Journal of the American Heart Association ORIGINAL RESEARCH Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival Javier Bermejo , MD, PhD; Ana González-Mansilla , MD, PhD; Teresa Mombiela, MD; Ana I. Fernández, MBiol, PhD; Pablo Martínez-Legazpi , MEng, PhD; Raquel Yotti , MD, PhD; Rocío García-Orta, MD, PhD; Pedro L. Sánchez-Fernández , MD, PhD; Mario Castaño, MD, PhD; Javier Segovia-Cubero, MD, PhD; Pilar Escribano-Subias, MD, PhD; J. Alberto San Román, MD, PhD; Xavier Borrás, MD, PhD; Angel Alonso-Gómez , MD, PhD; Javier Botas , MD, PhD; María G. Crespo-Leiro , MD, PhD; Sonia Velasco, MD, PhD; Antoni Bayés-Genís , MD, PhD; Amador López, MD, PhD; Roberto Muñoz-Aguilera, MD, PhD; Manuel Jiménez-Navarro , MD, PhD; José R. González-Juanatey, MD, PhD; Arturo Evangelista, MD, PhD; Jaime Elízaga, MD, PhD; Javier Martín-Moreiras, MD, PhD; José M. González-Santos , MD, PhD; Eduardo Moreno-Escobar, MD, PhD; Francisco Fernández-Avilés , MD, PhD; the SIOVAC (“Sildenafil for Improving Outcomes after VAlvular Correction”) Investigators BACKGROUND: The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with Downloaded from http://ahajournals.org by on April 3, 2023 this condition. METHODS AND RESULTS: We analyzed long-term follow-up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32–44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18–26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow-up of 4.5 years, 91 deaths accounted for 4.21 higher-than-ex- pected mortality in the age-matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance—either measured by catheterization or ap- proximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six-month changes in the composite clinical score and in the 6-minute walk test distance were related to survival. CONCLUSIONS: Persistent valvular heart disease–pulmonary hypertension is an ominous disease that is almost universally as- sociated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00862043. Key Words: heart failure ■ pulmonary hypertension ■ valvular heart disease Correspondence to: Javier Bermejo, MD, PhD, Department of Cardiology, Hospital General Universitario Gregorio Marañón, Dr. Esquerdo 46. 28007 Madrid. Spain. E-mail: javier.bermejo@salud.madrid.org Supplementary Material for this article is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.120.019949 *A complete list of the SIOVAC Investigators can be found in the Supplementary Material. For Sources of Funding and Disclosures, see page 15. © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. JAHA is available at: www.ahajournals.org/journal/jaha J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199491 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD mortality and disability.6–10 Selecting therapeutic CLINICAL PERSPECTIVE strategies in group 2 PH requires counterbalancing their risks against robust survival indicators of the un- What Is New? derlying disease. However, to our knowledge, there • Mortality of patients with persistent pulmonary are no prospective series of patients with unequiv- hypertension in successfully corrected valvular ocal persistent VHD-PH studied at late stages after heart disease is high. the valve correction. Extrapolating outcomes from • Major risk factors are age, male sex, diabetes other causes of LHD-PH such as heart failure may mellitus, advanced functional class, and high be misleading because additional risk factors that pulmonary vascular resistance. impact pulmonary pressures such as left ventricular (LV) systolic and diastolic dysfunction11 may be ab- What Are the Clinical Implications? sent in corrected VHD. • Chronically elevated left-sided heart pressures The present study was designed to assess the he- play a major role in the development and per- modynamic bases of persistent VHD-PH and to iden- petuation of persistent valvular heart disease– pulmonary hypertension. tify catheterization and imaging predictors of survival • Small valve prostheses, particularly in the mitral of patients with this condition, studied at least 1 year position, show the highest-risk hemodynamic after the primary valvular lesion was successfully cor- profile. rected. For this purpose, we related long-term survival • Thus, preventing the consequences of persis- with baseline variables of the SIOVAC (Sildenafil for tent valvular heart disease–pulmonary hyper- Improving Outcomes After Valvular Correction) trial co- tension should rely not only on an adequate hort.12 Additionally, we aimed to validate 6-month sur- timing of the valve interventions but also on rogate end points typically used in prospective clinical avoiding small residual valve areas, particularly trials in the field. in men and patients with diabetes mellitus. METHODS The data that support this study are available from the Nonstandard Abbreviations and Acronyms corresponding author on reasonable request. Downloaded from http://ahajournals.org by on April 3, 2023 6MWT 6-minute walk test LHD left-sided heart disease Patients and Study Design mPAP mean pulmonary arterial pressure SIOVAC was an investigator-driven, multicenter, ac- PAWP pulmonary artery wedge pressure ademically sponsored, randomized, double-blind, placebo-controlled, parallel clinical trial testing the PH pulmonary hypertension efficacy of sildenafil on 6-month outcomes of pa- PVR pulmonary vascular resistance tients with persistent VHD-PH.12 The study was per- PSAP pulmonary artery systolic pressure formed in 18 academic hospitals in Spain and the SIOVAC Sildenafil for Improving Outcomes After Fundación de Investigación Biomédica Hospital Valvular Correction Gregorio Marañón served as the coordinating center. VHD valvular heart disease The main results showed that sildenafil was related to worse clinical outcomes than placebo at 6 months.12 Patients were enrolled between May 2008 to T he most common cause of pulmonary hyperten- December 2015, and on September 2019 the sur- sion (PH) worldwide is left-sided heart disease vival status was updated from the electronic records (LHD),1,2 and valvular heart disease (VHD) is a sig- or telephonic interview. The investigator drug was in- nificant cause of this type of PH.3,4 Despite important terrupted at the end of the 6-month randomization improvements in the timing of valve interventions, long- period. The study was authorized by the Spanish standing PH after surgery is still frequent.5 Furthermore, Agency of Medicinal Products and Medical Devices as a result of nonestablished mechanisms, PH may and approved by the reference ethic committee and eventually develop in patients with corrected VHD who the local ethic committees of all participant institu- did not show PH before surgery.6 Understanding the tions. All patients provided written informed consent. physiological bases of persistent VHD-PH would ben- A second approval by the ethics committees was ob- efit of a comprehensive hemodynamic profiling of pa- tained for the purpose of extending follow-up, which tients with this condition. waived the need for signing a new informed consent. Signs of PH by Doppler echocardiography after The SIOVAC trial is registered with ClinicalTrials.gov correction of VHD are associated with long-term NCT00862043 and EudraCT 2007-007033-40. J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199492 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Patients were screened in outpatient clinics and pressure (PAWP) from the diastolic and mean pul- imaging laboratories of participating institutions.12 monary artery pressures, respectively. Pulmonary In summary, enrollment criteria included echocar- vascular resistance (PVR) and pulmonary arte- diographic signs of PH (systolic pulmonary artery rial compliance were calculated as transpulmonary pressure ≥50 mm Hg as measured by Doppler echo- pressure gradient/cardiac output and stroke vol- cardiography), a