2 respiratory cycles. The maximum IVC diameter (IVC_max) was measured at end-expiration about 1 to 3 cm from the IVC-RA junction during quiet respiration (Figure 1). The minimum IVC diameter (IVC_min) was measured during inspiratory sniff at the same location as IVC_max. IVC collapsibility index (IVC_CI) was calculated as (IVC_max − IVC_min) / IVC_max × 100. The reproducibility of IVC_max and IVC_min measurements was assessed in 20 randomly selected patients and expressed as intraclass correlation coefficient (ICC) and 95% confidence interval (CI). The purpose of intraobserver correlation, interobserver correlation, and test-retest correlation was to assess reproducibility. This was assessed in a sample of sample of 20 patients by having the same observer measure the variable at 2 different time points (intraobserver correlation), 2 different observers measure the variable at 2 different time points (interobserver correlation), and the same observer perform IVC measurements using the same image frame (test-retest correlation). Based on the ASE criteria, IVC_max >2.1 cm and IVC_CI <50% were used as the threshold to detect RAP >10 mmHg.⁴

Figure 1:

Measurement of the inferior vena cava (IVC) from the subcostal long-axis view. The diameter is measured perpendicular to the long axis of the IVC at end-expiration (left) and inspiration (right), just proximal to the junction of the hepatic veins that lie approximately 1 to 3 cm proximal to the IVC-right atrial (RA) junction.

Right Heart Catheterization

All studies were performed on chronic medications in the fasted state and mild sedation. Pressure measurements were recorded as an average of ≥5 cardiac cycles under spontaneous breathing. In patients without left heart catheterization, the brachial cuff blood pressure and pulse oximeter were used as surrogates for aortic pressures and systemic arterial oxygen saturation, respectively.

Cardiovascular Events

Cardiovascular event was defined as the composite endpoint of heart failure hospitalization, heart transplant or cardiovascular death occurring from the time of cardiac catheterization to the end of the study period. All study outcomes were ascertained by comprehensive review of the medical records. Heart failure hospitalization was defined as a hospital admission for volume overload requiring intravenous diuretics.¹¹

Statistical Analysis

All clinical, echocardiographic, and invasive hemodynamic variables obtained at baseline and during follow-up were presented as mean ± standard deviation, median (interquartile range), and count (%). Between-group comparisons were performed using unpaired t-test, and Fisher’s exact test. Pearson correlation was used to assess the relationship between continuous variables, and Bland Altman plot was used to assess the level of agreement between invasively measured versus estimated RAP. Logistic regression was used to calculate the area under the curve (AUC) to predict increased RAP, and receiver operating characteristic curve was used to determine the optimal cut-off point to detect increased RAP. The variables used in the logistic regression models were IVC_max, IVC_min, and IVC_CI. AUC comparison was performed to determine the incremental diagnostic value of IVC dynamics cut-off points derived from the current study as compared to the current ASE criteria using the method of DeLong.¹² Incremental diagnostic power was defined as the ability of the IVC dynamics cut-off points to correctly identify patients with elevated RAP as compared to the ASE criteria. Net reclassification indices were also used to evaluate the incremental positive and negative reclassification of diagnoses (i.e., the ability to correctly reclassify patients with invasively measured RAP >10 mmHg as having elevated RAP, and patients with invasively measured RAP ≤10 mmHg as having normal RAP) using IVC dynamics cut-off points derived from the current study as compared to the ASE criteria.¹³ Bootstrap validation was performed across 3000 bootstrapped replicates to evaluate variations in the ability of IVC dynamics to detect increased RAP.

In addition to IVC dynamics, we also assessed the discriminatory power of RA volume index and RA reservoir strain. The diagnostic power of RA volume index and RA reservoir strain to detect patients with elevated RAP was compared to that of IVC_CI using AUC comparison.

The following subgroup analyses to test the diagnostic power of IVC dynamics in different patient subgroups: (1) Patient with right heart disease versus no right heart disease. Right heart disease was defined as the presence of any of the following conditions: right ventricular (RV) enlargement (RV end-diastolic area >25 cm²), RV systolic dysfunction (RV fractional area change <35%), tricuspid valve disease (>mild tricuspid regurgitation or prior tricuspid valve repair/replacement), and pulmonary valve disease (>mild pulmonary regurgitation, pulmonary valve mean gradient >10 mmHg or prior pulmonary valve replacement). (2) Patients with other factors that can affected RAP such as chronic obstructive pulmonary disease (n=18), interrupted IVC (n=2), pregnancy (n=1), diuretics (n=236), and tricuspid valve prosthesis (n=43). Of note, several patients had more than one of these factors, and the total number of patients excluded was 241. (3) Male versus female; (4) Patients with versus without sternotomy/thoracotomy; (5) Patients with versus without ≥moderate tricuspid regurgitation.

