Circulation ORIGINAL RESEARCH ARTICLE Cardiac Remodeling After Hypertensive Pregnancy Following Phys

Circulation ORIGINAL RESEARCH ARTICLE Cardiac Remodeling After Hypertensive Pregnancy Following Physician-Optimized Blood Pressure Self-Management: The POP-HT Randomized Clinical Trial Imaging Substudy Jamie Kitt Paul A. Bateman , DPhil; Samuel Krasner , BA; Logan Barr , PhD; Annabelle Frost, MBBS; Katherine Tucker , PhD; , PhD; Katie Suriano, PhD; Yvonne Kenworthy, BSc; Winok Lapidaire , PhD; Miriam Lacharie , MSc; Rebecca Mills, MSc; Cristian Roman, PhD; Lucy Mackillop Vanessa Ferreira , MA; Alexandra Cairns , DPhil; Christina Aye , DPhil; Stefan Piechnik , DPhil; Elena Lukaschuk , MSc; Basky Thilaganathan Lucy C. Chappell , PhD; Adam J. Lewandowski , DPhil; Richard J. McManus , PhD; Paul Leeson , DPhil; , PhD; , PhD BACKGROUND: Hypertensive pregnancy disorders are associated with adverse cardiac remodeling, which can fail to reverse in the postpartum period in some women. The Physician-Optimized Postpartum Hypertension Treatment trial demonstrated that improved blood pressure control while the cardiovascular system recovers postpartum associates with persistently reduced blood pressure. We now report the effect on cardiac remodeling. Downloaded from http://ahajournals.org by on January 16, 2025 METHODS: In this prospective, randomized, open-label, blinded end point trial, in a single UK hospital, 220 women were randomly assigned 1:1 to self-monitoring with research physician-optimized antihypertensive titration or usual postnatal care from a primary care physician and midwife. Participants were 18 years of age or older, with preeclampsia or gestational hypertension, requiring antihypertensives on hospital discharge postnatally. Prespecified secondary cardiac imaging outcomes were recorded by echocardiography around delivery, and again at blood pressure primary outcome assessment, around 9 months postpartum, when cardiovascular magnetic resonance was also performed. RESULTS: A total of 187 women (101 intervention; 86 usual care) underwent echocardiography at baseline and follow up, at a mean 258±14.6 days postpartum, of which 174 (93 intervention; 81 usual care) also had cardiovascular magnetic resonance at follow-up. Relative wall thickness by echocardiography was 0.06 (95% CI, 0.07-0.05; P<0.001) lower in the intervention group between baseline and follow-up, and cardiovascular magnetic resonance at follow-up demonstrated a lower left ventricular mass (-6.37 g/m2; 95% CI, -7.99 to -4.74; P<0.001), end-diastolic volume (-3.87 mL/m2; 95% CI, -6.77 to -0.98; P=0.009), and end-systolic volume (-3.25 mL/m2; 95% CI, 4.87 to -1.63; P<0.001) and higher left and right ventricular ejection fraction by 2.6% (95% CI, 1.3-3.9; P<0.001) and 2.8% (95% CI, 1.4-4.1; P<0.001), respectively. Echocardiography-assessed left ventricular diastolic function demonstrated a mean difference in average E/E' of 0.52 (95% CI, -0.97 to -0.07; P=0.024) and a reduction in left atrial volumes of -4.33 mL/m2 (95% CI, -5.52 to -3.21; P<0.001) between baseline and follow-up when adjusted for baseline differences in measures. CONCLUSIONS: Short-term postnatal optimization of blood pressure control after hypertensive pregnancy, through self monitoring and physician-guided antihypertensive titration, associates with long-term changes in cardiovascular structure and function, in a pattern associated with more favorable cardiovascular outcomes. Correspondence to: Paul Leeson, PhD, Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom. Email p..n@cardiov.ox.ac.uk Supplemental Material, the podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.123.067597. For Sources of Funding and Disclosures, see page 539. © 2023 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. Circulation is available at www.ahajournals.org/journal/circ February 13, 2024 529 Circulation. 2024;149:529-541. DOI: 10.1161/CIRCULATIONAHA.123.067597 ORIGINAL RESEARCH ARTICLE February 13, 2024 Circulation. 