successful surgical or percutaneous ume/pulse pressure, respectively. Pulmonary arte- valvular replacement or repair procedure with com- rial elastance was calculated as systolic pulmonary plete correction of the left-sided heart valve disease artery pressure/stroke volume. performed at least 1 year before inclusion, and a stable We used current definitions of PH (mPAP ≥20 mm clinical condition. Major exclusion criteria included any Hg) as well as hemodynamic classification crite- significant residual prosthesis or native left-sided heart ria for defining precapillary PH (PAWP ≤15 mm Hg), valvular dysfunction and a life expectancy <2 years. isolated postcapillary PH (PAWP >15 mm Hg and Only patients with a mean pulmonary arterial pressure PVR <3 Wood units [WU]), and combined precap- (mPAP) ≥30 mm Hg by right-sided heart catheterization illary and postcapillary PH (PAWP >15 mm Hg and were randomized and received the investigation drug. PVR ≥3 WU).14 Patients with a PAWP ≤15 mm Hg but However, nonrandomized patients with PH (mPAP be- PVR <3 WU were designated as having “high-out- tween 20 and 30 mm Hg) underwent an identical fol- put” PH. All patients underwent clinical assessment, low-up protocol and are also included in the present 6-minute walk test (6MWT), and Doppler echocar- report. diography examinations at baseline and at 3 and 6 months. A blinded core laboratory analyzed cardiac im- Procedures ages.12 Mitral and aortic effective valve areas were All patients underwent clinical, imaging, and cath- determined by the continuity equation using stroke eterization procedures at enrollment. Hemodynamic volume values obtained by cardiac catheterization measures during right-sided heart cardiac catheteri- divided by their respective valvular Doppler time-ve- zation were obtained at baseline and after an acute locity integrals. Mitral valve mismatch was defined vasoreactivity test with 100 mg of sublingual silde- for repaired mitral valves or prostheses in the mitral nafil.12,13 The diastolic pressure gradient and (mean) position as an effective valve area index ≤1.2 cm2/m2 transpulmonary pressure gradient were calculated of body surface area, whereas aortic valve mismatch Downloaded from http://ahajournals.org by on April 3, 2023 subtracting the mean pulmonary artery wedge was defined as a prosthetic effective valve area index ≤0.65 cm2/m2. Blood sampling was performed at baseline and 6 months for brain natriuretic peptide measurements. All randomized patients stopped the investigation product after the 6-month period and underwent medical management as per criteria of their referring physicians. End Points For the extended follow-up period, the primary end point of the present investigation was all-cause mortal- ity and the secondary end point was cardiovascular mortality, which included all cardiac causes, stroke, and fatal hemorrhagic complications. The primary end point of the SIOVAC randomized clinical trial was change (improved, unchanged, or worsened) in the clinical composite score, in terms of: (1) death or hospital admission for heart failure, (2) change in func- tional class, and (3) patient global self-assessment at Figure 1. Enrollment of the study cohort. 6 months.12,15 Secondary end points of the clinical trial The confirmatory catheterization procedure excluded pulmonary were 6-month changes in the 6MWT distance, brain hypertension (PH) (mean pulmonary arterial pressure [mPAP] natriuretic peptide levels, and Doppler-derived systolic <20 mm Hg) in 3 patients, and 6 were lost to follow-up. pulmonary artery pressure. The primary and second- Consequently, 222 patients with catheterization-confirmed PH and complete follow-up data are the basis of this report. SIOVAC ary end points of the randomized clinical trial were indicates Sildenafil for Improving Outcomes After Valvular validated against the primary end point of the present Correction. long-term study. J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199493 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Table 1. Baseline Characteristics of the Study Cohort Not Randomized Randomized Full Cohort n= 27 n= 195 N= 222 Age, y 71 (66–76) 72 (66–77) 72 (66–77) Women, n (%) 20 (74) 149 (76) 169 (76) Weight, kg 68 (68–71) 67 (58–80) 67 (58–78) Systolic BP, mm Hg 129 (120–138) 136 (122–150) 135 (121–149) Diastolic BP, mm Hg 67 (61–72) 70 (64–80) 70 (63–79) -1 Heart rate, beats per min 68 (60–77) 70 (62–78) 70 (61–79) Atrial fibrillation, n (%) 20 (74) 138 (71) 158 (71) Hypertension, n (%) 19 (70) 126 (65) 145 (65) Hyperlipidemia, n (%) 12 (44) 84 (43) 96 (43) Diabetes mellitus, n (%) 7 (26) 57 (29) 64 (29) Smoking, n (%) 3 (11) 13 (7) 16 (7) Heart valve procedures Mitral valve repair, n (%) 5 (18) 21 (11) 26 (12) Mitral valve replacement, n (%) 15 (56) 156 (80) 171 (77) Aortic valve replacement, n (%) 14 (52) 90 (46) 104 (47) Tricuspid valve surgery, n (%) 8 (30) 75 (39) 83 (37) Mitral and aortic valve surgery, n (%) 7 (26) 72 (37) 79 (36) Patients with reinterventions, n (%) 5 (19) 61 (31) 66 (30) Time since last valvular surgery, y 9 (4–15) 7 (3–13) 7 (3–13) Type of valve prosthesis, n (%) Mechanical 22 (82) 153 (79) 175 (79) Biological 3 (11) 36 (19) 39 (18) Nominal size of prostheses, median (IQR) Downloaded from http://ahajournals.org by on April 3, 2023 Mitral 29 (27–29) 27 (25–29) 27 (25–29) Aortic 21 (21–25) 21 (19–23) 21 (20–23) Coronary artery revascularization Coronary artery bypass graft, n (%) 0 (0) 13 (7) 13 (6) Percutaneous coronary intervention, n (%) 0 (0) 12 (6) 12 (5) Functional status WHO functional classification, n (%) I or II 22 (81) 111 (57) 133 (60) III 5 (19) 84 (43) 89 (40) 6-min walk test distance, m 366 (318–410) 356 (270–408) 358 (272–408) Concomitant mediations Acenocoumarol or warfarin, n (%) 26 (96) 180 (92) 206 (93) Aspirin, n (%) 1 (4) 19 (10) 20 (9) Diuretics, n (%) 20 (80) 167 (86) 187 (84) Aldosterone receptor antagonist, n (%) 11 (41) 83 (43) 94 (42) ACE inhibitors, n (%) 11 (41) 77 (40) 88 (40) Angiotensin II receptor blocker, n (%) 4 (18) 41 (21) 45 (20) Laboratory BNP, pg mL-1 40 (21–68) 59 (25–153) 55 (24–135) Cardiac catheterization data Right atrial pressure, mm Hg 10 (8–14) 12 (9–17) 12 (9–16) Pulmonary artery oxygen saturation, % 66 (61–72) 64 (59–70) 64 (59–70) Mean pulmonary artery pressure, mm Hg 25 (23–28) 39 (34–44) 37 (32–44) (Continued) J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199494 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Table 1. Continued Not Randomized Randomized Full Cohort n= 27 n= 195 N= 222 Mean PAWP, mm Hg 17 (12–23) 22 (20–26) 22 (18–26) Cardiac index, L min-1/m-2 2.7 (2.3–3.1) 2.8 (2.4–3.3) 2.8 (2.4–3.3) Transpulmonary pressure gradient, mm Hg 9 (6–11) 16 (12–22) 15 (11–21) Diastolic pressure gradient, mm Hg 1 (−2–4) 3 (0–7) 2 (0–6) Pulmonary vascular resistance, WU 1.9 (1.3–2.7) 3.4 (2.3–5.0) 3.2 (2.1–4.8) Pulmonary arterial compliance, mL/mm Hg-1 2.5 (2.1–3.1) 1.9 (1.3–2.5) 2.0 (1.4–2.7) Pulmonary arterial elastance, mm Hg/mL 0.6 (0.5–0.8) 0.9 (0.7–1.2) 0.9 (0.7–1.2) PH classification, n (%) Precapillary PH 2 (7) 7 (4) 9 (4) Isolated postcapillary PH 14 (52) 80 (41) 94 (42) Combined postcapillary PH 2 (7) 108 (55) 110 (50) All values are described as median (interquartile range) unless otherwise indicated. ACE indicates angiotensin-converting enzyme; BNP, brain natriuretic peptide; BP, blood pressure; IQR, interquartile range; PAWP, pulmonary artery wedge pressure; PH, pulmonary hypertension; WHO, World Health Organization; and WU, Wood units. Statistical Analysis address predictors of PVR. Survival data were right- All data are presented as median (interquartile censored at 84 months and Kaplan-Meier plots and range) except when otherwise indicated. We used log-rank differences were calculated. The best cutoff multivariable imputation by chained equations for values were obtained