Tricuspid regurgitation (TR) is common in patients with heart failure (HF) and preserved ejection fraction (EF) (HFpEF), and increasing TR severity is associated with worsening symptoms, reduced aerobic capacity, and increased morbidity and mortality. Over 90% of TR in patients with HF is functional TR, which is caused by structural and functional abnormalities in the right side of the heart that lead to leaflet tethering, tricuspid annular (TA) dilation, and malcoaptation. ^, In HF with reduced EF (HFrEF), functional TR typically develops secondary to right ventricular (RV) dilation and tricuspid leaflet tethering caused by pulmonary hypertension (PH) (ventricular functional TR: VFTR). However, the mechanisms of functional TR in HFpEF have never been evaluated. Atrial fibrillation (AF) is more common in HFpEF than HFrEF, and right atrial (RA) remodeling may be more severe. We hypothesized that RA remodeling would be associated with functional TR in HFpEF through RA dilation and subsequent TA enlargement. ^, Accordingly, we sought to characterize the etiologies, functional and structural characteristics, and clinical outcomes of functional TR in patients with HFpEF.

This retrospective observational study investigated the etiologies of TR and its association with cardiac structure and function in patients with HFpEF. The majority of participants (n = 311, 95%) were also enrolled in our previous study, which focused on the prognostic value of semiquantitative measures of TR severity such as TR vena contracta width (VCW) in HFpEF. A total of 27,633 subjects who were referred to the echocardiographic laboratories of Gunma University Hospital in Maebashi, Japan (n = 17,507 [63%]) or Hokkaido University Hospital in Sapporo, Japan (n = 10,126 [37%]) between January 2014 and December 2018 were screened ( Supplementary Figure 1 ). The inclusion criteria of HFpEF were typical clinical symptoms of HF (exertional dyspnea, fatigue, and edema), an EF ≥50%, and at least 1 of the following: directly measured pulmonary capillary wedge pressure >15 mm Hg, B-type natriuretic peptide levels >200 pg/ml, the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity (E/e′) >15, left atrial (LA) volume index >34 ml/m ² , or previous HF-related hospitalization. ^, Subjects with a reduced EF (EF <50%), recovered EF (previous EF <40%), significant left-sided valvular heart disease (greater than moderate left-sided regurgitation, greater than mild stenosis), congenital or primary (TR not due to congenital disease and associated with structural changes in tricuspid valve apparatus, e.g., prolapse, perforation, or presence of vegetation) tricuspid valve disease, previous tricuspid valve surgery, acute coronary syndrome, nongroup II PH, congenital heart disease, or cardiomyopathies were excluded. Patients who underwent a comprehensive echocardiographic evaluation in a compensated state (as an outpatient or upon discharge from HF hospitalization) were identified. This study was approved by each institute’s clinical research review board with a waiver of consent.

Two-dimensional (2D) and Doppler echocardiography was performed according to American Society of Echocardiography guidelines. Left ventricular (LV) volume, LA volume, and EF were determined using the biplane disk method. RA pressure was estimated from the morphology of the inferior vena cava (eRAP), and RV systolic pressure (eRVSP) was calculated based on TR velocity and eRAP. The eRVSP was assumed to be 20 mm Hg in 30 patients from the absent TR group in whom TR velocity could not be obtained. There was no evidence of right-sided cardiac remodeling or dysfunction that suggests PH in these patients ( Supplementary Table 1 ). RV dimensions were measured at end-diastole using RV-focused views, whereas TA diameter was measured in an apical 4-chamber view at end-diastole. RV systolic function was assessed by tricuspid annular plane systolic excursion (TAPSE). Due to the unavailability of M-mode images, TAPSE was measured using 2D images (2D TAPSE) in 94 patients as previously described. The correlation between 2D and M-mode-derived TAPSE was examined in 20 patients, and a strong correlation was found between them ( r = 0.95, p <0.0001). RV–pulmonary artery (PA) coupling was assessed as the ratio of TAPSE to eRVSP. RA volumes were measured in the apical 4-chamber view, and the RA expansion index, an index of RA reservoir function, was calculated as previously described. RA deformation analyses were also performed offline with commercially available software (EchoPAC, GE Healthcare, Milwaukee, Wisconsin) to measure RA reservoir strain. This was performed in a subgroup of 158 patients examined using the same ultrasound vendor (Vivid 7, GE Healthcare, Milwaukee, Wisconsin).

TR severity was categorized as absent (none or trivial), mild, or significant (moderate or severe) based on the guideline-recommended multiparametric approach integrating tricuspid valve morphology, the semiquantitative indices (VCW and color flow jet area), visual assessment, and hepatic vein flow pulse-Doppler wave. VFTR was defined by either eRVSP >50 mm Hg or RV dilation. ^{, ,} The remaining patients were classified as having atrial function TR (AFTR) if they had RA dilation or TA enlargement. RA enlargement was defined as RA volume index >39 ml/m ² in men and >33 ml/m ² in women (cut-offs taken as 2 SD from the mean of the normal) or RA area >18 cm ² . TA enlargement was defined as TA diameter >40 mm. Patients with a cardiac implantable electronic device were classified using the same steps if they had characteristics of functional TR without apparent lead-related interference of the tricuspid valve. ^, Patient follow-up was initiated on the day of the echocardiographic examination. The primary end point of the current study was HF hospitalization, which was defined as dyspnea and pulmonary edema on chest radiography requiring intravenous diuretic treatment.

