Abstract
Background:
Secondary tricuspid regurgitation (STR) in heart failure (HF) and preserved ejection fraction (HFpEF) is linked to more advanced stages with pulmonary vascular disease (PVD), but may also develop at earlier stages of HFpEF, such as those with isolated exercise-induced congestion.
Objective:
To evaluate the prevalence, distribution, and prognostic significance of STR mechanisms across the spectrum of HFpEF.
Methods:
Cardiac structure, function, hemodynamics, and clinical outcomes were compared among patients with HFpEF phenotypes categorized according to the presence of PVD (pulmonary vascular resistance>2 WU), elevation in filling pressure at rest vs provocation (leg-elevation or exercise), and according to the presence of atrial or ventricular STR (A-STR, V-STR).
Results:
Of 1,091 patients (median age 65 years, 60.3% women), 669 (61.3%) had HFpEF [20.2% exercise HFpEF-PVD, 38.6% rest HFpEF-PVD, 15.5% exercise HFpEF+PVD, 25.7% rest HFpEF+PVD]. Moderate/severe STR was present in 17.4% overall, but increased with PVD [6.7%, 11.6%, 18.3%, 33.7%, respectively], though moderate/severe STR was still more common in exercise-only HFpEF vs non-cardiac dyspnea patients (11.7% vs 6.5%, p=0.047). Most STR (69%) fulfilled criteria for V-STR, but these individuals had similar AF prevalence and greater atrial remodeling compared to A-STR. V-STR was independently associated with composite of death or HF hospitalization [multivariable HR 1.70, (95% CI 1.10-2.65)] as well as death and HF hospitalizations each alone, whereas A-STR was associated with increased risk of HF hospitalizations [multivariable Fine-Gray HR 2.21 (1.12-4.37)].
Conclusion:
STR in HFpEF is associated with PVD and less strongly with higher resting filling pressure. While V-STR is the more common phenotype of STR in HFpEF, these patients also have substantial atrial myopathy, suggesting a mixed mechanism. TR was more prevalent in exercise HFpEF than non-cardiac dyspnea; with none in the latter group having moderate-severe/severe TR, highlighting the importance of exercise hemodynamics. While V-STR conferred excess mortality and HF hospitalizations, A-STR conferred only excess HF hospitalizations.
Keywords: Tricuspid regurgitation, heart failure, pulmonary vascular disease, echocardiography, hemodynamics
Central illustration:
Tricuspid regurgitation across the spectrum of heart failure with preserved ejection fraction
Condensed Abstract:
To evaluate the prevalence, distribution, and prognostic significance of secondary TR subtypes across the spectrum of HFpEF, 1,091 patients (median age 65 years, 60.3% women) with exercise right heart catheterization were included. HFpEF was present in 669 (61.3%); ≥moderate TR was present in 17.4% of HFpEF patients. TR prevalence in HFpEF ranged between 6.7% and 33.7% and increased more strongly with increased pulmonary vascular resistance but also with rest vs exercise-only elevation in left filling pressures. Most TR (69%) fulfilled criteria for the ventricular type than the atrial type and both types were independently associated with worse outcomes.
Introduction
Secondary tricuspid regurgitation (STR) can develop in the setting of many cardiopulmonary diseases,1-3 including heart failure and preserved ejection fraction (HFpEF).4-6 HFpEF is frequently overlooked in patients with STR7-11 and often mislabeled as idiopathic or isolated.12, 13 The spectrum of HFpEF spans patients with elevation in filling pressure exclusive during exercise to those with congestion apparent at rest,14, 15 and there are also patients with coexisting pulmonary vascular disease (PVD),16 which may lead to right ventricular (RV) dysfunction.5, 16 STR in HFpEF can develop in the setting RV dysfunction and PVD,5 but recent evidence suggests that STR may also develop in earlier stages or phenotypes of HFpEF,12, 13 even in the absence of RV dysfunction. There remains limited data on the prevalence and characteristics of STR across the spectrum of HFpEF.
STR is classified as atrial (A-STR) when right atrial (RA) remodeling results in tricuspid annular dilation and TR, and ventricular (V-STR) when TR occurs due to RV remodeling and subsequent tricuspid leaflet tethering and annular dilation.1, 17, 18 A-STR is more commonly linked with HFpEF, but the distribution and prognostic implications of this classification in HFpEF are not well-established. The prespecified aims of the present study were to (1) evaluate the prevalence of ≥moderate TR across the different phenotypes of HFpEF, classified according to the presence or absence of PVD, and the presence of rest vs exercise-induced elevation in PAWP, and across other groups of pulmonary hypertension and patients with noncardiac dyspnea; and (2) Evaluate and characterize the mechanism of ≥moderate TR (i.e., A-STR vs V-STR) in patients with HFpEF; and (3) Evaluate the prognostic impact of the different mechanisms of ≥moderate TR in HFpEF.
Methods
Study population
The study was approved by the Mayo Clinic institutional review board, who waived the requirement of informed consent. According to Minnesota state law, patients who denied authorization for their data to be used for research were excluded from the study. Adult patients who underwent right heart catheterization (RHC) both at rest and exercise at Mayo Clinic sites between February 2006 and June 2023 and who had a transthoracic echocardiogram within 90 days before the RHC were identified retrospectively. When multiple transthoracic echocardiograms were available, the closest to the RHC procedure was considered the index exam. Exclusion criteria included prior cardiac surgery, cardiac implantable electronic device, low current/previous EF<50%, ≥moderate aortic valve regurgitation or stenosis, ≥moderate mitral regurgitation, any mitral stenosis, primary tricuspid valve disease (e.g., rheumatic disease, carcinoid disease, tricuspid valve flail or prolapse, endocarditis), congenital heart disease, infiltrative/inflammatory/hypertrophic cardiomyopathy, or pericardial disease. Comorbidities were obtained using the International Classification of Diseases codes. In the case of atrial fibrillation (AF), electrocardiograms were additionally examined.
Echocardiography
All transthoracic echocardiograms were performed in routine clinical practice by professional sonographers, according to the guidelines19, and interpreted by level III board-certified echocardiologists. The severity of TR was classified as none/trivial, mild, moderate, and moderate-severe/severe using an integrative approach based on color flow Doppler, density and shape of the regurgitant jet, proximal isovelocity surface area (effective regurgitant orifice area and regurgitant volume, as available), inferior vena cava size, and hepatic vein flow pattern, according to the guidelines (Appendix 1).20 Subsets of 25 randomly selected patients from each TR severity grade (no, mild, moderate, moderate-severe/severe) for a total of 100 patients were reviewed de-novo to confirm TR severity and assess agreement. RV mid-ventricular diameter at end-diastole as well as RV end-systolic and end-diastolic areas were measured in the RV-focused apical 4-chamber view, and the RV fractional area change (RV-FAC) was calculated21. RA end-systolic area and volume were measured from the apical 4-chamber view; the RA volume was measured using the single-plane summation method. Tricuspid valve tenting height was measured at end-systole as the distance between the tricuspid annulus plane and the atrial aspect of the leaflets. These measurements were performed by 4 readers (J.A.N., T.H., A.T., C.K.W.). Interobserver agreement for measurements was assessed using the intraclass correlation coefficient (ICC) in a random 10-patient sample.