2024;149:529-541. DOI: 10.1161/CIRCULATIONAHA.123.067597 530 Kitt et al POP-HT Cardiac Imaging Substudy REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04273854. Key Words: hypertension, pregnancy-induced â—¼ postpartum period â—¼ pre-eclampsia â—¼ self-management â—¼ ventricular remodeling Editorial, see p 542 Hemodynamic demands during pregnancy result in substantial cardiac and vascular remodel ing,1 which, during the 6 weeks after pregnancy, known as the puerperium, rapidly reverses in normoten sive pregnancy.2 When the pregnancy is complicated by hypertension, the cardiac changes during pregnancy are more pronounced, and adverse features develop,3-5 such as reduced left ventricular systolic and diastolic function6 and concentric remodeling. Several studies have demon strated that adverse cardiac phenotypes can remain evi dent for several years after a hypertensive pregnancy.1,7-9 Furthermore, persistence of adverse cardiac pheno types predicts worse longer-term outcomes, including risk of hypertension1,6 and an increased incidence of earlier-onset heart failure.9 These findings suggest the postpartum "reverse remodeling" seen in normotensive pregnancy may not be occurring in all women who have a hypertensive pregnancy. Blood pressure levels immediately postpartum are unpredictable after a hypertensive pregnancy,10 and there is limited evidence to guide optimal blood pressure management.11 We hypothesized that "poor" blood pres sure control after a hypertensive pregnancy might limit normal postpartum reverse remodeling.12-15 In the POP HT (Physician-Optimized Postpartum Hypertension Treatment) randomized clinical trial, we demonstrated physician-guided antihypertensive self-management after hypertensive pregnancy results in lower blood pres sure for at least 9 months postpartum.16 Participants were also invited for multimodality imaging to investigate prespecified secondary imaging outcomes. These were included to test the underlying mechanistic hypothesis that better postpartum blood pressure control induces differences in cardiac structure and function, in param eters of potential relevance to long-term blood pressure control and future cardiovascular disorders, including heart failure. METHODS Study Design and Participants POP-HT was a single-center, 2-group parallel, prospectively randomized, open, blinded end point study. The primary article reporting blood pressure outcomes has been published and includes a detailed description of recruitment, patient charac teristics, and statistical analysis.16 A protocol article reporting the detailed methodology and prespecified outcome measures, including the secondary imaging outcomes, has previously been published.17 In brief, all participants were recruited from the Women's Centre at Oxford University Hospitals National Health Service Foundation Trust in the United Kingdom. Participants were 18 years of age or older, with a clinician-confirmed diagno sis of either gestational hypertension or preeclampsia according to the UK National Institute of Clinical Excellence guidance,13 and still requiring antihypertensive medication at the time of hos pital discharge. Participants with chronic/essential hypertension, defined as a blood pressure >140/90 mm Hg at their 12-week Clinical Perspective What Is New? • The POP-HT trial (Physician-Optimized Postpartum Hypertension Treatment), a randomized clinical trial of 220 participants, showed that blood pressure improvements in those who received physician- guided self-management of blood pressure post natally are also associated with beneficial left ventricular and left atrial remodeling by 9 months postpartum. • Clinically significant increases in left and right ven tricular systolic function as well as improvements in left ventricular diastolic function were evident in the intervention group when assessed by multimodality imaging, including transthoracic echocardiogram and cardiac magnetic resonance. What Are the Clinical Implications? • These multimodality imaging