using maximally selected rank relevant missing data. We used the Pearson linear statistics implemented for survival analyses.16 The correlation coefficient (r) to assess the relationship standardized mortality ratio (and its 95% CI) was cal- between quantitative variables, and paired t tests to culated comparing the cohort against the sex- and age-matched Spanish population for the studied Downloaded from http://ahajournals.org by on April 3, 2023 analyze the pre-/post-effects of the acute vasodila- tor test. We used multivariable linear regression to period.17 We used univariable and multivariable Cox proportional hazards models to analyze survival. For multivariable models, we selected predictors based on the results of univariate analyses and then un- derwent backwards stepwise selection using cross- validation of 1000 replicates; only variables entered >50% of the replicates were retained. Identical vari- ables were chosen in a sensitivity analysis performed using a purposeful selection strategy. For variable re- duction of Doppler echocardiography data, we fitted a multivariable least-squares linear regression model using measured PVR as the dependent variable (Data S1 and Figure S1). The noninvasive surrogate of PVR was then entered in the Cox models instead of measured PVR. Bias-adjusted metrics of overall per- formance of multivariable models was assessed cal- culating the R2 and the C-statistic by bootstrapping 1000 replicates. Proportional hazards assumptions were addressed by analysis of Schoenfeld residuals of each covariable and the global model. A cluster (random) effect of the recruiting center was excluded by mixed-effects Cox regression. For the validation analyses of 6-month end points, we also used the Figure 2. Hemodynamic characterization at enrollment. Kaplan-Meier method, log-rank tests and calculated CpcPH indicates combined postcapillary pulmonary hypertension; IpcPH, isolated postcapillary pulmonary hypertension; PAWP, their hazard ratios (HRs). We used R (version 4.0; The pulmonary capillary pressure; PH, pulmonary hypertension; and R Foundation) for all analyses and plots, and statisti- PVR, pulmonary vascular resistance cal significance was established at P<0.05. J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199495 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Table 2. Echocardiographic Data Not Randomized Randomized Full Cohort Total Population n=27 n=195 N=222 Available Data n=20 n=187 N=207 2 LV end-diastolic volume index, mL/m 58 (42–68) 54 (44–64) 52 (43–63) LV end-systolic volume index, mL/m2 22 (17–28) 22 (16–29) 21 (16–26) LV ejection fraction, % 61 (54–62) 59 (54–64) 60 (55–63) LV end-diastolic dimension, cm 49 (44–55) 50 (46–53) 50 (45–53) Interventricular septum diastolic thickness, cm 1.0 (0.9–1.1) 1.1 (1.0–1.2) 1.0 (0.9–1.2) RV end-diastolic area, cm2 20.9 (16.0–24.3) 19.9 (17.5–23.4) 19.8 (17.5–24.0) RV end-systolic area, cm2 12.0 (9.2–13.4) 13.0 (10.7–14.9) 13.1 (11.1–15.5) RV fractional area shortening, % 40 (40–50) 40 (30–40) 40 (30–40) 2 Right atrial area, cm 23.1 (19.8–33.2) 22.7 (19.0–28.2) 23.1 (18.9–28.6) Left atrial diameter, cm 5.2 (4.7–5.8) 5.0 (4.6–5.5) 5.1 (4.6–5.6) Left atrial volume index, mL·m-2 89 (65–104) 91 (71–116) 90 (71–115) Peak aortic jet velocity (native valve), m/s 1.8 (1.6–2.1) 1.9 (1.7–2.4) 1.9 (1.7–2.4) Peak aortic jet velocity (prostheses), m/s 2.5 (1.9–3.2) 2.7 (2.3–3.1) 2.7 (2.3–3.1) Effective aortic valve area index (prostheses), cm2/m2 0.96 (0.70–1.28) 0.88 (0.69–1.12) 0.88 (0.70–1.13) Aortic valve patient-prosthesis mismatch (prostheses), n (%) 2 (18) 20 (24) 22 (23) Aortic regurgitation, n (%) 0 11 (55) 94 (52) 105 (53) I 8 (40) 67 (37) 75 (37) II 1 (5) 19 (11) 20 (10) Peak E wave velocity (native valve), m/s 1.6 (1.3–1.7) 1.6 (1.4–1.8) 1.6 (1.4–1.8) Peak E wave velocity (surgical valve), m/s 1.9 (1.7–2.3) 2.0 (1.8–2.1) 2.0 (1.8–2.1) Downloaded from http://ahajournals.org by on April 3, 2023 Diastolic transmitral pressure gradient (surgical valve), mm Hg 5.0 (4.1–6.0) 4.9 (4.0–6.3) 4.9 (4.0–6.3) E wave deceleration time (native valve), ms 301 (211–373) 179 (160–247) 205 (163–290) E wave deceleration time (prostheses or repaired valve), ms 321 (224–354) 219 (186–287) 221 (188–299) 2 -2 Effective mitral valve area index (prostheses or repaired), cm ·m 0.92 (0.86–1.14) 1.05 (0.83–1.18) 1.04 (0.83–1.18) Mitral valve patient-prosthesis mismatch (prostheses or repaired), n (%) 8 (66) 126 (79) 134 (78) Mitral regurgitation, n (%) 0 14 (70) 106 (59) 120 (60) I 5 (25) 48 (27) 53 (27) II 1 (5) 26 (14) 27 (13) Tricuspid annular plane systolic excursion, cm 1.7 (1.5–2.0) 1.5 (1.2–1.7) 1.5 (1.3–1.8) Tricuspid regurgitation, n (%) 0 0 (0) 1 (1) 1 (1) I 5 (25) 18 (10) 23 (12) II 8 (40) 99 (56) 107 (54) III 7 (35) 50 (28) 57 (29) IV 0 (0) 9 (5) 9 (5) Pulmonary flow acceleration time, ms 96 (81–112) 69 (60–83) 69 (60–83) Tricuspid jet peak regurgitant velocity, m/s 3.0 (2.7–3.2) 3.5 (3.2–3.9) 3.5 (3.2–4.0) Estimated pulmonary systolic arterial pressure, mm Hg 46 (38–53) 61 (53–72) 61 (53–76) All values are described as median (interquartile range) unless otherwise indicated. LV indicates left ventricular; and RV, right ventricular. RESULTS median (interquartile range) age was 72 years (66–77 years), 169 patients (76%) were women, and 64 pa- Study Population tients (29%) had diabetes mellitus. The most frequent The present report is based on 222 patients of the valvular surgery was mitral valve replacement (n=171, 231 initially entering the SIOVAC cohort (Figure 1). The 77%), and roughly one third of patients had undergone J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199496 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Table 3. Correlation Analyses of Factors Related to PAWP Survival and PVR During the follow-up period (median 4.5 years [3.3–6.4 PAWP PVR years]), 91 deaths were recorded (41%). Causes of Mitral mean transvalvular pressure 0.21* −0.05 death were cardiovascular in 70 (78%), noncardiovas- gradient§ cular in 15 (16%), and undetermined in 6 (7%) patients. Mitral valve area index§ −0.05 −0.28* Cardiovascular deaths were of cardiac origin in 52 pa- Mitral prosthesis-patient mismatch 22 vs 22 mm Hg 2.8 vs 3.9 WU* tients (end-stage heart failure in 42, sudden cardiac (no vs yes)§ death in 5, acute myocardial infarction in 2, and other Aortic mean transprosthetic 0.20* −0.10 events in 3), fatal hemorrhagic events in 15, and ischemic pressure gradient stroke in 3. Median overall survival rates at 12, 24, and Aortic prosthetic valve area index −0.26* 0.03 60 months were 0.95 (95% CI, 0.92–0.98), 0.86 (95% CI, Aortic prosthesis-patient mismatch 22 vs 23 mm Hg 3.1 vs 3.9 WU 0.81–0.90), and 0.62 (95% CI, 0.55–0.69), respectively (no vs yes)† (Figure 3A). Compared with the Spanish age-matched Values represent Pearson correlation coefficient (r), except †, which shows population, the standardized mortality ratio was 4.21 mean values for either group. PAWP indicates pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; and WU, Wood units. (95% CI, 3.43–5.17; P<0.0001). Kaplan-Meier curves for *P<0.05. cardiovascular mortality and stratification according to § Patients with mitral valve repair or mitral valve replacement. the enrollment group are shown in Figure 3B and 3C. In randomized patients, 6-month exposure to the investiga- tion drug was unrelated to long-term survival (HR, 0.81; more than 1 valve procedure (Table 1). Most patients 95% CI, 0.52–1.25 [P=0.34], sildenafil versus placebo). (n=214, 93%) had mechanical prostheses. Among these, 85% were of bileaflet design. Survival Predictors Demographic, clinical, catheterization, and echocar- Catheterization and Echocardiographic diographic factors were related to all-cause mortal- Profiling ity (Table 4). Multivariable analyses (Table 5) showed Baseline hemodynamic results showed significant that the