The relationship between RAP and cardiovascular event was assessed using multivariable Cox regression, and the time of echocardiogram was used as the time zero for time to event analysis. First, we created a univariable Cox model to identify clinical, demographic, and echocardiographic indices associated with cardiovascular events (Supplementary Table S1). We then created a multivariable model with invasively measured RAP as the main predictor, and covariates with p<0.05 from the univariable model were entered into the multivariable model using stepwise backwards selection with p<0.2 set as the threshold for a covariate to remain in the model. We also adjusted for CHD severity by modeling CHD severity as severe versus non-severe CHD based on the classification scheme proposed by Marelli et al.¹⁴ The comparison of the prognostic power of invasively measured RAP versus estimated RAP was based on C-statistics and 95% CI. We accounted for missing data using conditional imputation. All statistical analyses were performed with JMP 14.0 (SAS Institute, Cary, NC, USA) and BlueSky Statistics software (version. 7.10; BlueSky Statistics LLC, Chicago, IL, USA), and p value <0.05 was considered statistically significant for all analyses.

RESULTS

Baseline Clinical and Hemodynamic Data (All patients, n=918)

Of 926 patients that had RHC and an echocardiogram, 918 (99%) had adequate subcostal images for assessment of the IVC, and these 918 patients comprised our study group. The most common congenital heart lesions were tetralogy of Fallot (n=264, 29%), coarctation of aorta (n=120, 13%) and Ebstein anomaly (n=71, 8%). The primary indication for RHC was for heart failure evaluation (unexplained exertional dyspnea, pulmonary congestion, or peripheral edema) (n=386; 46%), history of atrial arrhythmias (n=153; 17%), preoperative/pre-interventional assessment (n=379, 41%). The mean age at the time of RHC was 3900B003115 years and 467 (51%) were males. Supplementary Table S2 shows a comparison of the baseline clinical characteristics between the derivation and validation cohort. Compared to the derivation cohort (n=459), the validation cohort (n=459) had a higher prevalence of hypertension and use of renin angiotensin aldosterone system antagonists. Tetralogy of Fallot was more common in the derivation cohort but the other CHD diagnoses were equally distributed between the 2 samples.

Table 1 shows the invasive and noninvasive hemodynamic indices. The mean RAP was 11±6 mmHg, and 441 (48%) patients had elevated RAP (RAP >10 mmHg). Compared to the derivation cohort, the patients in the validation cohort were more likely to have smaller RA volume, lower RAP and higher pulmonary valve mean gradient (Table 1). The mean IVC_max was 2.1±0.7 cm, IVC_min was 1.4±0.5 cm, and IVC_CI was 39±14% (Table 1). There was excellent intraobserver correlation (ICC 0.97, 95% CI 0.95–0.99), interobserver (ICC 0.94, 95% CI 0.91–0.97) and test-retest correlation (ICC 0.96, 95% CI 0.95–0.97) for IVC_max. There was also excellent intraobserver correlation (ICC 0.96, 95% CI 0.94–0.98), interobserver (ICC 0.93, 95% CI 0.91–0.95) and test-retest correlation (ICC 0.95, 95% CI 0.94–0.96) for IVC_min.

Table 1:

Hemodynamic Indices

	All (n=918)	Derivation cohort (n=459)	Validation cohort (n=459)	p
Echocardiography
IVCmax, cm	2.1±0.7	2.2±0.5	2.1±0.6	0.6
IVCmin, cm	1.4±0.5	1.4±0.4	1.3±0.5	0.7
IVCCI, %	39±14	38±12	41±14	0.4
RA volume, ml/m2	35±14	39±14	31±12	0.008
RA reservoir strain, %	34±10	31±9	36±8	0.01
Tricuspid regurgitation velocity, m/s	3.2±0.9	3.3±0.8	3.1±0.6	0.2
RV systolic pressure, mmHg	48±17	51 ±18	45±16	0.3
Tricuspid valve mean gradient, mmHg	1 (1–4)	2 (2–5)	1 (1–3)	0.4
≥Moderate tricuspid regurgitation	256 (28%)	132 (29%)	124 (27%)	0.5
RV end-diastolic area, cm2	29±11	31 ±10	28±9	0.8
RV end-systolic area, cm2	20±7	22±7	18±6	0.2
RV fractional area change, %	32±10	30±9	34±8	0.1
≥Moderate pulmonary regurgitation	272 (30%)	125 (27%)	147 (32%)	0.2
Pulmonary valve mean gradient, mmHg	17±11	14±8	21±10	0.03
LA volume index, ml/m2	32±16	30±15	34±16	0.1
Septal e’ velocity, cm/s	8±4	9±4	8±5	0.5
Septal E/e’	12±7	11±7	13±8	0.2
LV ejection fraction, %	58±10	56±0.7	59±11	0.4
Cardiac catheterization
RA pressure, mmHg	11±6	13±7	10±5	0.04
RV end-diastolic pressure, mmHg	13±6	12±6	13±6	0.2
RV systolic pressure, mmHg	55±21	52±19	58±20	0.3
PA systolic pressure, mmHg	39±18	38±16	39±17	0.6
PA diastolic pressure, mmHg	16±11	18±9	14±8	0.1
PA mean pressure, mmHg	29±13	29±10	29±14	0.7
PA wedge pressure, mmHg	14±7	13±6	15±7	0.5
PVR index, wu*m2	4.1±1.2	3.9±0.9	4.2±1.1	0.6
Aortic systolic pressure, mmHg	121±23	117±21	125±35	0.7
Aortic diastolic pressure, mmHg	66±12	64±12	68±15	0.8
Aortic mean pressure, mmHg	87±17	85±16	89±17	0.8
Cardiac index, l/min/m2	2.6±0.4	2.5±0.4	2.6±0.7	0.6
Systemic saturation, %	96±3	96±4	95±4	0.5

IVC: inferior vena cava; IVC_CI: IVC collapsibility index; RA: right atrium; RV: right ventricle; LA: left atrium; e’: tissue Doppler inflow early velocity; E: pulsed wave inflow early velocity; LV: left ventricle; PA: pulmonary artery; PVR: pulmonary vascular resistance

Estimation of RAP Using IVC Dynamics (Derivation cohort, n=459)

In the derivation cohort, the mean RAP was 13±7 mmHg, and the mean IVC_max, IVC_min and IVC_CI were 2.2±0.5 cm, 1.4±0.4 cm, and 38±12% respectively. There was good correlation between IVC_max and invasively measured RAP (r=0.56, p<0.001); IVC_min and RAP (r=0.58, p<0.001); and IVC_CI (r=−0.72, p<0.001), Table 2. The mean IVC_max and IVC_min indexed to body surface area (BSA) was 1.1±0.4 cm/m² and 0.7±0.2 cm/m², respectively. There was a good correlation between IVC_max indexed to BSA and invasively measured RAP (r=0.58, p<0.001) and between IVC_min indexed to BSA and RAP (r=0.57, p<0.001). There was no significant difference in the correlation between IVC_max and invasively measured RAP versus between IVC_max indexed to BSA and invasively measured RAP (r=0.56 versus r=0.58, Meng test p=0.4). Similarly, there was no significant difference in the correlation between IVC_min and invasively measured RAP versus between IVC_min indexed to BSA and invasively measured RAP and (r=0.58 versus r=0.57, Meng test p=0.6).

Table 2:

Correlation between IVC Dynamics and Invasively Measured RAP (Derivation Cohort, n=459)

	Mean±SD	β±SE	r
IVCmax, cm	2.1±0.7	3.63±0.78	0.56
IVCmin, cm	1.4±0.5	3.81±0.71	0.58
IVCCI, %	39±14	−0.26±0.03	−0.72
	AUC (95%CI)	Cut-off point
IVCmax	0.70 (0.67–0.73)	1.8 cm
IVCmin	0.72 (0.69–0.75)	1.2 cm
IVCCI	0.84 (0.80–0.88)	60%

IVC: inferior vena cava; IVC_CI: IVC collapsibility index; RAP: right atrial pressure; SD: standard deviation; SE: standard deviation

β +/−SE and r were derived from univariable linear regression analysis of IVC dynamics and invasively measured RAP.

RAP can be estimated from IVC dynamics using this formula: RAP=16.89 – 0.12 (IVC_CI). There was excellent correlation between invasively measured RAP and estimated RAP using IVC_CI (r=0.80, p<0.001), Figure 2. Bland–Altman plot showed little bias for RAP (bias 0.6 mmHg, 95% limits of agreement −6 to +8 mmHg), Figure 2B. Of note, the IVC_CI correctly estimated RAP within 5 mmHg of the invasively measured RAP 79% of the time (361/459), underestimated RAP by more than 5 mmHg in 15% of the time (69/459), and overestimated RAP by more than 5 mmHg in 6% of the time (29/459).