Classification of STR
In accordance with current recommendations, STR was classified as V-STR when one or more of the following five criteria were met: RV-FAC <35%, tricuspid annular plane systolic excursion (TAPSE) ≤17 mm, tricuspid valve tenting height >9 mm, mid-RV diameter >38 mm, or end-systolic RA area-to-RV area ratio <1.5; otherwise, TR was classified as atrial STR (A-STR).17, 18 The presence of RA or tricuspid annular dilation was required in the definition of ≥moderate A-STR, with cutoffs of RA volume ≥29 mL/m2 in women and ≥34 in men and/or tricuspid annulus apical 4-chamber end-diastolic diameter ≥40 mm or ≥22 mm/m2 in men and ≥35 mm or ≥21 mm/m2 in women, as previously recommended.18 Notably, according to expert consensus, the presence of PH alone was not considered as meeting the criteria for V-STR in patients with HFpEF17, 18. In a sensitivity analysis, V-STR was defined as requiring at least two of the five above V-STR criteria.
Right heart catheterization and diagnostic classification
RHC was performed in the supine position; technical details are included in Appendix 1. Using invasive hemodynamic data obtained during RHC, HFpEF was defined by PAWP of ≥15 mmHg at rest, ≥19 mmHg on feet-up maneuver, or ≥25 mmHg during exercise.8 HFpEF was classified as “rest HFpEF” when PAWP at rest was ≥15 mmHg and “exercise HFpEF” when PAWP at rest was <15 mmHg but PAWP was ≥19 mmHg on feet-up maneuver or ≥25 mmHg with exercise22. PH was defined as mean pulmonary arterial pressure (mPAP) >20 mmHg at rest. In the absence of PH criteria at rest, exercise-induced PH was defined using an mPAP-to-cardiac output slope of >3 mmHg/L/min. Pre-capillary PH (or combined post- and pre-capillary PH in the setting of HFpEF) was defined with pulmonary vascular resistance (PVR) >2 WU. In a sensitivity analysis, the older PVR cutoff value >3 WU was used to increase specificity22. PH in the absence of HFpEF and with normal PVR was referred to as unclassified PH. In the absence of HFpEF or PH at rest or exercise, patients were defined as non-cardiac dyspnea patients based upon normal cardiac hemodynamic evaluation.
HFpEF was classified into four phenotypes according to the presence or absence of (1) pulmonary vascular disease (PVD)16, 23, 24 25reflected by PVR >2 WU and (2) rest vs exercise-only elevation in PAWP.14, 26, 27 These included HFpEF at rest with PVR >2 [rest HFpEF+PVD]; HFpEF at feet-up/exercise and PVR >2 WU [exercise HFpEF+PVD]; HFpEF at rest with PVR ≤2 WU [rest HFpEF-PVD]; and feet-up/exercise HFpEF with PVR ≤2 WU [exercise HFpEF-PVD].
The remaining patients without HFpEF were classified into one of four categories: pre-capillary PH [mPAP at rest of >20 mmHg and PVR >2 WU]; unclassified PH [mPAP at rest of >20 mmHg and PVR ≤2 WU]; exercise-induced PH without HFpEF; and normal hemodynamics.
The RV-FAC to mPAP ratio was calculated as a measure to reflect RV-PA coupling and compare it between groups. Left ventricular transmural pressure (LVTMP) was calculated as PAWP minus RA pressure.
Follow-up
Index exam (time zero) was the time of the invasive hemodynamic assessment. The primary outcome endpoint was a composite of all-cause mortality and HF hospitalizations. Secondary outcome endpoints included all-cause mortality and HF hospitalizations individually. The primary exposure for these endpoints was ≥moderate TR and its different mechanisms (A-STR and V-STR).
Statistical analysis
The primary prespecified aims of the current analyses were to (1) study the prevalence of ≥moderate TR among the different phenotypes of HFpEF according to PVD and rest vs exercise elevation in PAWP and among other causes of pulmonary hypertension and patients with noncardiac dyspnea; (2) evaluate and characterize the mechanism of ≥moderate TR based on current recommendations to stratify TR into A-SR and V-STR in HFpEF; and (3) assess the prognostic value of the different mechanisms of ≥moderate TR in HFpEF. Secondary prespecified aims were to (1) study the prevalence of ≥mild TR and moderate-severe/severe TR in the stated groups; and (2) compare the frequency of TR among patients with exercise-only HFpEF/PH and patients with otherwise normal hemodynamics. No adjustment for multiple hypothesis testing was performed, and the results should be considered in light of this.
All statistical analyses were performed using R version 4.3.1 (R Foundation) software or JMP version 17.2.0 (JMP Statistical Discovery LLC). Two-sided p-value <0.05 was considered statistically significant. Analysis of Variance (ANOVA) or Kruskal Wallis tests were used to compare continuous variables across groups, and the Chi square test was used to compare categorical variables. Kaplan–Meier curves were used for unadjusted survival analysis for death and the composite endpoint using the Log-rank test. Cumulative incidence rate curves accounting for competing risks of death were built for outcome of HF hospitalizations with p values calculated using the Fine Grey’s test. Cox regression models were used for survival analyses including other covariates; both cause specific and Fine Gray subdistribution hazard ratios were reported for HF hospitalizations. In Cox regression, analysis was adjusted to clinically important variables determined on a priori basis while avoiding colinearity. These covariates included age, sex, BMI, estimated GFR, atrial fibrillation, chronic lung disease, RV-FAC, PVR, mPAP and NT-proBNP (Model 1 covariates). Given colinearity, PAWP and RAP were not included in the model. In a sensitivity analysis, HFpEF phenotype was used in place of PVR and mPAP (Model 2). Variables with >10% missing data (i.e., NT-proBNP) were imputed using the median value. Otherwise, complete case analysis was used. The proportional hazards assumption was tested using the cox.zph() function from the ‘survival’ package in R and was met in all Cox models.
Results
Baseline characteristics
A total of 1,091 patients met the eligibility criteria and were included (Tables 1-2). Overall, median age was 65 (q1-q3: 54-72) years and 658 (60.3%) were women. Of those, only 63 patients had an echocardiogram in the inpatient setting, among whom only 5 had ≥ moderate TR; the rest of the patients had outpatient echocardiograms. Of the 1,091 patients, 669 were found to have HFpEF (61.3%); rest HFpEF+PVD in 172 (25.7%), exercise HFpEF+PVD in 104 (15.5%), rest HFpEF-PVD in 258 (38.6%), and exercise HFpEF-PVD in 135 (20.2%), Tables 1-2. Notably, all patients with rest HFpEF +PVD had an mPAP >20 mmHg, meeting the criteria for combined pre and postcapillary PH. Among the remaining 422 patients who did not have HFpEF, 135 (32.0%) had rest pre-capillary PH, 28 (6.6%) had unclassified PH, 90 (21.3%) had exercise PH without HFpEF, and 169 (40.0%) had normal hemodynamics at rest and exercise (Tables 1-2).