most determinant risk factor for mortality was elevation in mPAP and PAWP (37 mm Hg [32–44 male sex (HR, 1.92; 95% CI, 1.20–3.08). Age, diabetes mm Hg] and 23 mm Hg [18–26 mm Hg], respec- mellitus, and functional class were related to mortality. Downloaded from http://ahajournals.org by on April 3, 2023 tively), whereas cardiac index was in the low-nor- Among catheterization variables, mPAP, transpulmo- mal range (Table 1, Figure 2). Median PVR was 3.2 nary pressure gradient, pulmonary arterial elastance, WU (2.1–4.8 WU). One half of the study population and PVR were all related to survival (Table 4; Figure 4). (n=110) experienced combined postcapillary PH, However, the latter was the only catheterization vari- whereas 94 patients (42%) experienced isolated able entering multivariable prediction models (HR, postcapillary PH. Of the remaining 18 patients 1.10; 95% CI, 1.01–1.19 per WU [P=0.04]). Neither the showing a PAWP <15 mm Hg, precapillary PH was hemodynamic PH classification nor the response to present in 9 (4%). Results of acute vasodilator tests the acute vasodilator test predicted survival (Table 4, are summarized in Data S1. Figure 3D). Among echocardiographic variables, the Median LV ejection fraction was 60% (55%–63%) estimated PSAP, tricuspid annular plane systolic excur- and only 34 patients (15%) showed values <50% sion, and transmitral pressure gradient were all related (Table 2). Almost all patients had mild or moderate to survival (Table 4), but no echocardiographic vari- degrees of tricuspid regurgitation and tricuspid an- able alone added predictive value to clinical factors in nular plane systolic excursion was in the low lim- multivariable models. Echocardiographic data yielded its. Mitral prosthesis mismatch was found in 78% a relatively accurate estimate of PVR by multivariable of patients with previous mitral surgery and avail- linear regression (Figure 5). This noninvasive estimate able ultrasound data. These patients showed higher of PVR was the most powerful predictor of all-cause values of PVR, as PVR inversely correlated with ef- mortality in the multivariable model (HR, 1.25; 95% fective mitral valve area index (r=−0.28, P=0.0002; CI, 1.06–1.42 per 1 noninvasive WU). Optimal thresh- Table 3). Multivariable regression showed that PVR olds of PVR and noninvasive PVR to predict all-cause was directly related to the presence of diabetes mortality were identical: 4.3 WU. Performance of the mellitus (β=0.9 WU, P=0.005) and inversely related 3 multivariable models (clinical, clinical+catheterization, to mitral and aortic valve area indices (β=−1.5 WU and clinical+ultrasound) to predict survival was nearly and 0.8 WU per cm2 /m2 [P=0.003 and P=0.048], re- identical (bootstrapped C-index: 0.67 to 0.68, Table 5). spectively). In turn, valve area index correlated with Survival curves for the most relevant predictors of all- nominal size, both of mitral (r=0.30, P=0.001) and cause mortality are shown in Figure 6. Demographic, aortic (r=0.32, P=0.005) prostheses. clinical, catheterization, and ultrasound predictors J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199497 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Downloaded from http://ahajournals.org by on April 3, 2023 Figure 3. Survival curves of the study cohort. (A) Global survival of the full cohort compared with the Spanish age-matched control population. (B) Survival without cardiovascular mortality. (C, D) Stratification based on the role in the clinical trial and pulmonary hypertension (PH) classification group, respectively. CpcPH indicates combined postcapillary pulmonary hypertension; IpcPH, isolated postcapillary pulmonary hypertension; mPAP, mean pulmonary arterial pressure; PH, pulmonary hypertension; SIOVAC Sildenafil for Improving Outcomes After Valvular Correction; and SMR, standard mortality ratio. related to cardiovascular mortality were similar to those relatively well to predict survival, whereas the change related to all-cause mortality (Table 6). in brain natriuretic peptide levels performed worse The composite clinical score and changes in (Figure 7; bootstrapped C-indices: 0.62, 0.57, and 6MWT distance evaluated at 6 months performed 0.52, respectively). J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199498 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Table 4. Univariate Predictors of Mortality HR 95% CI P Value Clinical Age (per 10 y) 1.65 1.24–2.19 0.0006 Men 1.72 1.09–2.70 0.018 Diabetes mellitus 2.10 1.39–3.18 0.0005 WHO functional class III vs I or II 2.08 1.38–3.14 0.0005 Time from last surgery (per y) 1.00 0.98–1.03 0.57 6MWT distance (per 50 m) 0.83 0.75–0.93 0.0008 BNP (per 1 log pg mL-1) 1.27 1.05–1.53 0.01 Catheterization mPAP (per 10 mm Hg) 1.34 1.08–1.65 0.007 PAWP (per 10 mm Hg) 1.21 0.82–1.77 0.34 TPG (per 1 mm Hg) 1.04 1.01–1.06 0.009 DPG (per 1 mm Hg) 1.02 0.99–1.06 0.25 TPG >12 mm Hg (binary) 1.38 0.87–2.18 0.17 PVR (per 1 WU) 1.12 1.03–1.22 0.007 PVR >3 WU (binary) 1.19 0.79–1.81 0.40 PAC (per 1 mL/mm Hg) 1.00 0.87–1.17 0.96 Pulmonary arterial elastance (per 1 mm Hg/mL) 1.70 1.10–2.63 0.016 Acute vasoreactivity test Delta CO (per increase 0.5 mL/min) 1.04 0.89–1.22 0.58 Delta PVR (per decrease 0.5 WU) 1.00 0.90–1.11 0.98 Delta PAC (per increase 0.5 mL/mm Hg) 1.08 0.89–1.31 0.41 Echocardiography LV ejection fraction (per 10%) 0.95 0.74–1.21 0.65 Downloaded from http://ahajournals.org by on April 3, 2023 RV fractional area change (per 10%) 0.87 0.70–1.09 0.22 RV end-diastolic area (per 5 cm2) 1.05 0.85–1.29 0.65 2 RV end-systolic area (per 5 cm ) 1.18 0.87–1.59 0.29 Right atrial area (per 5 cm2) 1.03 0.92–1.16 0.62 Tricuspid annular plane systolic excursion (per 0.5 cm) 0.71 0.53–0.97 0.031 Mean diastolic transmitral pressure gradient (per 1 mm Hg) 1.10 1.01–1.19 0.025 Transmitral velocity deceleration time (per 100 ms) 0.89 0.69–1.16 0.38 Prosthetic/repaired mitral valve area index (per 0.5 cm2/m-2) 1.08 0.76–1.53 0.66 Prosthetic aortic valve area index (per 0.5 cm2/m-2) 0.97 0.71–1.32 0.87 Pulmonary acceleration time (per 10 ms) 0.93 0.84–1.03 0.16 Tricuspid regurgitation (per 1 degree) 0.92 0.68–1.25 0.60 Peak TR jet velocity (per 1 m/s) 1.31 1.08–1.59 0.005 Estimated PSAP (per 10 mm Hg) 1.17 1.04–1.33 0.01 Estimated PVR (per 1 WU) 1.23 1.06–1.42 0.007 6MWT indicates 6-minute walk test; BNP, brain natriuretic peptide; CO, cardiac output; DPG, diastolic pulmonary gradient; HR, hazard ratio; LV, left ventricular; mPAP, mean pulmonary arterial pressure; PAC, pulmonary arterial compliance; PAWP, pulmonary artery wedge pressure; PSAP, pulmonary artery systolic pressure; PVR, pulmonary vascular resistance; RV, right ventricular; TPG, transpulmonary pressure gradient; TR, tricuspid regurgitation; WHO, World Health Organization; and WU, Wood units. pressures, with only 4% of patients showing precap- DISCUSSION illary PH according to current definitions. Men with In the largest prospective cohort of patients with in- diabetes mellitus in World Health Organization (WHO) vasively documented persistent VHD-PH reported functional class III and a PVR >4.3 WU—either meas- so far, we demonstrate that the long-term survival of ured by catheterization or estimated using echocardi- this condition is poor. In most cases, this complica- ography—are patients at highest risk for dying. These tion is related to a chronic elevation of left-sided heart findings have important implications for understanding J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.0199499 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Table 5. Multivariable Models of Any-Cause Mortality Model Variable HR 95% CI Χ2 P Value Clinical Sex (male vs female) 1.92 1.20–3.08 7.42 0.006 Age (per 10 y) 1.49 1.11–2.01 7.04 0.008 Diabetes mellitus 1.69 1.10–2.59 5.68 0.01 WHO functional class 1.62 1.05–2.53 4.64 0.03 III vs I or II 6MWT distance (per 0.92 0.82–1.04 2.65 0.10 50 m) Bootstrapped R2=0.13; C-index=0.67 Clinical+catheterization Age (per 10 y) 1.56 1.17–2.09 8.96 0.011 WHO functional class 1.76 1.15–2.68 6.87 0.008 III vs I or II Sex (male vs female) 1.82 1.15–2.87 6.50 0.011 Diabetes mellitus 1.70 1.11–2.61 5.97 0.014 PVR (per 1 WU) 1.10 1.01–1.19 4.02 0.04 2 Bootstrapped R =0.13; C-index=0.67 Clinical+echocardiography Predicted PVR (per 1.25 1.06–1.46 7.52 <0.001 1 WU) WHO functional class 1.82 1.14–2.92 6.33 0.011 III vs I or II Age (per 10 y) 1.44 1.05–1.98 5.17 0.02 Sex (male vs female) 1.73 1.03–2.92 4.26 0.04 Diabetes mellitus 1.47 0.91–2.37 2.53 0.11 Downloaded from http://ahajournals.org by on April 3, 2023 Bootstrapped R2=0.14; C-index=0.68 For each model, predictors are sorted by their statistical relevance. 