findings suggest that improved blood pressure control postnatally may help reverse the adverse remodeling known to occur during a hypertensive pregnancy, and that these benefits persist for at least 9 months postpartum. • The early postpartum period may represent a criti cal window for intervention to improve long-term maternal cardiovascular health after hypertensive pregnancy. Nonstandard Abbreviations and Acronyms CMR cardiac magnetic resonance COVID-19 coronavirus disease 2019 POP-HT Physician-Optimized Postpartum Hypertension Treatment V visit Downloaded from http://ahajournals.org by on January 16, 2025 Kitt et al POP-HT Cardiac Imaging Substudy booking assessment, or those already on antihypertensive treat ment before pregnancy, were excluded. Participant information on race and ethnicity were self-reported using the UK Office of National statistics prespecified categories. Individuals with hypertension before pregnancy; those with medical conditions that made self-monitoring impractical or unsafe, eg, severe post partum anxiety or depression; those unable to follow the English app-based instructions; and those unable to provide written consent were excluded. The trial was prospectively registered at clinicaltrials.gov (URL: https://www.clinicaltrials.gov; Unique identifier: NCT04273854) and supervised by a trial steering and data safety monitoring committee. Ethical and research gover nance approval was gained from the London-Surrey Research Ethics Committee (reference no. 19/L0/1901; Integrated Research Application System Project ID No. 273353). Randomization and Blinding After a baseline visit, eligible participants were randomized 1:1 to either telemonitored home blood pressure monitoring with physician-assisted self-management or standard National Health Service-led care from their primary care practitioner and midwives. Randomization was conducted with secure web based software (Castor Electronic Data Capture) with minimi zation for gestational age, whether the patient had a diagnosis of preeclampsia or gestational hypertension, and prescription of an angiotensin-converting inhibitor at time of randomization. Because of the nature of the intervention, neither participants nor investigators assigning trial groups were blinded to group assignment. Downloaded from http://ahajournals.org by on January 16, 2025 Procedures Participants assigned to the usual care arm were discharged from the hospital for ongoing management according to local standard care. National UK guidance recommends standard care as a minimum of a blood pressure review with a family physician or community midwife at day 1 to 14 postpartum, a 2-week review with their family physician, and a 6- to 8-weeks review with their family physician or specialist.13 Titration of antihypertensive treatment was conducted at the discretion of their supervising health care professionals (primary care physi cian and midwife). As previously reported,16 participants in the intervention group had initial discharge medications decided by their clinical care team,13 and then dose titration after hospital discharge was guided remotely by the research team physi cians, including cardiologists and obstetricians, in response to daily self-monitored blood pressure measurements (increased to twice daily if out of target range; see published protocol article for further details).17 Choice of medication and titration regimens were standardized on the basis of recommendations from the 2019 UK National Institute of Clinical Excellence guidance.13 There were 4 study visits, after prescreening enrollment, occurring at days 1 to 6 postpartum (visit [V] 1; baseline), 1 week (V2), 6 weeks (V3), and 6 to 9 months (V4). Participants in both groups had research measurements of “clinic blood pressure” at each study visit, and all participants were invited to have an echocardiogram (CX50 or EPIQ 7, Philips, Amsterdam, The Netherlands) at baseline (V1) with data collection based on a British Society of Echocardiography