Figure 2.

: Correlation and prognostic power of estimated right atrial pressure (RAP). (A) Pearson correlation of estimated RAP versus invasive RAP using the derivation cohort; (B) Bland Altman plot showing level of agreement (LoA) between estimated RAP versus invasive RAP using the derivation cohort; (C) Forrest plot showing hazard ratio (HR) and 95% confidence interval (CI) for 3 separate multivariable Cox models. All models were adjusted for age, congenital heart disease severity, atrial fibrillation, glomerular filtration rate, right and left ventricular systolic function. In Model 1, RAP > 10 mmHg was based on invasively measured RAP. In model 2, RAP > 10 mmHg was based on estimated RAP using inferior vena cava collapsibility index <60%. In model 3, RAP > 10 mmHg was based on estimated RAP using American society of echocardiography criteria (IVC_max >2.1 cm and inferior vena cava collapsibility index <50%)

Table 2 summarizes the optimal cut-off points for IVC_max, IVC_min and IVC_CI to detect increased RAP (invasively measured RAP >10 mmHg). IVC_CI had the best discriminatory power to identify patients with increased RAP (AUC 0.84, 95%CI 0.80–0.88, p<0.001), with IVC_CI <60% providing the optimal cut-off point to detect increased RAP with a sensitivity of 93% and specificity of 89%. IVC_max and IVC_min were inferior to IVC_CI in identifying patients with increased RAP (AUC difference 0.14, 95%CI 0.11–0.17, p<0.001 and AUC difference 0.12, 95%CI 0.08–0.16, p<0.001, respectively). Validation across 3000 bootstrapped replicates confirmed good stability in the selected threshold value of 60%, 1.8 cm and 1.2 cm for IVC_CI, IVC_max and IVC_min respectively. Specifically, the optimal threshold in the bootstrap analysis was estimated to be 63% (95%CI 59–67) for IVC_CI, 1.78 cm (95%CI 1.75–1.81) for IVC_max and 1.23 (95%CI 1.20–1.26) for IVC_min.

In addition to IVC dynamics, we also assessed the discriminatory power of RA volume index and RA reservoir strain. Supplementary Figure S1 show receiver operating characteristics curves showing the diagnostic performance of IVC_CI, RA reservoir strain, and RA volume index to detect patients with increased RAP (RAP >10 mmHg). Compared to IVC_CI, RA volume index had inferior discriminatory power (AUC 0.84 versus 0.59, AUC difference 0.25, 95% CI 0.19–0.30, p<0.001) while RA reservoir strain had a comparable discriminatory to detect increased RAP (AUC 0.84 versus 0.82, AUC difference 0.0, 95% CI −0.02–0.06, p=0.4).

Diagnostic Performance of IVC Dynamics and ASE Criteria (Validation Cohort, n=459)

The cut-off points of IVC dynamics generated from the derivation cohort were tested in the validation cohort. We observed that IVC_CI <60% had a more robust diagnostic performance as compared to IVC_max >1.8 cm (AUC difference 0.13) and IVC_min >1.2 cm (AUC difference 0.11), Table 3. However, combining IVC_max >1.8 cm with IVC_CI <60% did not result in a further improvement in diagnostic performance above that IVC_CI alone (AUC difference −0.02, p=0.09), Table 3.

Table 3:

Diagnostic Performance of IVC Dynamics for Detecting Increased RAP (RAP >10 mmHg) in the Validation Cohort

	AUC (95% CI)	AUC difference	p	Sen (%)	Spec (%)	PPV (%)	NPV (%)
Criteria from derivation cohort
IVCmax >1.8 cm	0.69 (0.64–0.74)	0.13 (0.07–0.19)	<0.001	78	85	69	90
IVCmin >1.2 cm	0.71 (0.68–0.74)	0.11 (0.05–0.17)	<0.001	89	81	68	93
IVCCI <60%	0.82 (0.79–0.85)	Reference	---	91	89	82	94
IVCmax >1.8 cm and IVCCI <60%	0.84 (0.80–0.88)	−0.02 (−0.05– +0.01)	0.09	87	97	78	97
ASE criteria
IVCmax >2.1 cm	0.67 (0.64–0.70)	0.15 (0.09–0.21)	<0.001	63	89	57	74
IVCCI <50%	0.73 (0.69–0.77)	0.09 (0.03–0.15)	0.008	85	72	80	78
IVCmax >2.1 cm and IVCCI <50%	0.76 (0.73–0.79)	0.06 (0.03–0.09)	0.02	65	99	55	89

IVC: inferior vena cava; IVC_CI: IVC collapsibility index; RAP: right atrial pressure; PPV: positive predictive value; NPV: negative predictive value; ASE: American Society of Echocardiography; CI: confidence interval; AUC: area under the curve

AUC difference means difference in AUC between ASE criteria and the variable on interest.