Table 1: Baseline characteristics among patients with and without HFpEF.
| Phenotypes of HFpEF | No HFpEF | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Rest HFpEF +PVD (N=172) |
Exercise HFpEF +PVD (N=104) |
Rest HFpEF − PVD (N=258) |
Exercise HFpEF −PVD (N=135) |
p value ‡ |
Pre- capillary PH (N=135) |
Unclassified PH (N=28) |
Exercise PH without HFpEF (N=90) |
Noncardiac dyspnea (N=169) |
p value § |
|
| Age, years | 70 (64, 76) | 68 (63, 73) | 64 (55, 70) | 67 (59, 72) | <.01 | 64 (56, 72) | 54 (39, 66) | 68 (61, 76) | 53 (46, 63) | <.01 |
| Sex, women | 115 (66.9%) | 72 (69.2%) | 133 (51.6%) | 69 (51.1%) | <.01 | 88 (65.2%) | 16 (57.1%) | 56 (62.2%) | 109 (64.5%) | <.01 |
| BMI, kg/m2 | 33.2 (27.9, 38.0) | 31.6 (26.7, 36.2) | 35.4 (29.4, 40.5) | 31.1 (27.0, 35.0) | <.01 | 30.2 (26.0, 34.9) | 30.2 (26.1, 34.9) | 28.0 (23.6, 31.0) | 28.3 (24.7, 31.7) | <.01 |
| Chronic kidney disease | 27 (15.7%) | 7 (6.8%) | 34 (13.2%) | 8 (5.9%) | 0.11 | 14 (10.3%) | 2 (6.7%) | 8 (9.0%) | 8 (4.8%) | 0.01 |
| Diabetes mellitus | 45 (26.2%) | 20 (19.2%) | 70 (27.1%) | 24 (17.8%) | 0.69 | 20 (14.8%) | 5 (17.9%) | 21 (23.3%) | 23 (13.6%) | <.01 |
| Hypertension | 75 (43.6%) | 50 (48.1%) | 129 (50.0%) | 62 (45.9%) | 0.32 | 52 (38.5%) | 9 (32.1%) | 45 (50.0%) | 44 (26.0%) | <.01 |
| Sleep apnea | 47 (27.3%) | 34 (32.7%) | 89 (34.5%) | 37 (27.4%) | 0.44 | 41 (30.4%) | 8 (28.6%) | 22 (24.4%) | 29 (17.2%) | 0.02 |
| Ischemic stroke | 10 (5.8%) | 2 (1.9%) | 10 (3.9%) | 5 (3.7%) | <.01 | 7 (5.2%) | 0 (0.0%) | 6 (6.7%) | 2 (1.2%) | 0.20 |
| Atrial fibrillation | 67 (39.0%) | 23 (22.1%) | 52 (20.2%) | 19 (14.1%) | 0.04 | 18 (13.3%) | 2 (7.1%) | 7 (7.8%) | 5 (3.0%) | <.01 |
| Chronic lung disease | 27 (15.7%) | 17 (16.3%) | 27 (10.5%) | 9 (6.7%) | 0.62 | 33 (24.4%) | 1 (3.6%) | 8 (8.9%) | 2 (1.2%) | <.01 |
| Coronary artery disease | 47 (27.3%) | 31 (29.8%) | 85 (32.9%) | 44 (32.6%) | <.01 | 36 (26.7%) | 8 (28.6%) | 25 (27.8%) | 30 (17.8%) | 0.06 |
| Hemoglobin, g/dL | 13.0 (11.9, 13.9) | 13.0 (12.1, 14.1) | 13.3 (12.2, 14.3) | 13.6 (12.7, 14.5) | 0.41 | 13.4 (12.1, 14.9) | 13.7 (12.2, 14.6) | 13.6 (12.6, 14.3) | 13.7 (12.8, 14.6) | 0.62 |
| NTproBNP, pg/mL † | 662 (205, 1744) | 180 (96.2, 665.1) | 172.5 (67.8, 543.5) | 174 (73, 380) | 0.22 | 222 (60, 790) | 91 (46, 225) | 164 (80.8, 397.2) | 123 (55, 451) | <.01 |
| eGFR, mL/min/ 1.73 m 2 | 65.1 (48.5, 79.2) | 69.6 (60.2, 85.4) | 70.7 (60.3, 85.6) | 74.1 (62.8, 85.9) | <.01 | 72.4 (55.2, 92.2) | 85.5 (63.8, 101.7) | 69.7 (59.1, 81.9) | 81.8 (69.7, 94.4) | <.01 |
Values are presented as median (q1-q3) or number (percentage). BMI: body mass index. PVD: pulmonary vascular disease
estimated using the CKD-EPI 2021 equation
available in 524 patients of HFpEF patients
p value for comparison across HFpEF phenotypes
p value for comparison across all groups
Table 2: Echocardiographic and hemodynamic parameters among patients with and without HFpEF.
| Phenotypes of HFpEF | No HFpEF | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Rest HFpEF +PVD (N=172) |
Exercise HFpEF +PVD (N=104) |
Rest HFpEF −PVD (N=258) |
Exercise HFpEF −PVD (N=135) |
p value* |
Pre-capillary PH (N=135) |
Unclassified PH (N=28) |
Exercise PH without HFpEF (N=90) |
Noncardiac dyspnea (N=169) |
p value† |
|
| TR severity | <.01 | <.01 | ||||||||
| None | 56 (32.6%) | 52 (50.0%) | 171 (66.3%) | 89 (65.9%) | 56 (41.5%) | 19 (67.9%) | 50 (55.6%) | 123 (72.8%) | ||
| Mild | 58 (33.7%) | 33 (31.7%) | 57 (22.1%) | 37 (27.4%) | 49 (36.3%) | 7 (25.0%) | 23 (25.6%) | 35 (20.7%) | ||
| moderate | 41 (23.8%) | 15 (14.4%) | 20 (7.8%) | 6 (4.4%) | 18 (13.3%) | 2 (7.1%) | 13 (14.4%) | 11 (6.5%) | ||
| moderately severe / severe | 17 (9.9%) | 4 (3.8%) | 10 (3.9%) | 3 (2.2%) | 12 (8.9%) | 0 (0.0%) | 4 (4.4%) | 0 (0.0%) | ||
| >=Moderate TR | 58 (33.7%) | 19 (18.3%) | 30 (11.6%) | 9 (6.7%) | <.01 | 30 (22.2%) | 2 (7.1%) | 17 (18.9%) | 11 (6.5%) | <.01 |
| >=Mild TR | 116 (67.4%) | 52 (50.0%) | 87 (33.7%) | 46 (34.1%) | <.01 | 79 (58.5%) | 9 (32.1%) | 40 (44.4%) | 46 (27.2%) | <.01 |
| LV ejection fraction, % | 63 (59, 66) | 63 (60, 65) | 62 (60, 65) | 63 (60, 65) | 0.80 | 64.0 (60.0, 66.0) | 63.5 (58.5, 65.8) | 63.0 (60.0, 65.0) | 62.0 (59.0, 65.0) | 0.88 |
| LVEDD, mm | 48 (45, 52) | 48 (45, 51) | 50 (48, 54) | 49 (46, 53) | <.01 | 46.0 (44.0, 50.0) | 49.0 (46.0, 51.0) | 47.0 (44.5, 51.0) | 48.0 (44.8, 51.0) | <.01 |