Data are reported as mean (SD), median (interquartile range), or number (%). Intergroup differences were analyzed using the chi-square test, t test, Mann-Whitney U test, analysis of variance, or Kruskal-Wallis test as appropriate. Correlations were assessed using Pearson’s (normally distributed data) or Spearman’s (non-normally distributed data) correlation coefficients. Event-free rates were assessed using the Kaplan-Meier curve analysis, and univariable and multivariable Cox proportional hazards models were used to assess the independent prognostic power. All tests were two-sided with a significance level of p <0.05. All statistical analyses were performed using JMP 14.0.0 (SAS Institute Inc., Cary, North Carolina).

Of the 27,633 subjects screened, 328 with HFpEF were included in the final analysis after evaluation of the inclusion and exclusion criteria. Of these 328 patients with HFpEF, 69 (21%) had significant TR (Table ; moderate TR, n = 52; severe TR, n = 17). The TR jet was central in all patients. Clinical demographics according to TR grading are listed in Table 1 . Patients with significant TR had a higher prevalence of AF and cardiac implantable electronic device use and higher levels of γ-glutamyl transferase than those in the other groups. There was a modest relation between biomarker levels and TR severity as assessed by increasing VCW (ln B-type natriuretic peptide, r = 0.23; ln γ-glutamyl transferase, r = 0.24; ln total bilirubin, r = 0.30; all p <0.0001).

The presence of significant TR was associated with remarkable abnormalities in biventricular structure and function ( Table 2 ). Particularly, patients with significant TR displayed lower mitrals’ tissue velocity, larger LA volume index, higher prevalence of moderate mitral regurgitation (MR), higher eRVSP, more impaired RV-PA coupling (lower TAPSE/eRVSP ratio), and larger RV basal and mid diameters than the other groups ( Table 2 ). There was a strong relation between eRVSP and the semiquantitative measures of TR severity (VCW, r = 0.65, p <0.0001; and TR jet area, r = 0.64; p <0.0001). The prevalence of RV dilation as defined by RV mid diameter >35 mm was the highest in the significant TR group, but only one-third of the patients fulfilled RV enlargement ( Figure 1) . Patients with mild or significant TR had lower TAPSE than patients with HFpEF but without TR.

Table 2

Cardiac structure and function according to TR status

Variable	Absent (n = 128)	Mild Tricuspid Regurgitation (n = 131)	Significant Tricuspid Regurgitation (n = 69)	p Value
LV end-diastolic volume (ml)	89 ± 35	94 ± 35	82 ± 34	0.07
LV mass index (g/m 2 )	107 ± 32	107 ± 32	102 ± 30	0.5
LV ejection fraction (%)	61 ± 7	62 ± 7	62 ± 6	0.3
Stroke volume (ml)	57 ± 19	59 ± 19	53 ± 20	0.2
Cardiac output (L/min)	4.2 ± 1.7	4.2 ± 1.5	3.8 ± 1.4	0.2
Mitral E-wave (cm/s)	75 ± 24	87 ± 29*	95 ± 26*	<0.0001
Mitral e’ velocity (cm/s)	5.2 ± 1.8	5.6 ± 2.1	6.6 ± 2.4 * , †	<0.0001
Mitral s’ velocity (cm/s)	6.3 ± 1.7	5.8 ± 1.6 *	5.0 ± 1.3 ⁎†	<0.0001
E/e’ ratio	16 ± 6	17 ± 7	16 ± 6	0.3
LA volume index (ml/m 2 )	44 ± 21	58 ± 53*	78 ± 46 ⁎†	<0.0001
Mitral regurgitation (%) Absent/ mild/ moderate	70%/27%/3%	31%*/64%*/5%	22%*/61%*/17% ⁎†	<0.0001
eRVSP (mm Hg)	23 ± 6	34 ± 10*	40 ± 12 ⁎†	<0.0001
TAPSE (mm)	19 ± 5	17 ± 5*	15 ± 5*	0.0001
TAPSE/eRVSP (mm/mm Hg)	0.84 ± 0.34	0.54 ± 0.22*	0.41 ± 0.15 ⁎†	<0.0001
RV basal diameter (mm)	32 ± 7	37 ± 7*	41 ± 8 ⁎†	<0.0001
RV mid diameter (mm)	26 ± 6	29 ± 6*	33 ± 7 ⁎†	<0.0001
RV long diameter (mm)	61 ± 8	61 ± 8	61 ± 9	0.9
TV annular diameter (mm)	23 ± 4	27 ± 6*	33 ± 6 ⁎†	<0.0001
TR vena contracta width (mm)	0.8 ± 0.6	2.1 ± 0.7*	5.4 ± 2.3 ⁎†	<0.0001
TR jet area (cm 2 )	0.3 ± 0.4	1.6 ± 1.1*	6.8 ± 5.1 ⁎†	<0.0001
eRAP (mm Hg)	4 ± 2	5 ± 3*	6 ± 4 ⁎†	<0.0001
RA max area (cm 2 )	13 ± 4	17 ± 7*	25 ± 11 ⁎†	<0.0001
RA max volume index (ml/m 2 )	19 ± 10	30 ± 16*	58 ± 42 ⁎†	<0.0001
RA min volume index (ml/m 2 )	13 ± 9	21 ± 16*	46 ± 35 ⁎†	<0.0001
RA expansion index (%)	63 (37, 94)	47 (19, 89)	24 (15, 41) ⁎†	<0.0001
RA reservoir strain (%), n = 158	22 ± 11	16 ± 11*	9 ± 5 ⁎ , †	<0.0001

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