Next, we tested the diagnostic performance of the ASE criteria for detecting increased RAP (IVC_max >2.1 cm and IVC_CI <50%). We observed that IVC_CI <60% had superior diagnostic performance as compared to ASE criteria (IVC_max >2.1 cm, AUC difference 0.15, p<0.001; IVC_CI <50%, AUC difference 0.09, p=0.008; combination of IVC_max >2.1 cm and IVC_CI <50%, AUC difference 0.06, p=0.02), Table 3. IVC_CI demonstrated a net reclassification improvement (i.e., the ability to correctly reclassify patients with invasively measured RAP >10 mmHg as having elevated RAP, and patients with invasively measured RAP ≤10 mmHg as having normal RAP) when IVC was substituted for each of the ASE criteria for IVC size and collapsibility (Table 4).

Table 4:

Net Reclassification Improvement of Substituting IVCCI <60% For ASE Criteria in the Validation Cohort

	NRI (95% CI)	p	NR −event	p	NR +event	p
ASE criteria
IVCmax >2.1 cm	+0.165 (+0.062 – +0.274)	0.003	+0.018	0.4	+0.162	<0.001
IVCCI <50%	+0.131 (+0.024 – +0.241)	0.008	+0.05	0.2	+0.092	0.01
IVCmax >2.1cm and IVCCI <50%	+0.153 (+0.029 – +0.294)	0.01	+0.167	<0.001	−0.006	0.9

IVC: inferior vena cava; IVC_CI: IVC collapsibility index; ASE: American Society of Echocardiography; NRI: net reclassification; CI: confidence interval

Classification Based on Estimated RAP

We used the formula (RAP=16.89 – 0.12 (IVCCI)) to estimated RAP in the entire cohort of 918 patients. We then divided the patients into 3 categories based on estimated RAP (0–5 mmHg, 6–10 mmHg, and >10 mmHg), Supplementary Table S3. There were significant differences in the invasive and invasive indices of right heart function between the different estimated RAP categories (Supplementary Table S4).

Subgroup Analyses

The following subgroup analyses were performed to determine whether the discriminatory power of IVC_CI <60% differed between different patient subgroups.

(1) Patients with versus without right heart disease. Based on pre-defined criteria for right heart disease, we identified 728 (79%) with right heart disease and 190 (21%) without right heart disease. Among the patients with right heart disease, IVC_CI <60% had an excellent diagnostic performance to detect increased RAP (AUC 0.87, p<0.001). We observed that IVC_CI <60% had superior diagnostic performance as compared to ASE criteria (IVC_max >2.1 cm, AUC difference 0.22, p<0.001; IVC_CI <50%, AUC difference 0.15, p<0.001; combination of IVC_max >2.1 cm and IVC_CI <50%, AUC difference 0.12, p<0.001), Table 5. We also assessed the diagnostic performance of IVC_CI <60% to detect increased RAP for the most common CHD lesions affecting the right heart in our sample. We observed an AUC of 0.88 for tetralogy of Fallot, AUC of 0.83 for atrial septal defect/anomalous pulmonary venous return, AUC of 0.86 for Ebstein anomaly, AUC of 0.87 for valvular pulmonic stenosis, and AUC of 0.85 for pulmonary atresia with intact ventricular septum.