minimum dataset.18 All baseline visits took place on the postnatal ward. Participants were invited for the same echocardiography protocol when attending in person for their final study visit (V4) along with a cardiac magnetic resonance (CMR) scan (3T PRISMA, Siemens Healthineers, Erlangen, Germany) in the Oxford Centre for Clinical Magnetic Resonance Research. This was performed with an 18-channel body coil and a spine array. Images were retrospectively ECG-gated with a precordial 4-lead ECG. CMR images were acquired using a standard previously reported protocol19 that allows assessment of cardiac structure, func tion, and myocardial characteristics, and full technical details are provided in the supplementary information based on the magnetic resonance vendor protocol file. Outcomes The primary outcome has been previously reported, and was 24-hour mean diastolic blood pressure, measured by ambu latory blood pressure monitoring (model 90217; Spacelabs Healthcare, Snoqualmie, Washington) at the time of V4.20 Herein, we report the prespecified secondary cardiovascular imaging outcomes including transthoracic echocardiographic assessment at V1 and V4 and CMR assessment of cardiac structure and function at V4. Full details of these prespecified outcomes of cardiac structure and function using echocardio gram and CMR were reported in the protocol article.17 Echocardiograms were performed using a Philips CX50 portable echocardiography machine for all baseline visits at V1. All follow-up echocardiograms at V4 were done using a Philips EPIQ 7 or IE33. All echocardiography machines were equipped with a 2-dimensional phased array transducer, and scans were performed in the left lateral decubitus position. All echocardiog raphy measurements followed standard society guidelines,18,21 and the modality was primarily performed to assess diastolic function including pulsed wave Doppler assessment of the mitral valve inflow and pulmonary vein inflow, tissue Doppler imaging of lateral and septal walls of the left ventricle, and assessment of left atrial volumes. In addition, standard 2-dimensional mea sures of left ventricular wall thickness as well as volumes based on Simpson biplane measures were used to assess cardiac structure and function. Relative wall thickness as a measure of concentric hypertrophy was calculated as 2× posterior wall diameter/left ventricular internal diastolic diameter.21 Left ven tricular global longitudinal strain was assessed by speckle track ing using semiautomated 2-dimensional Cardiac Performance Analysis Software (TomTec, Munich, Germany). Apical 4, 2 and 3 chamber 2-dimensional images were processed, and the endo cardial border was delineated in end-diastole. The endocardial border was tracked through a single cardiac cycle, and the tracking was then inspected and manually corrected if poorly correlated with myocardial margin. Peak global values of lon gitudinal strain in systole are reported. Intra- and interobserver coefficients of variation for echocardiographic measurements are reported in the Supplementary Material (Table S1). For the CMR, balanced steady-state free precession images were acquired during breath hold at end expiration. Using 2-, 3-, and 4-chamber views to plan images in line with the atrioventricular valves, a stack of short-axis images was acquired at 1-cm intervals to include the entire left and right ventricles. Image analysis was performed using CVI42 version 5.12.1 (Circle Cardiovascular Imaging Inc, Calgary, Canada). The short-axis stack of images was analyzed for left and right 531 ORIGINAL RESEARCH ARTICLE Circulation. 