| LVESD, mm | 31 (28, 34) | 30 (29, 33) | 32 (30, 35) | 32 (29, 35) | <.01 | 29.0 (27.0, 32.0) | 31.0 (29.0, 34.0) | 31.0 (28.0, 32.0) | 31.0 (28.0, 34.0) | <.01 |
| Medial e velocity, cm/sec | 7 (5, 8) | 7 (6, 8) | 8 (6, 9) | 7 (6, 9) | <.01 | 7.0 (6.0, 9.0) | 9.0 (7.0, 11.0) | 7.0 (6.0, 8.2) | 9.0 (7.0, 10.0) | <.01 |
| Medial E/e ratio | 13.3 (11.3, 18.0) | 10.0 (8.6, 12.9) | 10.0 (8.3, 12.9) | 8.9 (7.8, 12.0) | <.01 | 8.9 (7.1, 12.2) | 8.9 (8.0, 11.3) | 10.0 (7.5, 12.3) | 7.8 (6.7, 10.0) | <.01 |
| TR velocity, m/sec | 3.1 (2.8, 3.6) | 2.7 (2.5, 3.0) | 2.6 (2.4, 2.8) | 2.4 (2.2, 2.7) | <.01 | 3.1 (2.8, 3.5) | 2.5 (2.3, 2.7) | 2.5 (2.3, 2.7) | 2.3 (2.2, 2.5) | <.01 |
| RA pressure at rest, mmHg | 12 (9, 14) | 7 (5, 9.5) | 11.5 (9, 14) | 7 (5, 9) | <.01 | 7 (5, 9) | 7.5 (6, 8) | 5 (3, 7) | 5 (4, 7) | <.01 |
| RA pressure during exercise, mmHg | 22 (18, 27) | 17 (14, 20) | 20 (16, 24) | 15 (12, 18.8) | <.01 | 13 (11, 19) | 11 (5.8, 15.2) | 11.5 (9, 14) | 9 (7, 11) | <.01 |
| PAWP at rest, mmHg | 19 (16, 22) | 11 (9, 13) | 18 (16, 20) | 12 (10, 13) | NA | 9.0 (8.0, 12.0) | 11.0 (10.0, 12.0) | 7.5 (6.0, 10.0) | 9.0 (7.0, 10.0) | <.01 |
| PAWP at exercise, mmHg | 30 (25, 34) | 27 (25, 32) | 31 (26, 36.8) | 28 (26, 32) | <.01 | 16.0 (13.0, 20.0) | 18.0 (14.0, 20.2) | 18.0 (14.0, 22.0) | 15.0 (11.0, 18.0) | <.01 |
| Mean PA pressure at rest, mmHg | 35 (30, 42) | 23 (21, 27) | 25.7 (23, 29) | 19 (17, 21) | <.01 | 29.0 (24.0, 39.0) | 22.0 (21.0, 25.0) | 16.0 (14.0, 18.0) | 16.0 (14.0, 18.0) | <.01 |
| Mean PA pressure at exercise, mmHg | 54 (48, 62) | 45 (40, 50) | 45 (39, 52) | 40.7 (36, 46) | <.01 | 48.0 (38.8, 59.2) | 34.0 (30.7, 36.5) | 32.5 (28.0, 37.0) | 25.0 (21.0, 30.0) | <.01 |
| PVR, WU | 3.2 (2.5, 4.4) | 2.6 (2.3, 3.3) | 1.1 (0.8, 1.5) | 1.4 (1.1, 1.7) | NA | 3.8 (2.8, 6.6) | 1.6 (1.4, 1.8) | 1.7 (1.4, 2.1) | 1.4 (1.0, 1.8) | <.01 |
| CO at rest, L/min | 4.6 (3.9, 5.6) | 4.7 (4.0, 5.5) | 5.8 (4.9, 7.0) | 5.5 (4.7, 6.3) | <.01 | 4.8 (3.9, 5.8) | 6.8 (6.1, 7.7) | 4.8 (4.0, 5.7) | 5.3 (4.6, 6.3) | <.01 |
| CO at peak exercise, L/min | 7.2 (5.5, 8.9) | 8.8 (6.8, 10.6) | 10.1 (8.2, 12.5) | 10.1 (8.2, 12.0) | <.01 | 8.7 (6.2, 10.8) | 11.4 (9.9, 13.2) | 8.4 (7.4, 10.1) | 11.2 (9.4, 12.9) | 0.44 |
| RAP to PAWP ratio at rest | 0.6 (0.5, 0.7) | 0.7 (0.6, 0.8) | 0.6 (0.5, 0.7) | 0.6 (0.5, 0.7) | 0.03 | 0.7 (0.6, 0.9) | 0.7 (0.6, 0.7) | 0.7 (0.4, 0.9) | 0.7 (0.5, 0.8) | <.01 |
| RAP to PAWP ratio at exercise | 0.7 (0.6, 0.9) | 0.6 (0.5, 0.7) | 0.6 (0.5, 0.7) | 0.5 (0.4, 0.6) | <.01 | 0.8 (0.6, 1.1) | 0.6 (0.4, 0.7) | 0.6 (0.5, 0.8) | 0.6 (0.5, 0.8) | <.01 |
| LV transmural pressure, rest, mmHg | 7.0 (5.0, 10.0) | 3.0 (2.0, 5.0) | 7.0 (5.0, 9.0) | 4.0 (3.0, 6.0) | <.01 | 3.0 (1.0, 4.0) | 4.0 (3.0, 5.0) | 2.5 (1.0, 4.0) | 3.0 (1.2, 4.0) | <.01 |
| LV transmural pressure, exercise, mmHg | 9.0 (2.0, 13.0) | 12.0 (7.0, 15.8) | 11.0 (7.2, 15.0) | 13.0 (9.5, 17.0) | <.01 | 3.0 (−1.0, 6.0) | 7.0 (6.0, 9.8) | 7.0 (4.0, 10.0) | 6.0 (3.0, 9.0) | <.01 |
Values are presented as median (q1-q3) or number (percentage). CO: cardiac output. LV: left ventricle. LVEDD: left ventricular end diastolic dimension. LVESD: left ventricular end systolic dimension. PA: pulmonary artery. PAWP: pulmonary arterial capillary pressure. PVD: pulmonary vascular disease. PVR: pulmonary vascular resistance. RA: right atrial. TR: tricuspid regurgitation
p value for comparison across HFpEF phenotypes
p value for comparison across all groups
Among patients with HFpEF, those with HFpEF and PVD were generally older, more likely women, had lower BMI, and more frequent AF and chronic lung disease compared to patients with HFpEF and no PVD (Tables 1 and S1, Figure S1). Patients with exercise-only HFpEF generally had less AF, chronic kidney disease, and diabetes mellitus and had lower BMI compared to patients with rest HFpEF (Tables 1 and S1). Among the four phenotypes of HFpEF, those with exercise HFpEF-PVD had the lowest prevalence of AF and comorbidities (Table 1). As expected, resting RA pressure was higher with rest vs exercise phenotypes of HFpEF, but in all four phenotypes doubled with exercise (Table 2). LVTMP increased with exercise in all HFpEF phenotypes (Table 2)
Compared to patients with HFpEF, patients without HFpEF generally had a lower BMI and lower prevalence of hypertension and AF. Patients with unclassified PH or normal hemodynamics were relatively young with low comorbidity burden (Table 1-2).