Table 5:

Diagnostic Performance of IVC Dynamics for Detecting Increased RAP (RAP >10 mmHg) in Patients with Right Heart Disease (n=728)

	AUC (95% CI)	AUC difference	p
ASE criteria
IVCmax >2.1 cm	0.65 (0.61–0.69)	0.22 (0.18–0.26)	<0.001
IVCCI <50%	0.74 (0.69–0.78)	0.15 (0.11–0.19)	<0.001
IVCmax >2.1 cm and IVCCI <50%	0.75 (0.71–0.79)	0.12 (0.08–0.16)	<0.001
Diagnostic Performance of IVC Dynamics for Detecting Increased RAP (RAP >10 mmHg) in Patients without Right Heart Disease (n=190)
	AUC (95% CI)	AUC difference	p
ASE criteria
IVCmax >2.1 cm	0.68 (0.62–0.74)	0.10 (0.02–0.18)	0.02
IVCCI <50%	0.75 (0.69–0.81)	0.03 (−0.01–0.07)	0.1
IVCmax >2.1 cm and IVCCI <50%	0.77 (0.73–0.81)	0.01 (−0.03–0.07)	0.4

AUC: area under the curve; IVC: inferior vena cava; IVC_CI: IVC collapsibility index; RAP: right atrial pressure; ASE: American Society of Echocardiography; CI: confidence interval

AUC difference means difference in AUC between ASE criteria and the variable on interest.

On the other hand, IVC_CI <60% had a less robust diagnostic performance among the patients without right heart disease (AUC 0.78, p=0.008). IVC_CI <60% provided only a marginal improvement in diagnostic performance as compared to IVC_max >2.1 cm, AUC difference 0.10, p=0.02). There was no significant difference in the diagnostic performance between IVC_CI <60%, and the other ASE criteria in patients without right disease, Table 5.

(2) Patients without potential confounders for RAP such as chronic obstructive pulmonary disease, interrupted IVC, pregnancy, diuretics, and tricuspid valve prosthesis. Of the 918 patients, 241 patients were excluded while 667 patients were included in the analysis. We observed that IVC_CI <60% had an excellent discriminatory power to detect increased RAP (AUC 0.86, 95% CI 0.81–0.91, p<0.001), similar to the results observed from the derivation cohort (AUC difference −0.02, p=0.5).

(3) IVC_CI <60% had similar discriminatory power to detect increased RAP in males (AUC 0.83, 95% CI 0.77–0.89, p<0.001), and in females (AUC 0.84, 95% CI 0.79–0.89, p<0.001), AUC difference 0.01, p=0.6).

(4) Similarly, IVC_CI <60% had similar discriminatory power to detect increased RAP in patients with prior sternotomy/thoracotomy (n=631, 69%) (AUC 0.83, 95% CI 0.79–0.87, p<0.001), and patients without prior sternotomy/thoracotomy (n=287, 31%) (AUC 0.85, 95% CI 0.78–0.92, p<0.001), AUC difference 0.02, p=0.4).

(5) However, IVC_CI <60% has less robust discriminatory power to detect increased RAP in patients with moderate (or greater) severity of tricuspid regurgitation (n=256, 28%) as compared to patients with less than moderate tricuspid regurgitation (n=662, 72%); AUC 0.82, 95% CI 0.76–0.88, versus AUC 0.87, 95% CI 0.83–0.91, AUC difference −0.05, p=0.008).

Prognostic Performance of Estimated versus Invasive RAP (All patients, n=918)

The median follow-up for the 918 patients was 6.9 (3.8–10.1) years, and during this period, 132 (14%) patients were hospitalized for heart failure, 141 (15%) patients died from cardiovascular causes (end-stage heart failure n=86, arrhythmic/sudden cardiac death n=24, stroke-related deaths n=12, and postoperative death n=19), and 18 (2%) patients underwent heart transplant for end-stage heart failure. The combined outcome of cardiovascular events occurred in 228 (25%) patients. Table 6 shows 3 different multivariable models assessing the relationship between RAP and cardiovascular events. In Model 1, elevated RAP (RAP >10 mmHg) based on invasively measured RAP was independently associated with cardiovascular events (hazard ratio 2.65, 95%CI 2.29–3.07; c-statistic 0.739, 95%CI 0.713–0.762). There was no significant change in hazard ratio or c-statistic after replacing invasive RAP with estimated RAP derived from IVC_CI in Model 2 (Table 6, Figure 2C). However, there was a significant reduction in hazard ratio and c-statistic after replacing invasive RAP with estimated RAP derived from the ASE criteria in Model 3 (Table 6, Figure 2C). Collectively, these results suggest that invasively measured RAP and estimated RAP based on IVC_CI had a comparable prognostic power, while estimated RAP based on ASE criteria had a less robust prognostic power in this group of adults with CHD.