2024;149:529-541. DOI: 10.1161/CIRCULATIONAHA.123.067597 February 13, 2024 Kitt et al POP-HT Cardiac Imaging Substudy RESULTS ORIGINAL RESEARCH ARTICLE Downloaded from http://ahajournals.org by on January 16, 2025 ventricular volumes, ejection fractions, and left ventricular mass. Left and right ventricular endocardial and epicardial borders were manually contoured at end-diastole and endocardial bor ders only in end-systole. Papillary muscles and trabeculations were excluded from the myocardial mass in line with standard guidance22 Myocardial mass was calculated from the sum of the myocardial area in the stack of images multiplied by 1.05 g/ cm3 (specific gravity of myocardium per cubic centimeter). End diastolic and end-systolic volumes were calculated from the sum of ventricular areas in the stack of images. Stroke volume was calculated as the difference between the end-diastolic and the end-systolic volume. Ejection fraction was calculated as stroke volume divided by end-diastolic volume. Wall thickness was measured at midventricular level in 6 segments (ante rior, lateral, inferior, inferolateral, inferoseptal, and anterosep tal).23 Mean wall thickness values were calculated from these 6 measures. Myocardial T1 values were measured from short modified look locker inversion sequences using standardized protocols published previously.24 A single-slice T2 map was performed using Siemens MYOMAPS product sequences. All T1 and T2 map analyses were performed blinded to the clini cal information. T1 maps were analyzed using in-house soft ware Mc-Roi (programmed by S. Piechnik in IDL, v8.8; Exelis Visual Information Solutions, Inc, Boulder, Colorado). T2 maps were analyzed using CVI42 version 5.12.1. Normal values for comparison were obtained on the same 3T PRISMA scanner in 16 age-matched female subjects using the same protocol. Extracellular volume was calculated using hematocrit obtained at time of scan and using T1 values before and after gadolinium administration.19 Late gadolinium administration and sequences were performed using standard Siemens acquisitions. Statistical Analysis Analysis was based on principles of intention-to-treat, including all participants with at least 1 postrandomization outcome. Mean differences between groups with 95% CI and P value were estimated from adjusted linear regression models at a single time point (V4) with adjustment for the prespecified minimiza tion factors stated in the statistical analysis plan. The level of statistical significance was tested as a 5% 2-tailed significance level (P<0.05). Differences in imaging-based secondary out comes between groups were evaluated using an adjusted linear regression model, including V1 measures for echocardiography. For CMR measures, no V1 measures were available, so linear models were adjusted for baseline blood pressure readings. Where measures did not satisfy the model assumptions for lin ear regression, nonparametric tests/regressions were used. Sensitivity analyses were performed using antenatal book ing blood pressure in place of baseline postpartum blood pres sure, and further post hoc analyses were done removing those remaining on antihypertensive treatment at V4. No adjustment was made for multiple testing. Analysis was done using R ver sion 4.3.1 and SPSS version 28.0.0. Analysis of intra and inter operator variation is displayed in Table S1. Data Sharing The data that support the findings of this study are available from the chief investigator (P.L.), upon reasonable request sub ject to the approval of the sponsor (University of Oxford) and the trial steering committee. 532 Demographics Between February 21, 2020, and March 21, 2021, a to tal of 220 participants were enrolled, with 112 assigned to the intervention arm and 108 to the usual care (con trol) arm. Of these participants, 216 underwent a com plete baseline transthoracic echocardiogram, of whom 101 in the intervention group and 86 in the usual care group underwent repeat imaging at V4. The repeat scan was performed at an overall mean of 258 days postpar tum (259±7 days for the intervention arm and 257±8 days for the usual care arm). The demographics of those undergoing repeat imaging, as a whole and according to randomization group, are presented in Table 1. De mographics of all those randomized and the subgroup who had CMR are presented in Tables S2 and S3, re spectively, and are