Prevalence of TR among patients with and without HFpEF
Among 669 total patients with HFpEF, 301 (45.0%) had ≥mild TR, 116 (17.4%) patients had ≥moderate TR, and 34 (5.1%) had moderately severe or severe TR (Table 2). Moderate or greater TR (Figure 1) was most prevalent in patients with rest HFpEF+PVD, occurring in 33.7% of the patients, followed by exercise HFpEF+PVD (18.3%, Table 2). Patients without PVD had a lower prevalence of ≥moderate TR, which occurred in 11.6% of patients with rest HFpEF-PVD and 6.7% of patients with exercise HFpEF- PVD. Notably, the association of PVD with at least moderate TR was stronger than the association of rest (vs exercise) HFpEF (Table S2). Similar trends were observed for mild or greater TR as well as for moderately severe or severe TR, Table 2.
Figure 1: Prevalence and types of ≥moderate TR (A-STR and V-STR) across HFpEF phenotypes.
As for patients without HFpEF, patients with isolated pre-capillary PH had the second highest prevalence of moderate or severe TR after rest HFpEF +PVD, observed in 22.2%. Moderate or greater TR was present in 7.1% of patients with unclassified PH and 6.5% of patients with normal hemodynamics (Table 2). Similar trends were observed for mild or greater TR and moderately severe or severe TR (Table 2). Notably, exercise-only HFpEF had greater severity of STR (p=0.005) compared to non-cardiac dyspnea patients, with a higher prevalence of ≥moderate TR (11.7% vs 6.5%, p=0.047) and of ≥mild TR (41.0% vs 27.2%, p=0.001). A sensitivity analysis using a PVR cutoff of 3 WU instead of 2 WU showed similar results (Tables S3-S4).
Notably, there was near perfect agreement between the reported and the de-novo assessed TR severity grade (no, mild, moderate, moderate-severe/severe) in the 100-patient sample with Cohen’s kappa of 0.96 (95% CI 0.92-1.00).
Characteristics and Mechanisms of TR in HFpEF
Among patients with HFpEF, those with ≥moderate TR were generally older, more frequently women with smaller LV dimensions, lower BMI, more atrial fibrillation, larger RA volume, higher E/e’ ratio and TR velocity on echocardiography, and higher resting PAWP, resting mPAP, exercise mPAP, and PVR compared to patients with HFpEF and no or mild TR (Table 3). There were no differences in exercise PAWP or in rest or exercise cardiac index in patients with or without TR (Table 3), likely as most TR cases were moderate rather than severe (Table 2). There was good interobserver reliability for offline measurements (ICC 0.74 for RV end-diastolic area; 0.82 for RV end-systolic area; 0.84 for RA volume; 0.81 for RA-to-RV end-systolic area ratio; 0.86 for tenting height of tricuspid leaflets). In addition, reproducibility of reported TAPSE was evaluated in a 10-patient sample and ICC was 0.96.
Table 3: Characteristics of patients with HFpEF by presence and type of TR.
| No TR (N=371) | Mild TR (N=182) |
ASTR (N=35) | VSTR (N=80) | p value |
|
|---|---|---|---|---|---|
| Age, years | 65 (56, 70) | 69.5 (62, 75) | 72 (65.5, 78) | 71 (66, 77.2) | < 0.01 |
| Sex, women | 187 (50.4%) | 119 (65.4%) | 31 (88.6%)* | 52 (65.0%) | < 0.01 |
| BMI, kg/m2 | 34.0 (29.2, 39.4) | 32.2 (27.1, 37.8) | 29.3 (25.0, 34.2) | 30.9 (25.5, 36.7) | < 0.01 |
| Diabetes mellitus | 83 (22.4%) | 47 (25.8%) | 7 (20.0%) | 21 (26.2%) | 0.71 |
| Hypertension | 173 (46.6%) | 87 (47.8%) | 19 (54.3%) | 36 (45.0%) | 0.82 |
| Sleep apnea | 121 (32.6%) | 59 (32.4%) | 7 (20.0%) | 20 (25.0%) | 0.27 |
| Ischemic stroke | 14 (3.8%) | 7 (3.8%) | 2 (5.7%) | 4 (5.0%) | 0.91 |
| Atrial fibrillation | 56 (15.1%) | 46 (25.3%) | 19 (54.3%) | 39 (48.8%) | < 0.01 |
| Chronic lung disease | 40 (10.8%) | 23 (12.6%) | 7 (20.0%) | 10 (12.5%) | 0.43 |
| Coronary artery disease | 115 (31.0%) | 60 (33.0%) | 9 (25.7%) | 22 (27.5%) | 0.74 |
| Hemoglobin, g/dL | 13.4 (12.4, 14.5) | 13.0 (11.9, 13.9) | 13.0 (12.1, 13.7) | 12.8 (11.6, 13.8) | < 0.01 |
| NTproBNP, pg/mL# | 145 (67.2, 443.8) | 292 (139.5, 614.8) | 405.5 (213.5, 905.8)* | 1030 (390, 2329) | < 0.01 |
| eGFR, mL/min/ 1.73 m 2 | 71.1 (60.2, 87.3) | 68.1 (57.4, 84.0) | 67.3 (57.0, 79.2) | 65.6 (49.5, 79.0) | < 0.01 |
| LV ejection fraction, % | 62 (59, 65) | 63 (60, 66) | 63 (60, 65) | 63 (60, 66) | 0.24 |
| LVEDD, mm | 50 (47, 54) | 48 (46, 52) | 47 (44, 49) | 48 (44, 51) | < 0.01 |
| LVESD, mm | 32 (29, 35) | 31 (29, 34) | 29.5 (27.2, 32) | 31 (28, 34) | < 0.01 |
| Medial e velocity, cm/sec | 7 (6, 9) | 7 (6, 8) | 8 (7, 9.5)* | 7 (5, 8) | < 0.01 |
| Medial E/e ratio | 10.0 (8.1, 12.9) | 11.4 (8.9, 15.0) | 11.3 (8.9, 13.4)* | 13.2 (11.3, 16.8) | < 0.01 |
| TR velocity, m/sec | 2.5 (2.3, 2.8) | 2.8 (2.6, 3.1) | 3.1 (2.8, 3.3) | 3.1 (2.8, 3.7) | < 0.01 |
| RA end-systolic volume, mL | 45.8 (32.7, 64.9) | 49.0 (36.8, 69.0) | 65.0 (50.1, 105.4)* | 88.6 (57.8, 123.1) | < 0.01 |
| RV end-diastolic area, cm2 | 24.1 (19.0, 28.1) | 23.4 (19.6, 28.0) | 20.6 (18.2, 24.4)* | 27.4 (22.3, 34.1) | < 0.01 |
| RV end-systolic area, cm2 | 13.7 (10.2, 17.1) | 14.1 (11.5, 17.9) | 10.5 (9.1, 12.9)* | 17.8 (13.5, 23.2) | < 0.01 |
| RV FAC, % | 42.1 (35.1, 48.6) | 39.1 (32.0, 45.5) | 48.8 (43.4, 53.9)* | 35.7 (26.9, 42.9) | < 0.01 |
| TV tenting Height, mm | 2.7 (1.0, 7.7) | 4.0 (1.0, 8.2) | 2.3 (1.1, 4.0)* | 4.6 (2.9, 7.9) | < 0.01 |