6MWT indicates 6-minute walk test; HR, hazard ratio; PVR, pulmonary vascular resistance; WHO, World Health Organization; and WU, Wood units. the foundations of persistent VDH-PH as well as for its restrictive valves (see below),5 LV diastolic dysfunc- potential prevention. tion, and progressive vascular remodeling at the arteriolar, undetermined, and venular vessels21 may be involved. In addition, the high prevalence of atrial Understanding Persistent VHD-PH fibrillation and the large atrial volumes observed in Unlike in other causes of LHD-PH, the causative left- our cohort support a potential role of atrial dysfunc- sided heart lesion is usually corrected in persistent tion.22 Some authors have suggested the early role VHD-PH, and only in 15% of patients showed LV sys- of reactive increase in pulmonary arterial tone related tolic dysfunction in our series. It is classically believed to neurohormonal (eg, endothelin-mediated) and that valvular hemodynamics return to normal after cor- neurogenic mechanisms.23 This functional impair- rection of the valvular lesion and that LV systolic dys- ment could be unmasked by the response to acute function is prevented when valvular interventions are vasodilation tests, which, in theory, would be able accurately timed. Because patients with preoperative to discriminate (early) “reversible” from (late) “fixed” PH frequently do not have normalized pulmonary pres- mechanisms of precapillary and combined postcap- sure after surgery, the focus has been usually placed illary PH. However, the results of our study show no on preoperative vascular damage.5,8,18 Therefore, PH long-term prognostic value of acute or chronic use in operated valvular patients is frequently designated of sildenafil.12 These findings further advise against “residual PH,” attributing PH to irreversible changes in the indiscriminate use of vasoreactivity tests in fields arterial and arteriolar pulmonary vessels caused by de- other than specific causes of group 1 PH.1 layed surgery.19,20 Our finding of almost universal PAWP elevation in most patients with VHD-PH challenges this interpre- Survival of Patients With Persistent VHD-PH tation. The foundations of a chronic elevation of PAWP Survival in patients with persistent VHD-PH was 62% remain unknown, but factors such as functionally at 5 years, and all-cause mortality was 4.2 times J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.01994910 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Figure 5. Results of the multivariable regression fitting for predicting pulmonary vascular resistance (PVR) from ultrasound data. AccTimePV indicates Doppler acceleration time as measured by pulsed-wave Doppler at the level of the pulmonary valve (ms); BSA, body surface area (m2); HR, heart rate (min-1); PVR, pulmonary vascular resistance (Wood units [WU]); SysDTI_RV, peak systolic myocardial velocity as measured by Doppler tissue imaging of the right ventricular free wall (cm/s); TVILVOT, Figure 4. The relationship between pulmonary vascular left ventricular outflow-tract pulsed-wave Doppler time velocity Downloaded from http://ahajournals.org by on April 3, 2023 resistance (PVR) and outcomes. integral (cm); and VmaxTR, peak jet velocity of the tricuspid (A) Kaplan-Meir survival curves based on the PVR quartile regurgitation jet (m/s). distribution. (B) Per-quartile hazard ratio (HR) analysis. When analyzed by quantiles of the distribution, only quartile 4 vs quartile 1 was significant (HR not including 1), without significant neither PAWP nor the PH group classification were differences in the intermediate categories. related to mortality. This lack of association may be attributable to the fact that elevated PAWP in VHD is not an indicator of advanced LV systolic or diastolic higher than in the matched population. Compared dysfunction.29 In our cohort, the PVR cutoff value for with global cohorts of group 2 PH, this survival rate predicting survival was 4.3 WU, slightly higher than the is close to rates previously reported in some groups 4 3.0 WU threshold that defines combined postcapillary but markedly lower than the standard mortality ratio PH in current guidelines.14 This higher cutoff explains 7.1 value reported by others.2 It is also similar to the why PH classification was not related to outcomes in mortality rate of patients with heart failure,24,25 but our series, and, again, emphasizes the singularity of it doubles the mortality rate of unselected carriers this condition. As in other cohorts, we found no rela- of mechanical valve prostheses (standard mortality tionship between the diastolic pressure gradient and ratio, 1.74–1.99).26 More than two thirds of our co- outcomes.28,30 hort were women, and female sex was associated Among the Doppler echocardiographic variables, with a better prognosis, 2 typical findings of other tricuspid annular plane systolic excursion, the trans- causes of PH,27 and persistent VHD-PH.5 The high prosthetic mitral pressure gradient, and peak tricus- prognostic value we observed for WHO functional pid regurgitation jet velocity correlated with survival. class III and 6MWT distance underscores the role Remarkably, tricuspid regurgitation was not related to of functional characterization of patients with PH. mortality, in concordance with recent observations.31 Importantly, clinical variables yielded the most useful Echocardiographic variables added no prognostic infor- prognostic information. mation to clinical and demographic data in univariable A unique characteristic of our cohort is its exhaus- modeles. Instead, clustered as estimated PVR, they tive characterization by right-sided cardiac catheter- were significantly related to global and cardiovascular ization. Inconsistent with other LHD-PH reports,28,29 survival. J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.01994911 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Downloaded from http://ahajournals.org by on April 3, 2023 Figure 6. Kaplan-Meier overall-survival curves based on most relevant predictors. Stratification based on sex (A), World Health Organization (WHO) functional class (B), and pulmonary vascular resistance (PVR), either measured (C) or estimated by ultrasound (D). Clinical Implications for Preventing PH of its direct impact on survival but also because it and its Consequences showed an additive effect on PVR. Although the inter- action between diabetes mellitus and LHD-PH is not a In the present article, we identified procedural issues novel finding,32–35 its potential implications in VHD-PH that have a direct impact on outcomes. Diabetes mel- had not been reported. A significant number of pa- litus was particularly deleterious, not only because tients in our cohort met the criterion of patient-valve J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.01994912 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Table 6. Multivariable Models of Cardiovascular Mortality Model Variable HR 95% CI Χ2 P Value Clinical Sex (male vs female) 2.43 1.45–4.08 11.45 0.0007 Age (per 10 y) 1.47 1.05–2.05 5.02 0.025 6MWT distance (per 0.86 0.75–0.98 4.91 0.03 50 m) WHO functional class 1.57 0.94–2.60 3.03 0.08 III vs I or II Diabetes Mellitus 1.31 0.79–2.16 1.09 0.30 2 Bootstrapped R =0.11; Dxy=0.36; C-index=0.68 Clinical+catheterization Sex (male vs female) 2.16 1.31–3.59 8.98 0.003 Age (per 10 y) 1.58 1.14–2.19 7.41 0.007 WHO functional class 1.81 1.12–2.93 5.90 0.02 III vs I or II PVR (per 1 WU) 1.10 1.01–1.19 3.90 0.05 Diabetes mellitus 1.93 0.85–2.30 1.71 0.19 2 Bootstrapped R =0.10; Dxy=0.34; C-index=0.67 Clinical+echocardiography Sex (male vs female) 2.17 1.20–3.92 6.59 0.01 WHO functional class 1.87 1.08–3.25 4.98 0.03 III vs I or II Predicted PVR (per 1.24 1.02–1.50 4.81 0.03 1 WU) Age (per 10 y) 1.45 1.00–2.08 3.95 0.05 Diabetes mellitus 1.09 0.60–1.96 0.08 0.78 Downloaded from http://ahajournals.org by on April 3, 2023 Bootstrapped R2=0.08; Dxy=0.27; C-index=0.64 For each model, predictors are sorted by their statistical relevance. 