similar to those presented in Table 1. Approximately 40% had gestational hypertension and ~60% preeclampsia, which is consistent with the inclu sion criteria of the trial requiring on ongoing medication requirement at hospital discharge. The 2 groups were similar in obstetric and pregnancy characteristics at baseline, except a higher proportion of participants had a previous hypertensive pregnancy in the intervention arm. Diet and lifestyle characteristics of participants at the time of V4 echocardiogram and CMR were also statisti cally similar by χ2 analysis with the exception of a higher proportion breastfeeding at time of V4 in the intervention arm (P=0.04) (Table S4). Antihypertensive Treatment Antihypertensive prescription by classes was similar in each group (enalapril 57%, nifedipine 27%, and labet alol 30% for intervention versus enalapril 43%, nifedip ine 30%, and labetalol 27% for usual care). At 6 weeks, ~30% of participants in each group were still on medi cation, which reduced to ~12% by V4. Participants in the intervention group were medicated for a median of 39 days (interquartile range, 13.9-41.5 days). Amount of antihypertensives prescribed, defined by median World Health Organization-defined daily dose,25 was similar between groups at V1 and V4. However, at V2 (week 1), more antihypertensives were prescribed (World Health Organization-defined daily dose, 1.5 versus 0.7; P=0.01) in the intervention group. Echocardiography Echocardiography measures of left and right ventricular structure and function at V4, adjusted for baseline mea sures at V1, are reported in Table 2 and Figure 1. Rela tive wall thickness showed a greater reduction between V1 and V4 in the intervention arm by -0.06 (95% CI, -0.07 to -0.05; P<0.001). Both septal and posterior left February 13, 2024 Circulation. 2024;149:529-541. DOI: 10.1161/CIRCULATIONAHA.123.067597 ORIGINAL RESEARCH ARTICLE Circulation. 2024;149:529-541. DOI: 10.1161/CIRCULATIONAHA.123.067597 February 13, 2024 533 Kitt et al POP-HT Cardiac Imaging Substudy Table 1. Characteristics of Participants Who Underwent Echocardiographic Imaging Parameter Intervention (n=110) Usual care (n=107) Patient characteristics Mean age, y (SD) 33.7 (5.1) 32.8 (5.0) Mean booking BMI, kg/m² (SD) 28.1 (5.1) 28.7 (7.6) Mean booking height, cm (SD) 165.5 (6.4) 164.7 (6.9) Mean booking BSA, m² (SD) 1.9 (0.2) 1.9 (0.2) Mean systolic blood pressure at first antenatal visit, mm Hg (SD) 118.5 (10.7) 117.5 (10.6) Mean diastolic blood pressure at first antenatal visit, mm Hg (SD) 72.1 (8.7) 72.5 (8.7) Prepregnancy smoking reported*, n (%) 24 (21.8) 31 (29.0) IMD quintile†, median (IQR) 2 (1, 3) 1 (1, 2) Race and ethnicity‡, n (%) Asian 10 (9.1) 8 (7.5) Hispanic or Latino 4 (3.6) 4 (3.7) Non-Hispanic Black 6 (5.5) 4 (3.7) Non-Hispanic White 90 (81.8) 88 (82.2) Pacific Islander 0 (0.0) 3 (2.8) Pregnancy characteristics Preeclampsia§, n (%) 67 (60.9) 64 (59.8) Gestational hypertension§, n (%) 43 (39.1) 43 (40.2) HELLP syndrome subset of preeclampsia§, n (%) 5 (4.5) 1 (0.9) Median duration of antenatal antihypertensive treatment, d (IQR) 4.0 (2.0, 15.8) 5.0 (1.0, 18.8) Early diagnosis of preeclampsia or gestational hypertension ≤33 wk and 6 d gestation, n (%) 24 (21.8) 23 (21.5) Median gestation at delivery, wk (IQR) 39.2 (37.0, 40.3) 39.1 (37.0, 40.6) Primiparous, No. (%) 67 (60.9) 75 (70.1) Previous hypertensive pregnancy, n (%) 30 (27.3) 10 (9.3) Assisted reproduction pregnancy, n (%) 7 (6.4) 11 (10.3) Multifetal pregnancy, n (%) 6 (5.5) 8 (7.5) Spontaneous vaginal birth (%) 42 (38.2) 33 (30.8) Assisted vaginal birth (%) 16 (14.5) 28 (26.2) Emergency cesarean section¶ (%) 47 (42.7) 40 (37.4) Elective cesarean section¶ (%) 5 (4.5) 6 (5.6) Fetal growth restriction‡#, n (%) 25 (22.7) 28 (26.2) Neonatal unit admission**, n (%) 29 (26.4) 33 (30.8) Mean birthweight, kg (SD) 3.1 (0.8) 3.1 (2.9) BMI indicates body mass index; BSA, body surface area; HELLP, hemolysis, elevated liver enzymes, and low platelets; IQR, interquartile