| Mid-RV diameter, cm | 3.3 (2.8, 3.7) | 3.4 (3.0, 3.7) | 3.2 (3.0, 3.6)* | 4.0 (3.3, 4.4) | < 0.01 |
| RA to RV end-systolic area | 1.2 (1.0, 1.5) | 1.3 (1.0, 1.5) | 2.0 (1.7, 2.3)* | 1.3 (1.0, 1.8) | < 0.01 |
| TAPSE, mm | 23 (20, 25) | 23 (20, 26) | 23 (21, 25.2)* | 19 (15.8, 23) | < 0.01 |
| PAWP at rest, mmHg | 16 (12, 19) | 16 (13, 20) | 18 (14, 20.5) | 18 (15, 21.2) | < 0.01 |
| PAWP at exercise, mmHg | 30 (26, 35) | 29 (25, 34) | 29 (26, 32) | 29 (25, 34) | 0.60 |
| Mean PA pressure at rest, mmHg | 24 (21, 28.8) | 26 (22, 34) | 28 (24.7, 32.5)* | 33.5 (26.8, 43.7) | < 0.01 |
| Mean PA pressure at exercise, mmHg | 45 (38.3, 51) | 47 (41, 54.1) | 42.7 (38.1, 48)* | 53.2 (44.8, 62.6) | < 0.01 |
| RA pressure at rest, mmHg | 10 (7, 12) | 10 (7, 12) | 10 (8, 13)* | 12.5 (9, 17.2) | < 0.01 |
| RA pressure at exercise, mmHg | 18 (15, 22) | 19 (15, 22) | 17 (14.5, 22)* | 26 (18, 29) | < 0.01 |
| PVR, WU | 1.5 (1.0, 2.1) | 1.9 (1.2, 2.9) | 2.4 (1.4, 3.3)* | 3.3 (2.0, 4.6) | < 0.01 |
| CO at rest, L/min | 5.5 (4.6, 6.6) | 5.0 (4.2, 6.4) | 4.6 (3.6, 5.5) | 4.9 (4.1, 5.9) | < 0.01 |
| CO at exercise, L/min | 10.0 (8.2, 12.0) | 8.6 (7.2, 11.2) | 7.1 (5.7, 9.0) | 6.9 (5.1, 8.9) | < 0.01 |
| CI at rest, L/min/m2 | 2.6 (2.2, 3.0) | 2.5 (2.2, 3.1) | 2.4 (2.0, 2.8) | 2.5 (2.0, 2.9) | 0.10 |
| CI at exercise, L/min/m2 | 4.7 (3.9, 5.6) | 4.4 (3.7, 5.5) | 3.9 (2.9, 4.8) | 3.6 (2.7, 4.6) | < 0.01 |
| RV FAC to mPAP ratio | 1.7 (1.3-2.0) | 1.4 (1.0-2.0) | 1.7 (1.4-2.0)* | 1.0 (0.6, 1.4)* | < 0.01 |
| RAP to PAWP ratio at rest | 0.6 (0.5, 0.7) | 0.6 (0.5, 0.8) | 0.6 (0.5, 0.7) | 0.7 (0.6, 0.9)* | < 0.01 |
| RAP to PAWP ratio at exercise | 0.6 (0.5, 0.7) | 0.6 (0.5, 0.7) | 0.6 (0.5, 0.8) | 0.8 (0.7, 1.0)* | < 0.01 |
| LV transmural pressure, rest, mmHg | 6.0 (4.0, 8.0) | 6.0 (3.0, 9.0) | 7.0 (5.0, 8.8) | 5.0 (2.0, 8.0)* | 0.03 |
| LV transmural pressure, exercise, mmHg | 12.0 (8.0, 16.0) | 11.0 (8.0, 15.0) | 11.0 (6.5, 16.5) | 7.0 (2.0, 11.0)* | < 0.01 |
| Phenotypes of HFpEF | < 0.01 | ||||
| Rest HFpEF +PVD | 14 (3.8%) | 12 (6.6%) | 1 (2.9%) | 8 (10.0%) | |
| Rest HFpEF −PVD | 129 (34.8%) | 56 (30.8%) | 9 (25.7%) | 9 (11.2%) | |
| Exercise HFpEF +PVD | 19 (5.1%) | 31 (17.0%) | 10 (28.6%) | 34 (42.5%) | |
| Exercise HFpEF −PVD | 209 (56.3%) | 83 (45.6%) | 15 (42.9%) | 29 (36.2%) |
different between ASTR and VSTR
Values are presented as median (q1-q3) or number (percentage). CO: cardiac output. FAC: fractional area change. LV: left ventricle. LVEDD: left ventricular end diastolic dimension. LVESD: left ventricular end systolic dimension. PA: pulmonary artery. PAWP: pulmonary arterial capillary pressure. PVD: pulmonary vascular disease. PVR: pulmonary vascular resistance. RA: right atrial. RV: right ventricle. TAPSE: Tricuspid Annular Plane Systolic Excursion. TR: tricuspid regurgitation. TV: tricuspid valve.
Of the 116 patients with HFpEF and ≥moderate TR, A-STR was present in 35 (30.2%) patients and V-STR in 80 (69.0%) patients; one patient did not have enough obtainable data to classify type of TR. Compared with V-STR, patients with A-STR were more likely to be women, had lower rest and exercise mPAP, lower PVR, lower RA pressure (which was similar to patients with no/mild TR), and by definition, better RV function and smaller RV size (Table 3 and Figure S2). Interestingly, patients with ≥moderate A-STR and V-STR had comparable age and prevalence of AF (54.3% and 48.8%, respectively), and patients with V-STR had larger RA volume (median 88.6 mL vs 65.0, p=0.04, Figure S2).
Notably, when considering the different phenotypes of HFpEF, the prevalence of ≥moderate V-STR in patients with HFpEF and PVD (rest or exercise) was approximately 3 times that of A-STR (Tables S1 & S5; Figure 1 & S3). Importantly, the difference in prevalence of TR between phenotypes of HFpEF was mainly related to difference in prevalence of V-STR, rather than A-STR, across the phenotypes (Table S5 and Figure 1), in tandem with differences in RV function.
Association of TR types with outcomes
Over a median 4.9 (q1-q3: 3.1-7.1) years of follow-up, there were 100 deaths and 96 HF hospitalizations. The composite endpoint occurred in 154 patients. The presence of ≥moderate TR was associated with increased risk of the composite endpoint [HR 2.55, (95% CI 1.80-3.59), p<.01). The presence of ≥moderate V-STR and A-STR was associated with increased risk of the composite endpoint vs no/mild TR [V-STR: HR 2.84, (95% CI 1.94-4.15), p<.01; A-STR: 1.96 (1.05-3.64), p=0.03], Figure 2. In multivariable Cox analysis, ≥moderate V-STR and remained associated with the composite endpoint although the association of ≥moderate A-STR was weakened [Model 1: HR 1.70, (95% CI 1.10-2.65); HR 1.67 (0.85-3.29), respectively, for V-STR and A-STR] (Table 4). In multivariable analysis including covariates of Model 1 except for the continuous RV-FAC variable, there was no interaction between abnormal RV-FAC (cutoff <35%) and V-STR (vs no/mild STR) in relation to the composite endpoint (p=0.60). Testing the interaction between RV-FAC<35% and A-STR was not feasible given all patients had RV-FAC≥35%.
Figure 2: Association of TR type with all-cause mortality and heart failure hospitalizations.