6MWT indicates six-minute walk test; HR, hazard ratio; PVR, pulmonary vascular resistance; WHO, World Health Organization; and WU, Wood units. mismatch (>79% of patients with mitral disease), and If PH is suspected at least 1 year after the primary effective residual valve area was inversely related valvular lesion has been corrected, patients should with PVR. These observations constitute an invasive undergo a comprehensive workup. Valvular dysfunc- and long-term confirmation of prior Doppler-based tion must be ruled out in the first place. Noninvasive reports relating prosthesis-patient mismatch and re- estimates of PVR and pulmonary pressures should be strictive annuloplasties to persistent VHD-PH.5,7,36 As obtained, but a right-sided catheterization procedure expected, effective valve area was, in turn, related to ought to characterize the hemodynamic substrate. prosthetic nominal size. In consequence, whenever Patients should be closely followed, and aggressive possible, mitral valve repair should be preferred over therapeutic interventions may occasionally be con- replacement, but restrictive annuloplasties should be sidered, particularly in men with diabetes mellitus, as avoided. Prostheses with sizes and designs showing well as in patients with functional class III or PVR val- the largest functional areas are preferable but may ues >4.3 WU. The observation of a direct relationship require more complex surgical techniques. Thus, pro- between walking distance and survival suggests a cedural risks must be carefully balanced, keeping in potential benefit of cardiac rehabilitation.37 Treatment mind that based on the results of our study, elderly options for these patients must be further studied, patients and those with diabetes mellitus are at the and the survival rates described herein are a suitable highest risk of the consequences of persistent PH. reference to balance their risks. For future clinical tri- Furthermore, adequate sizing of prostheses should als in the field, our results support 6-month changes not be overlooked in men, despite their larger body in the composite clinical score and in 6MWT distance surface area. For aortic valve procedures, transcath- as valid end points. However, longer-term studies eter aortic valves yield larger effective area than their with clinical end points continue to be preferred for surgical sutural equivalents. phase 3 studies. J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.01994913 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Figure 7. Survival curves of the 6-month end points of the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. (A, B, C) Split survival curves based on the clinical composite score, median change in brain natriuretic peptide (BNP) levels, and median change in the 6-minute walk test (6MWT) distance, respectively. HR indicates hazard ratio. Study Limitations Data on the primary valvular lesions and hemodynamic profiles immediately before and after surgery were unavailable, precluding a longitudinal picture of PH in these patients. However, the period elapsed from the last surgery to recruitment was long (median 7 years), almost one third of the cohort had undergone prior rein- terventions, and the finding of high PAWPs was almost universal. These issues suggest that postcorrection factors are the major determinants of outcomes in pa- tients with persistent VHD-PH. Because the SIOVAC cohort was recruited for participating in a clinical trial, we cannot exclude certain selection bias toward more severe disease. Median mPAP of the full study cohort was 37 mmHg, far above the cutoff of 20 mm Hg now established as PH diagnostic criterion.14 Therefore, re- sults should be extrapolated with caution to milder de- grees of PH. The multivariable ultrasound PVR model was calculated and validated in the same sample. Even though bootstrapping was used to palliate overfitting, future studies are needed. Finally, pulmonary functional Downloaded from http://ahajournals.org by on April 3, 2023 tests were not performed and, therefore, a combination of group 2 and group 3 PH causes cannot be excluded in some patients. However, the infrequent usage of bronchodilator medications suggests a low prevalence of pulmonary disease in the cohort. CONCLUSIONS Elevated left-sided heart pressures play a major role in persistent VHD-PH. Mortality of patients with per- sistent VHD-PH is more than 4 times higher than in the age- and sex-matched general population. Risk factors for mortality in patients with this condition are age, male sex, diabetes mellitus, advanced func- tional class, and high PVR—measured by cardiac catheterization or approximated using ultrasound. Patients with diabetes mellitus and those with small valve prostheses show the worst hemodynamic pro- files. These findings present an opportunity for pre- venting this complication. ARTICLE INFORMATION Received October 26, 2020; accepted November 3, 2020. Affiliations From the Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Facultad de Medicina, J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.01994914 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD Universidad Complutense de Madrid, and CIBERCV, Madrid, Spain hypertension on long-term surgical outcome after mitral valve repair (J.B., A.G.-M., T.M., A.I.F., P.M.-L., J.E., F.F.-A.); Instituto de Salud Carlos for degenerative mitral regurgitation. Ann Thorac Cardiovasc Surg. III, Madrid, Spain (R.Y.); Hospital Virgen de las Nieves, Granada, Spain 2015;21:53–58. doi:10.5761/atcs.oa.13-00364. (R.G.-O.); Hospital Clínico Universitario de Salamanca, and CIBERCV 7. Magne J, Mathieu P, Dumesnil JG, Tanne D, Dagenais F, Doyle D, Salamanca, Salamanca, Spain (P.L.S.-F., J.M.-M., J.M.G.-S.); Hospital Pibarot P. Impact of prosthesis-patient mismatch on survival after mitral Universitario de León, León, Spain (M.C.); Hospital Puerta de Hierro valve replacement. Circulation. 2007;115:1417–1425. doi:10.1161/CIRCU​ Majadahonda and CIBERCV, Majadahonda, Spain (J.S.-C.); Hospital 12 LATIO​NAHA.106.631549. de Octubre and CIBERCV, Madrid, Spain (P.E.-S.); Hospital Clínico de 8. Kainuma S, Taniguchi K, Toda K, Funatsu T, Kondoh H, Nishino M, Valladolid and CIBERCV, Valladolid, Spain (J.A.S.); Hospital Santa Creu Daimon T, Sawa Y. Pulmonary hypertension predicts adverse cardiac i San Pau and CIBERCV, Barcelona, Spain (X.B.); Hospital Universitario events after restrictive mitral annuloplasty for severe functional mitral re- de Araba-Txagorritxu, Vitoria, Spain (A.A.-G.); Hospital Universitario gurgitation. J Thorac Cardiovasc Surg. 2011;142:783–792. doi:10.1016/j. Fundación Alcorcón, Alcorcón, Spain (J.B.); Complejo Hospitalario jtcvs.2010.11.031. Universitario de A Coruña and CIBERCV, A Coruña, Spain (M.G.C.-L.); 9. Chen Y, Liu JH, Chan D, Sit KY, Wong CK, Ho KL, Ho LM, Zhen Z, Hospital de Galdakao-Usansolo, Usansolo, Spain (S.V.); Hospital Lam YM, Lau CP, et al. Prevalence, predictors and clinical outcome of Universitari Germans Trias i Pujol and CIBERCV, Badalona, Spain (A.B.