Table 6:

Multivariable Cox Models Showing Risk Factors Associated with Cardiovascular events

	Model 1 HR (95% CI)	Model 2 HR (95%CI)	Model 3 HR (95%CI)
RAP >10 mmHg	2.65 (2.29–3.07)	2.24 (1.92–2.67)	1.41 (1.03–1.78)
Age, per year	1.02 (1.01–1.03)	1.02 (1.01–1.03)	1.02 (1.01–1.04)
Severe CHD	1.39 (1.02–1.87)	1.32 (1.14–1.73)	---
Atrial fibrillation	1.28 (1.05–1.84)	---	1.22 (1.04–1.89)
GFR, per 5-unit increment	0.98 (0.97–0.99)	1.10 (1.02–1.23)	---
RV fractional area change, per %	---	0.98 (0.96–0.99)	0.98 (0.97–0.99)
LV ejection fraction, %	0.97 (0.95–0.99)	0.98 (0.97–0.99)	0.99 (0.98–1.00)
	c-statistic (95% CI)	c-statistic (95% CI)	c-statistic (95% CI)
	0.739 (0.713–0.762)	0.722 (0.701–0.741)	0.681 (0.663–0.698)

RAP: right atrial pressure; CHD: congenital heart disease; RV: right ventricle; LV: Left ventricle; GFR: Glomerular filtration rate; HR: Hazard rate; CI: Confidence interval

^*Note that severe CHD was modeled as binary variable (severe vs non-severe CHD) based on the definition of CHD proposed by Marelli et al.

---denotes a non-statistically significant association

In Model 1, RAP > 10 mmHg was based on invasively measured RAP. In model 2, RAP > 10 mmHg was based on estimated RAP using inferior vena cava collapsibility index <60%. In model 3, RAP > 10 mmHg was based on estimated RAP using American society of echocardiography criteria (IVCmax >2.1 cm and inferior vena cava collapsibility index <50%)

Classification Based on Estimated RAP

We used the formula (RAP=16.89 – 0.12 (IVCCI)) to estimated RAP, and then divided the patients into 3 categories based on estimated RAP (0–5 mmHg, 6–10 mmHg, and >10 mmHg)

DISCUSSION

In this study, we assessed the diagnostic and prognostic role of IVC dynamics for estimating RAP in adults with CHD. The main findings are: (1) Echocardiographic assessment of IVC dynamics was feasible in 99% of the patients with excellent reproducibility; (2) Of all the IVC indices assessed, IVC_CI had the best correlation with non-simultaneous invasively measured RAP, and had superior diagnostic performance for correctly identifying patients with increase RAP as compared to the ASE criteria; (3) Estimated RAP based on IVC_CI had a comparable prognostic performance as invasively measured RAP, and a superior prognostic performance as compared ot estimated RAP based on the ASE criteria.

The RAP is a barometer of right heart function, and it is also a determinant of left heart preload and cardiac output. ^{5, 15–17} RAP is routinely used for risk stratification and to guide medical therapy in patients with heart failure because of the correlation between RAP and clinical outcomes.^{1, 4} RHC is the gold standard for the assessment of RAP, and it is frequently used for risk stratification in patients with acquired heart disease and to determine optimal management strategy especially in patients with clinical or hemodynamic deterioration.^{18, 19} RHC is invasive and expensive, and hence has limited application in clinically stable and ambulatory patients.

Echocardiography is a robust non-invasive tool for hemodynamic assessment, and of the echocardiographic indices used for estimation of RAP, IVC dynamics (size and collapsibility) is the most commonly used in clinical practice.^{7, 9, 19} This is because IVC dynamics have been shown to correlate with invasively measured RAP in different disease conditions.^5–9 Based on these studies, the ASE endorses IVC diameter > 2.1 cm and IVC collapsibility <50% as the optimal threshold to identify patients with increased RAP (RAP > 10 mmHg).⁴ Patients with elevated RAP based on these IVC cut-off points have been shown to have worse clinical outcomes, and hence provide empirical validation for the use of IVC dynamics in clinical practice.

Although the IVC cuff-points recommended by the ASE are also applied to adults with CHD, it is unclear how well these indices correlate with invasively measured RAP and with clinical outcomes in this population. The current study addresses this knowledge gap and shows a robust correlation between IVC dynamics (IVC_max, IVC_min, and IVC_CI) and invasively measured RAP. In contrast to previous data, the current study presents two novel findings. First, the threshold to detect increased RAP was lower in the current study (IVC_max >1.8 cm and IVC_CI <60%) as compared to the threshold endorsed by the ASE (IVC_max >2.1 cm and IVC_CI <50%).⁴ Second, IVC collapsibility alone (rather that the combination of IVC size and collapsibility) provided the most robust estimate for RAP. We postulated that these novel findings may be related to the unique pathophysiology and hemodynamics of patients with CHD.