Left panel: Association of V-STR and A-STR with the composite endpoint of all-cause mortality or heart failure (HF) hospitalizations; hazard ratio (HR) was calculated using cause-specific hazard ratios. Middle panel: Association of V-STR and A-STR with all-cause mortality, HR was calculated using cause-specific hazard ratios. Right panel: Association of V-STR and A-STR with heart failure (HF) hospitalizations, analyzed using competing risk curves and Fine-Gray model with subdistribution HR shown.
Table 4: Multivariable Cox Model for the composite of all-cause mortality or HF hospitalization.
| Hazard ratio | Lower CI limit | Upper CI limit | P value | |
|---|---|---|---|---|
| Model 1 (N events = 145) | ||||
| Age, years * | 1.00 | 0.98 | 1.02 | 0.96 |
| Female sex | 0.87 | 0.61 | 1.24 | 0.44 |
| Estimated GFR, ml/min/1.73m2 * | 1.00 | 0.98 | 1.03 | 0.74 |
| BMI, kg/m2 * | 0.99 | 0.98 | 1.00 | 0.02 |
| Atrial fibrillation | 1.48 | 1.01 | 2.17 | 0.04 |
| Chronic lung disease | 2.01 | 1.34 | 3.01 | <.01 |
| RV FAC, % * | 0.99 | 0.98 | 1.01 | 0.52 |
| Type of TR (vs no/mild TR) | ||||
| ≥Moderate VSTR | 1.70 | 1.10 | 2.65 | 0.02 |
| ≥Moderate ASTR | 1.67 | 0.85 | 3.29 | 0.14 |
| NT-proBNP, pg/ml * | 1.00 | 1.00 | 1.00 | 0.96 |
| PVR, WU * | 1.03 | 0.94 | 1.13 | 0.58 |
| Resting mPAP, mmHg * | 1.03 | 1.02 | 1.05 | <.01 |
| Model 2 (N events = 145) | ||||
| Age, years * | 0.99 | 0.98 | 1.01 | 0.41 |
| Female sex | 0.88 | 0.61 | 1.26 | 0.48 |
| Estimated GFR, ml/min/1.73m2 * | 1.01 | 0.99 | 1.03 | 0.47 |
| BMI, kg/m2 * | 0.99 | 0.98 | 1.00 | 0.02 |
| Atrial fibrillation | 1.50 | 1.03 | 2.18 | 0.04 |
| Chronic lung disease | 2.08 | 1.39 | 3.10 | <.01 |
| RV FAC, % * | 0.99 | 0.98 | 1.01 | 0.48 |
| Type of TR (vs no/mild TR) | ||||
| ≥Moderate VSTR | 2.05 | 1.34 | 3.13 | <.01 |
| ≥Moderate ASTR | 1.74 | 0.89 | 3.42 | 0.10 |
| NT-proBNP, pg/ml * | 1.00 | 1.00 | 1.00 | 0.72 |
| HFpEF phenotype (reference is Exercise HFpEF −PVD) | ||||
| Exercise HFpEF +PVD | 1.23 | 0.59 | 2.57 | 0.58 |
| Rest HFpEF −PVD | 1.47 | 0.80 | 2.68 | 0.21 |
| Rest HFpEF +PVD | 2.40 | 1.29 | 4.46 | 0.01 |
Hazard ratio is presented per unit change. Abbreviations as in Table 3. Each variable other than RV-FAC had 154 events; RV-FAC had 145 events due to missing values.
Moderate or greater V-STR was associated with mortality individually compared to no/mild TR [HR 3.41 (2.19-5.35), p<.001], whereas ≥moderate A-STR was not significantly associated with mortality [p=0.37], Figure 2. On multivariable analysis, ≥moderate V-STR remained associated with mortality compared to no/mild TR; Table S6. Both ≥moderate V-STR and A-STR were associated with increased HF hospitalizations compared to no/mild TR at the univariate level [Fine-Gray Subdistribution HR: V-STR: HR 2.82 (1.74-4.55), p<.01; A-STR: 2.89 (1.51-5.51), p<.01, Figure 2] and multivariable level [Table S7].
Additional Sensitivity analyses
Sensitivity analyses where V-STR was categorized more stringently, HFpEF was defined exclusively by exercise (without leg elevation), or echocardiograms were confined to <30 days of invasive assessment showed findings did not meaningfully differ from the primary analysis and are included in the Appendix 2 and Tables S8-S13.
Discussion
In this study, we evaluated the prevalence, mechanisms, and prognostic significance of STR across the spectrum of HFpEF, as stratified by invasively assessed presence or absence of PVD and rest vs exercise-only elevation in left-sided filling pressure. Our major findings were (1) There was significant variability in prevalence of ≥moderate STR across HFpEF phenotypes, ranging between 6.7% in those with exercise HFpEF −PVD to 33.7% in patients with rest HFpEF +PVD, mainly related to differing prevalence of V-STR rather than A-STR, which was mainly driven by PVD to greater extent than PAWP; (2) the presence of PVD was also associated with TR in patients without HFpEF; (3) V-STR was the predominant TR type in HFpEF, although atrial myopathy was even greater in those with V-STR than A-STR, reflected by greater RA dilatation, suggesting a mixed mechanism; (4) Importantly, ~1 in every 8 patients with exercise-only HFpEF had ≥moderate TR, which was more frequent, when in the presence of PVD, compared to patients with normal hemodynamics, highlighting the importance of evaluation for exercise abnormalities in patients with significant TR; and (5) The presence of ≥moderate V-STR was associated with increased risk of the composite endpoint of mortality and HF hospitalizations, whereas ≥moderate A-STR was associated with increased risk of HF hospitalizations alone, indicating differential prognostic impact by TR mechanism. These data underline the importance of TR in HFpEF and its relationship with PVD, highlight the importance of exercise hemodynamics in TR, and suggest that therapies that can arrest or reverse HFpEF progression and mitigate RV loading across stages may reduce the burden of TR and improve clinical status and outcomes.
Pathophysiology of TR in HFpEF
STR in HFpEF can develop via different mechanisms.9, 13 One is a consequence of advanced HFpEF with pulmonary vascular remodeling leading to RV enlargement and dysfunction, tricuspid leaflet tethering, and tricuspid annulus dilation, resulting in a V-STR phenotype.5, 7, 16, 28 However, even patients without overt RV dysfunction or enlargement can develop significant TR in the setting of RA enlargement and tricuspid annulus dilation, resulting in an A-STR phenotype.2, 12, 13 The associated atrial myopathy is believed to result from the same pathophysiologic process that underlie the development of diastolic dysfunction, including systemic inflammation, excess adipose tissue, and metabolic comorbidities,29-32 as well as coexistent atrial fibrillation, another consequence and biomarker of atrial myopathy. 2, 5, 30, 33-35
Prevalence of TR in HFpEF: importance of pulmonary vascular disease
The prevalence of ≥moderate STR in HFpEF has ranged between 18% and 27% in prior reports,5, 28, 36, 37 which is consistent with the current study. In its earlier stages, HFpEF is characterized by normal natriuretic peptide levels and resting PAWP, with elevation in PAWP during exercise.14, 27, 38 The presence of PVD in HFpEF suggests a more advanced disease stage, wherein patients have higher natriuretic peptide levels, worse pulmonary pressures, more RV dysfunction and worse ventricular interdependence.16, 23 The present study highlights the importance of HFpEF phenotype in association with the prevalence of STR. In patients with elevated PAWP exclusively with exercise14, 26, 27 in the absence of PVD,16, 23, 24 ≥moderate TR was present in only 6.7% of cases, as compared to 33.7% in patients with both rest elevation in PAWP and PVD. Notably, the impact of PVD on the frequency of STR in HFpEF appeared to be stronger than the impact of rest vs exercise-only elevation in PAWP, with prevalence of ≥moderate STR of 11.6% in patients with rest HFpEF without PVD (1.7 times that in exercise HFpEF without PVD) as compared to 18.3% in patients with exercise HFpEF and PVD (2.7 times that in exercise HFpEF without PVD). This finding could be related to the worse RV remodeling and pressure overload in the setting of increased PVR, leading to worse RV-PA coupling and more V-STR in these patients.