-G.); residual pulmonary hypertension following tricuspid annuloplasty. J Am Hospital Universitario Reina Sofía, Córdoba, Spain (A.L.); Hospital Heart Assoc. 2016;5:e003353. doi:10.1161/JAHA.1116.003353. Infanta Leonor, Madrid, Spain (R.M.-A.); Hospital Virgen de la Victoria 10. Testa L, Latib A, De Marco F, De Carlo M, Fiorina C, Montone R, Agnifili and CIBERCV, Málaga, Spain (M.J.-N.); Hospital Clínico de Santiago de M, Barbanti M, Petronio AS, Biondi Zoccai G, et al. Persistence of se- Compostela and CIBERCV, Santiago de Compostela, Spain (J.R.G.-J.); vere pulmonary hypertension after transcatheter aortic valve replace- Hospital Universitario de la Vall d’Hebron and CIBERCV, Barcelona, Spain ment: Incidence and prognostic impact. Circ Cardiovasc Interv. 2016;9. (A.E.); and Hospital Universitario San Cecilio, Granada, Spain (E.M.-E.). doi:10.1161/CIRCI​NTERV​ENTIO​NS.115.003563. 11. Kjaergaard J, Akkan D, Iversen KK, Kjoller E, Kober L, Torp-Pedersen C, Acknowledgments Hassager C. Prognostic importance of pulmonary hypertension in pa- We are in debt to Ana Fernández-Baza for her kind assistance in all admin- tients with heart failure. Am J Cardiol. 2007;99:1146–1150. doi:10.1016/j. istrative issues. amjca​rd.2006.11.052. 12. Bermejo J, Yotti R, García-Orta R, Sánchez-Fernández PL, Castaño Sources of Funding M, Segovia-Cubero J, Escribano-Subías P, San Román JA, Borrás X, This study was funded by the Instituto de Salud Carlos III, Ministerio de Alonso-Gómez A, et al. Sildenafil for improving outcomes in patients Ciencia e Innovación, Spain, the European Union–European Regional with corrected valvular heart disease and persistent pulmonary hyper- Development Fund (EC07/90772 and PI19/00649), and the Consorcio tension: a multicenter, double-blind, randomized clinical trial. Eur Heart de Investigación Biomédica en Red de Enfermedades Cardiovasculares J. 2018;39:1255–1264. doi:10.1093/eurhe​artj/ehx700. (CIBERCV). 13. Gomez-Sanchez MA, Saenz de la Calzada C, Escribano Subias P, Francisco Delgado Jimenez J, Lazaro Salvador M, Albarran Gonzalez Disclosures A, Cea CL. Pilot assessment of the response of several pulmonary None. hemodynamic variables to sublingual sildenafil in candidates for heart transplantation. Eur J Heart Fail. 2004;6:615–617. doi:10.1016/j.ejhea​ Supplementary Material rt.2003.11.015. Appendix: List of SIOVAC Investigators 14. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Downloaded from http://ahajournals.org by on April 3, 2023 Data S1 Krowka M, Williams PG, Souza R. Haemodynamic definitions and up- FIGURE S1 dated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913. doi:10.1183/13993​0 03.01913​-2018. 15. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail. 2001;7:176–182. doi:10.1054/jcaf.2001.25652. REFERENCES 16. Seckinger A, Meiβner T, Moreaux J, Depeweg D, Hillengass J, Hose K, 1. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Rème T, Rösen-Wolff A, Jauch A, Schnettler R, et al. Clinical and prog- Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, et al. 2015 nostic role of annexin A2 in multiple myeloma. Blood. 2012;120:1087– ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 1094. doi:10.1182/blood​-2012-03-415588. hypertension: The Joint Task Force for the Diagnosis and Treatment 17. Instituto Nacional de Estadistica. Life tables: national results. Mortality of Pulmonary Hypertension of the European Society of Cardiology tables for Spain by year, sex, age and functions. INEbase. URL: (ESC) and the European Respiratory Society (ERS): Endorsed by: https://www.ine.es/dyngs/ ​I NEba ​s e/en/opera​c ion.htm?c=Estad ​i sti- Association for European Paediatric and Congenital Cardiology (AEPC), ca_C&cid=12547​3 6177​0 04&menu=resul​t ados​& idp=12547​35573002. International Society for Heart and Lung Transplantation (ISHLT). Eur Published 12/11/2019. Accessed January 8, 2020. Heart J. 2016;37:67–119. doi:10.1093/eurhe​artj/ehv317. 18. Barbash IM, Escarcega RO, Minha Sa’ar, Ben-Dor I, Torguson R, 2. Wijeratne DT, Lajkosz K, Brogly SB, Lougheed MD, Jiang L, Housin A, Goldstein SA, Wang Z, Okubagzi P, Satler LF, Pichard AD, et al. Barber D, Johnson A, Doliszny KM, Archer SL. Increasing incidence Prevalence and impact of pulmonary hypertension on patients with aor- and prevalence of world health organization groups 1 to 4 pulmonary tic stenosis who underwent transcatheter aortic valve replacement. Am hypertension: A population-based cohort study in Ontario, Canada. J Cardiol. 2015;115:1435–1442. doi:10.1016/j.amjca​rd.2015.02.022. Circ Cardiovasc Qual Outcomes. 2018;11:e003973. doi:10.1161/CIRCO​ 19. Goodale F Jr, Sanchez G, Friedlich AL, Scannell JG, Myers GS. UTCOM​ES.117.003973. Correlation of pulmonary arteriolar resistance with pulmonary vas- 3. Weitsman T, Weisz G, Farkash R, Klutstein M, Butnaru A, Rosenmann cular changes in patients with mitral stenosis before and after val- D, Hasin T. Pulmonary hypertension with left heart disease: vulotomy. N Engl J Med. 1955;252:979–983. doi:10.1056/NEJM1​ Prevalence, temporal shifts in etiologies and outcome. Am J Med. 95506​0 9252​2303. 2017;130:1272–1279. 20. Magne J, Pibarot P, Sengupta PP, Donal E, Rosenhek R, Lancellotti P. 4. Hurdman J, Condliffe R, Elliot CA, Davies C, Hill C, Wild JM, Capener D, Pulmonary hypertension in valvular disease: a comprehensive review on Sephton P, Hamilton N, Armstrong IJ, et al. ASPIRE registry: assessing pathophysiology to therapy from the HAVEC Group. JACC Cardiovasc the Spectrum of Pulmonary hypertension Identified at a REferral centre. Imaging. 2015;8:83–99. doi:10.1016/j.jcmg.2014.12.003. Eur Respir J. 2012;39:945–955. doi:10.1183/09031​936.00078411. 21. Fayyaz AU, Edwards WD, Maleszewski JJ, Konik EA, DuBrock HM, 5. Li M, Dumesnil JG, Mathieu P, Pibarot P. Impact of valve prosthe- Borlaug BA, Frantz RP, Jenkins SM, Redfield MM. Global pulmo- sis-patient mismatch on pulmonary arterial pressure after mitral valve nary vascular remodeling in pulmonary hypertension associated with replacement. J Am Coll Cardiol. 2005;45:1034–1040. doi:10.1016/j. heart failure and preserved or reduced ejection fraction. Circulation. jacc.2004.10.073. 2018;137:1796–1810. doi:10.1161/CIRCU​L ATIO​NAHA.117.031608. 6. Murashita T, Okada Y, Kanemitsu H, Fukunaga N, Konishi Y, Nakamura 22. Inciardi RM, Giugliano RP, Claggett B, Gupta DK, Chandra A, Ruff CT, K, Koyama T. The impact of preoperative and postoperative pulmonary Antman EM, Mercuri MF, Grosso MA, Braunwald E, et al. Left atrial J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.01994915 Bermejo et al. Persistent Pulmonary Hypertension in Corrected VHD structure and function and the risk of death or heart failure in atrial fibril- does not predict survival in patients with pulmonary hypertension due lation. Eur J Heart Fail. 2019;21:1571–1579. doi:10.1002/ejhf.1606. to left heart disease. JACC Heart Fail. 2015;3:9–16. 23. Guazzi M, Labate V. Pulmonary hypertension in heart failure patients: 31. Mutlak D, Khoury E, Lessick J, Kehat I, Agmon Y, Aronson D. Lack Pathophysiology and prognostic implications. Curr Heart Fail Rep. of increased cardiovascular risk due to functional tricuspid regurgita- 2016;13:281–294. doi:10.1007/s1189​7-016-0306-8. tion in patients with left-sided heart disease. J Am Soc Echocardiogr. 24. Muntwyler J, Abetel G, Gruner C, Follath F. One-year mortality among 2019;32:e1531. doi:10.1016/j.echo.2019.08.014. unselected outpatients with heart failure. Eur Heart J. 2002;23:1861– 32. Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati 1866. doi:10.1053/euhj.2002.3282. A, Shroff P, Rich S. Clinical characteristics of pulmonary hypertension 25. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield in patients with heart failure and preserved ejection fraction. Circ Heart MM. Trends in prevalence and outcome of heart failure with preserved Fail. 2011;4:257–265. doi:10.1161/CIRCH​E ARTF​AILURE.110.958801. ejection fraction. N Engl J Med. 2006;355:251–259. doi:10.1056/NEJMo​ 33. Robbins IM, Newman JH, Johnson RF, Hemnes AR, Fremont RD, Piana a052256. RN, Zhao DX, Byrne DW. Association of the metabolic syndrome with 26. Bryan AJ, Rogers CA, Bayliss K, Wild J, Angelini GD. Prospective pulmonary venous hypertension. Chest. 2009;136:31–36. doi:10.1378/ randomized comparison of CarboMedics and St. Jude Medical bileaf- chest.08-2008. let mechanical heart valve prostheses: ten-year follow-up. J Thorac 34. Ranchoux B, Nadeau V, Bourgeois A, Provencher S, Tremblay É, Omura Cardiovasc Surg. 2007;133:614–622. doi:10.1016/j.jtcvs.2006.08.075. J, Coté N, Abu-Alhayja’a R, Dumais V, Nachbar RT, et al. Metabolic syn- 27. Humbert M, Sitbon O, Chaouat A, Bertocchi Michèle, Habib G, Gressin drome exacerbates pulmonary hypertension due to left heart disease. V, Yaïci A, Weitzenblum E, Cordier JF, Chabot François, et al. Survival Circ Res. 2019;125:449–466. doi:10.1161/CIRCR​ESAHA.118.314555. in patients with idiopathic, familial, and anorexigen-associated pulmo- 35. Fernández AI, Yotti R, González-Mansilla A, Mombiela T, Gutiérrez- nary arterial hypertension in the modern management era. Circulation. Ibanes E, Pérez del Villar C, Navas-Tejedor P, Chazo C, Martínez- 2010;122:156–163. doi:10.1161/CIRCU​L ATIO​NAHA.109.911818. Legazpi P, Fernández-Avilés F, et al. The biological bases of group 2 28. Tampakakis E, Shah SJ, Borlaug BA, Leary PJ, Patel HH, Miller WL, pulmonary hypertension. Int J Mol Sci. 2019;20. doi:10.3390/ijms2​ Kelemen BW, Houston BA, Kolb TM, Damico R, et al. Pulmonary ef- 0235884. fective arterial elastance as a measure of right ventricular afterload 36. Ammannaya GKK, Mishra P, Khandekar JV, Mohapatra CKR, Seth and its prognostic value in pulmonary hypertension due to left heart HS, Raut C, Shah V, Saini JS. Effect of prosthesis patient mismatch in disease. Circ Heart Fail. 2018;11:e004436. doi:10.1161/CIRCH​E ARTF​ mitral position on pulmonary hypertension. Eur J Cardiothorac Surg. AILURE.117.004436. 2017;52:1168–1174. doi:10.1093/ejcts/​ezx167. 29. Weber L, Rickli H, Haager PK, Joerg L, Weilenmann D, Brenner R, 37. Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, Nechwatal Taramasso M, Baier P, Maisano F, Maeder MT. Haemodynamic mech- R, Uiker S, Halank M, Olsson K, Seeger W, et al. Exercise training im- anisms and long-term prognostic impact of pulmonary hypertension in proves peak oxygen consumption and haemodynamics in patients patients with severe aortic stenosis undergoing valve replacement. Eur with severe pulmonary arterial hypertension and inoperable chronic J Heart Fail. 2019;21:172–181. doi:10.1002/ejhf.1322. thrombo-embolic pulmonary hypertension: a prospective, random- 30. Tampakakis E, Leary PJ, Selby VN, De Marco T, Cappola TP, Felker GM, ized, controlled trial. Eur Heart J. 2016;37:35–44. doi:10.1093/eurhe​ Russell SD, Kasper EK, Tedford RJ. The diastolic pulmonary gradient artj/ehv337. Downloaded from http://ahajournals.org by on April 3, 2023 J Am Heart Assoc. 2021;10:e019949. DOI: 10.1161/JAHA.120.01994916 SUPPLEMENTAL MATERIAL Downloaded from http://ahajournals.org by on April 3, 2023 Appendix List of SIOVAC Investigators The following investigators, participated in the SIOVAC study: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Facultad de Medicina, Universidad Complutense de Madrid, and CIBERCV, Madrid. Spain: Javier Bermejo, Ana I Fernández, Francisco Fernández-Avilés, Teresa Mombiela, Ana Gónzález-Mansilla, Jaime Elízaga, José A García-Robles, Esther Pérez-David, Candelas Pérez del Villar, Ricardo Sanz, Enrique Gutierrez-Ibanes, María E Vázquez, Ana Mur, Yolanda Benito, Pablo Martínez-Legazpi, Alicia Barrio, and Alexandra Vázquez. Instituto de Salud Carlos III: Raquel Yotti. Hospital Virgen de las Nieves, Granada. Spain: Rocío García-Orta, Inés Uribe, and Mercedes González. Hospital Clínico Universitario de Salamanca, and CIBERCV Salamanca. Spain: Pedro Luis Sánchez, José M González-Santos, Javier Martín-Moreiras, Antonio Arribas, M. Milagros Clemente Lorenzo and Alejandro Diego Nieto. Hospital Universitario de León, León, Spain: Mario Castaño, Armando Pérez de Prado and David Alonso. Hospital Puerta de Hierro Majadahonda and CIBERCV, Majadahonda, Madrid. Spain: Javier Segovia-Cubero, Manuel Gómez-Bueno, Inés Sayago Silva and Miguel Ángel Cavero. Downloaded from http://ahajournals.org by on April 3, 2023 Hospital Doce de Octubre and CIBERCV, Madrid. Spain: Pilar Escribano-Subias, Laura Domínguez, Rocío Tello de Meneses, M José Ruiz Cano and Carmen Jiménez López-Guarch. Hospital Clínico de Valladolid and CIBERCV, Valladolid. Spain: J. Alberto San Román, Pedro Mota Hospital Santa Creu i San Pau and CIBERCV, Barcelona. Spain: Xavier Borrás, Carmen Amorós Galitó. Hospital Universitario de Araba-Txagorritxu, Vitoria. Spain: Angel Alonso-Gómez, M. Concepción Belló Mora, Dolores Mesa Rubio. Complejo Universitario Fundación Alcorcón, Alcorcón. Spain: Javier Botas, Raquel Campuzano. Complejo Hospitalario Universitario de A Coruña and CIBERCV, A Coruña. Spain: María G Crespo-Leiro, Raquel Marzoa, José Cuenca. Hospital de Galdakao-Usansolo, Usansolo. Spain: Sonia Velasco. Hospital Infanta Leonor, Madrid. Spain: Roberto Muñoz, Verónica Suberviola, Cristina Beltrán Herrera, Laura Mora, M. Mar Sarrión and David Vaqueriza. Hospital Universitari Germans Trias i Pujol and CIBERCV, Badalona. Spain: Antoni Bayes- Genís, Elena Ferrer. Hospital Clínico de Santiago de Compostela and CIBERCV, Santiago de Compostela. Spain: José R. González-Juanatey, Belén Cid and Amparo Martínez Monzonís. Hospital Universitario Reina Sofía, Córdoba. Spain: Amador López, José M. Arizón de Prado, Marta Santisteban and Dolores Mesa Rubio. Hospital Universitario de la Vall d’Hebron and CIBERCV, Barcelona. Spain: Arturo Evangelista and David García-Dorado. Hospital Virgen de la Victoria and CIBERCV, Málaga, Spain: Eduardo de Teresa, Manuel Jiménez-Navarro and Fernando Carrasco Chinchilla. Hospital Universitario San Cecilio, Granada. Spain: Eduardo Moreno-Escobar. Hospital Universitario de Getafe, Madrid. Spain: Joaquín Alonso. Downloaded from http://ahajournals.org by on April 3, 2023 Data S1. Supplemental Methods Because no single echocardiographic variable was related to survival in the multivariable model, we underwent a variable-reduction strategy to cluster Doppler- echocardiographic variables into a single metric. For this purpose, we underwent a multivariable linear regression model to predict PVR, as measured by cardiac catheterization. Combining ultrasound variables shown in Table 2 with other relevant noninvasive information we underwent automatic variable selection by cross-validation backwards selection algorithm using 1,000 replicates. Predicted values of PVR estimated noninvasively were then entered in the uni and multivariable Cox proportional-hazard models to predict survival. Supplemental Results The acute vasoreactivity test (n= 140) induced significant reductions in PAWP (mean decrease -1.1 mm Hg, p= 0.003), mPAP (-3.3 mm Hg, p< 0.0001), and PVR (-0.6 W.U, p< 0.0001), without significantly changing cardiac output (-0.46 l/min, p= 0.22), and significantly increasing PAC (+0.46 mL/mm Hg; Figure S1). Despite these changes, the impact of sildenafil on the PAC-PVR nonlinear relationship was negligible (Figure S1). Downloaded from http://ahajournals.org by on April 3, 2023 Figure S1. Acute Vasoreactivity Test. Downloaded from http://ahajournals.org by on April 3, 2023 Values for each patient with available data are shown for baseline (red) and post-sildenafil (100 mg, sublingual) connected by a dotted line. Global effects for the full cohort are shown in the marginal boxplots.