RAP is dependent on RA function, RV function, right heart volume overload (from tricuspid and pulmonary regurgitation), and pericardial factors.^{5, 15–17} These factors are typically abnormal in patients with CHD,^{15, 20–22}. About 79% of the patients in our cohort had prior cardiac surgery or evidence of right heart disease, and these factors can result in scaring and fibrosis of the RA, RV, and pericardium. Right heart scaring and fibrosis will lead to impaired right heat compliance, which will in turn lead to a greater increase in RAP per unit change in RA volume.¹⁵ Since the pressure in the RAP parallels that in the IVC, a smaller IVC size (RA volume) will therefore correlate to higher IVC pressure (RAP) in the setting of impaired right heart compliance. Consistent with this postulate, we observed a steeper IVC_max/RAP relationship between CHD patients with right heart disease as compared to CHD patients without right heart disease. Of note, a majority of CHD patient have hemodynamic lesions involving the right heart.^{23, 24}

Another explanation for the differences in IVC cut-off points observed in this study is likely related to respirophasic changes in intrathoracic pressure. Inspiration results in a negative intrathoracic pressure, which in turn, leads to a reduction in intrapericardial pressure and RAP.⁵ A reduction in RAP leads to augmentation of venous return from the IVC resulting in a respirophasic reduction in IVC size (IVC collapsibility). IVC collapsibility, therefore, reflects to some extent, a reduction in intrathoracic pressure during inspiration and the rapidity of pressure change in the RAP in response to the increase in RA preload during inspiration. We postulate that the CHD patients are younger (mean age 3900B003115 years) and are potentially able to generate more negative intrathoracic pressure, and hence a lower IVC collapsibility will correlate with higher RAP as compared to the older patients with acquired heart disease.

Clinical Implications and Future Direction

IVC_CI can be used as a continuous variable to estimate RAP based on a simple formula, and hence estimated RAP as continuous variable will potentially provide a better diagnostic and prognostic performance. Even without the formula, the use of IVC_CI <60% (rather than 2 different indices: IVC_max >2.1 and IVC_CI <50%) to identify patients with elevated RAP will be easier and simpler to apply in clinical practice

Limitations

This is a retrospective single center study of patients referred for RHC, and hence it is prone to selection, referral, and ascertainment bias. Since the patients referred for RHC are typically ‘sicker’, therefore the clinical characteristics of our cohort may differ from that of other CHD patients seen in the ambulatory clinic. Finally, the loading conditions at the time of echocardiogram may be different from the loading conditions at the time of cardiac catheterization since both tests were not performed simultaneously. Although the grouping of patients into derivation cohort versus validation cohort was based on randomization, both groups still had some important hemodynamic differences such as a higher RA volume index and RA pressure in the derivation cohort as compared to the validation cohort. In spite of these differences, we observed a robust diagnostic performance of IVC dynamics in both cohorts, suggesting that these estimates should be generalizable to other CHD populations. The current study is prone to type 1 error due to multiple comparisons.

Conclusions

The assessment of IVC dynamics was feasible in 99% of the patients with excellent reproducibility. IVC_CI can reliably be used to estimated RAP, and IVC_CI <60% can identify adult CHD patients with elevated RAP with a greater diagnostic power than the ASE criteria. Furthermore, IVC_CI has comparable prognostic performance as invasively measured RAP. We propose new IVC size and collapsibility criteria based on data derived from adults with CHD. Further studies are required to determine whether the use of the proposed IVC criteria in clinical decision making will improve clinical outcomes in this population.

CLINCAL SUMMARY.

The purpose of this study was to assess the role of inferior vena cava (IVC) dynamics for estimating right atrial pressure (RAP) in adults with congenital heart disease. We observed that RAP can be estimated using IVC collapsibility index (IVC_CI), and there was an excellent correlation between invasive RAP and estimated RAP (r=0.80, p<0.001). We also observed that IVC_CI <60% had superior diagnostic and prognostic performance as compared to American Society of Echocardiography IVC criteria. Further studies are required to determine whether the use of these IVC criteria in clinical decision making will improve clinical outcomes in this population.

Abbreviations:

IVC

inferior vena cava

RAP

right atrial pressure

RHC

Right heart catheterization

CHD

congenital heart disease

ICC

intraclass correlation coefficient

CI

confidence interval

ASE

American Society of Echocardiography

AUC

area under the curve

RV

right ventricle

BSA

body surface area