Importance of exercise hemodynamics in TR
Another notable observation in the present study was that even patients with exercise-only HFpEF may present with significant STR. The prevalence of ≥mild and ≥moderate STR was 41.0%, and 11.7% in patients with exercise-only HFpEF and 44.4% and 18.9% in patients with exercise only precapillary PH in the absence of HFpEF. This is in comparison to 27.2% and 6.5% in patients with non-cardiac dyspnea. Although the prevalence of STR was similar between patients with exercise HFpEF without PVD and noncardiac dyspnea, none of the latter group had moderately severe or severe TR, emphasizing the importance of exercise hemodynamics in the evaluation of patients with STR.14, 15, 26, 27, 39 Importantly, LVTMP increased with exercise in patients with exercise HFpEF, suggesting against a primary role of pericardial restraint and ventricular interdependence in elevation in PAWP in these patients, though this may contribute in some.
These findings suggest that intervention with medical therapy directed at HFpEF during the early stages/phenotypes of HFpEF (e.g., exercise-only HFpEF, no PVD) could mitigate or even prevent progression of STR, underlining the importance of early recognition and diagnosis of HFpEF to implement treatment.
Distribution of mechanisms of TR in HFpEF
As currently defined, STR was found to be predominantly related to the ventricular secondary mechanism in patients with HFpEF (69% of ≥moderate STR), and the prevalence of V-STR varied significantly with the phenotype of HFpEF, related to varying prevalence of PVD and RV dysfunction. The prevalence of A-STR was less variable between HFpEF phenotypes. Notably, despite this predominance of V-STR, there was a clear evidence of atrial myopathy in patients with V-STR, including greater RA dilatation and similar prevalence of AF. These findings suggest the presence of mixed mechanisms of STR in patients with HFpEF meeting the current criteria for V-STR and that it may be too simplistic to classify patients with STR in HFpEF into either V-STR or A-STR. Due to the cross-sectional nature of the study, the contribution from RV dysfunction and pulmonary hypertension to the RA myopathy and STR as compared to an initial A-STR phenotype complicated by RV volume overload from STR and subsequent RV dysfunction in later stages cannot be determined, although the association of V-STR prevalence with PVD among HFpEF phenotypes suggests an important potential contribution of pulmonary pressures to the TR.
Importantly, history of AF was absent in 46% of patients with ≥moderate A-STR, which is notable given the current guidelines that use AF history to define A-STR.40 There was also a comparable frequency of AF in patients with A-STR and V-STR, highlighting the lack of sensitivity and specificity of AF in diagnosing the mechanism of STR.
Implications of TR mechanism on clinical outcomes
STR has been recognized as marker of more advanced HFpEF,28, 37, 46, 47 but there is limited and conflicting evidence whether the association between STR and outcomes is independent of RV dysfunction and whether there is a differential impact of A-STR vs V-STR.2, 48 In the present study, we show that ≥moderate V-STR was associated with the composite endpoint of death and HF hospitalizations as well as mortality alone compared to no/mild STR, independent of AF, chronic lung disease, HFpEF phenotype, pulmonary pressure, PVR, RV function, and NT-proBNP level. A-STR was also clearly associated with worse rates of HF hospitalizations compared to no TR, without significant relationship to mortality alone, indicating that mechanism of STR may help risk stratify patients with HFpEF.
Limitations
This was a retrospective study involving all Mayo Clinic sites; some of which are considered tertiary centers, leading to referral bias. All included patients were referred in routine clinical practice for invasive hemodynamic evaluation that included both rest and exercise assessments, introducing selection bias. However, without such assessment, definitive diagnosis of HFpEF and its various phenotypes (as compared to other causes of PH) would be unreliable. The study evaluated prevalent rather than incident TR, and survival bias affecting prevalence of TR and distribution of its types cannot be excluded. However, studying incident TR in HFpEF would require a much larger sample size and serial/longitudinal exercise invasive hemodynamic assessments, which is not currently available. Given the retrospective nature of the study, obtaining 3-dimensional echocardiographic datasets to evaluate RA and RV volumes was not possible. There was a small number of patients with HFpEF and ≥moderate A-STR, which likely reduced statistical power in some analyses. Transthoracic echocardiograms were interpreted by multiple echocardiologists, and interobserver variability is possible. However, echocardiographic grading of TR remained consistent between Mayo Clinic sites in the study period, and reproducibility of TR severity assessment in a 100-patient sample was near perfect. Furthermore, RA and RV measurements were performed by four readers for this study, with good interobserver reliability. We used ICD codes to identify many comorbidities, with the potential of underestimation of their prevalence.
Conclusion
Clinically significant STR was present in 17% of patients with invasively diagnosed HFpEF, with wide variability across the phenotypes of HFpEF, ranging from 6.7% to 33.7%, mainly related to differing prevalence of V-STR than A-STR. STR was mainly driven by PVD, to a greater extent than PAWP. Patients with exercise-only HFpEF and exercise-only PH had more STR compared to non-cardiac dyspnea patients, and none of noncardiac dyspnea patients had moderate-severe or severe TR. This indicates that it is unusual for significant STR to exist in isolation, and its presence should prompt further evaluation, including assessment of exercise hemodynamics. Most patients with HFpEF and STR have V-STR, although these patients display more atrial remodeling than A-STR, suggesting a mixed mechanism. Finally, the presence of V-STR conferred greater risk of mortality and HF hospitalizations, whereas A-STR conferred greater risk of HF hospitalizations alone, suggesting that mechanism classification may help risk-stratify patients.
Supplementary Material
Disclosures:
Dr Reddy is supported by grant K23HL164901 from the National Heart, Lung, and Blood Institute, National Institutes of Health, grants from Sleep Number, Bayer, Merck, United Pharmaceuticals, and the Earl Wood Career Development Award from Mayo Clinic. Dr Borlaug is supported in part by grants R01 HL128526, R01 HL162828, and U01 HL160226 from the National Institutes of Health, W81XWH2210245 from the US Department of Defense, and the Schoen Foundation. Dr. Borlaug also receives research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk, and Tenax Therapeutics. Dr. Borlaug has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations, and is named inventor (US Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. The other authors report no disclosures.
Abbreviations
- AF
atrial fibrillation
- A-STR
atrial secondary tricuspid regurgitation
- FAC
fractional area change
- mPAP
mean pulmonary artery pressure
- PAWP
pulmonary artery wedge pressure
- PVD
pulmonary vascular disease
- PVR
pulmonary vascular resistance
- RHC
right heart catheterization
- STR
secondary tricuspid regurgitation
- V-STR
ventricular secondary tricuspid regurgitation
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