range. *Smoking before pregnancy for a >12-month period. †IMD refers to the Index of Multiple Deprivation, a measure of socioeconomic disadvantage defined in quintiles with 1 describing the least deprived and 5 the most deprived. Data from n=213 (intervention n=109, usual care n=104). ‡In accordance with UK recommendations, self-reported ethnicity was recorded using standard descriptions derived from those used by the UK Office for National Statistics. §Classification as gestational hypertension, preeclampsia, and HELLP syndrome were based on definitions provided in the National Institute of Clinical Excellence guideline (NG 133) “Hypertension in Pregnancy; Diagnosis and Management,” definitions for which can be found in the protocol provided in the Supplemental Material. ∥DDD refers to the defined daily doses as per the World Health Organization25, described as the assumed average maintenance dose per day for a drug used for its main indication in adults. Here the total DDD includes the sum of the total of the individual DDD for each prescribed antihypertensive. ¶Category of cesarean section was defined as per National Institute of Clinical Excellence guidance on cesarean birth (NG 192). The term “elective cesarean” refers to an electively scheduled cesarean timed to suit the patient or health care provider. “Emergency cesarean” spans the categories of “no maternal or fetal compromise but needs early birth” to “immediate threat to the life of the patient or fetus.” #Intrauterine growth restriction defined as a fetus whose weight was <10th percentile for its gestational age postpartum. **A neonatal unit is a part of a hospital that provides care for babies who are born prematurely (before 37 weeks' gestation) and is used as an umbrella term here to includes the neonatal intensive care unit, high-dependency unit, and special care baby unit. Downloaded from http://ahajournals.org by on January 16, 2025 ORIGINAL RESEARCH ARTICLE February 13, 2024 Circulation. 2024;149:529-541. DOI: 10.1161/CIRCULATIONAHA.123.067597 534 Kitt et al POP-HT Cardiac Imaging Substudy ventricular wall thickness were reduced in the interven tion group by -0.18 mm (95% CI, -0.21 to -0.16 mm; P<0.001) and -0.14 mm (95% CI, -0.17 to -0.12 mm; P<0.001), respectively. Left ventricular stroke volume was 2.15 mL/m2 (95% CI, 3.01-1.00 mL/m2; P<0.001) lower in the intervention group at V4 with reductions in indexed end-diastolic (-4.74 mL/m2; 95% CI, -6.23 to -3.26; P<0.001) and end-systolic volumes (-2.69 mL/ m2; 95% CI, -3.57 to -1.81 mL/m2; P<0.001). Left ventricular remodeling was accompanied by higher left ventricular systolic function in the intervention group, as sessed by the Simpson biplane method (+1.79%; 95% CI, 0.84%-2.75%; P<0.001), and improved peak global longitudinal systolic strain (-1.19%; 95% CI, -0.65 to -1.72; P<0.001). Left ventricular diastolic function was also improved in the intervention group. Average E/E' was 0.52 (95% CI, -0.97 to -0.07; P=0.024) lower in the intervention group, which was accompanied by a sig nificant reduction in indexed left atrial volume of 4.33 mL/m2 (95% CI, -5.52 to -3.21; P<0.001). Cardiovascular Magnetic Resonance CMR scans were obtained in 174 participants at V4, of whom 93 were in the intervention group and 81 in the usual care group. Cardiac measures (reported in Table 3 Table 2. Echocardiographic Measures of Cardiac Structure and Function From Baseline to V4 Adjusted for Baseline Echocardiographic Measurements* Hemodynamics Intervention Usual care Adjusted regression coefficients* Baseline mean (SD) (n=109) V4 mean (SD) (n=101) Baseline mean (SD) (n=107) V4 mean (SD) (n=86) Difference 95% CI P value HR, bpm 79.6 (12.56) 79.3 (11.9) 78.70 (11.27) 79.1 (12) SV indexed, mL/m2 45.2 (6.33) 38.7 (4.83) 44.7 (6.70) 40.77 (6.31)-2.15 (-3.01 to -1.00) <0.001†CO, L/min‡ (IQR) 6.57 (1.30) 5.58 (1.09) 6.41 (1.26) 5.78 (1.13)-0.24 (-0.55 to 0.57) 0.111 SVR, mm Hg/min/mL-1 1.56 (0.39) 1.80 (0.38) 1.58 (0.37) 1.80 (0.39) 0.006 (-0.10, 0.11) 0.912 Left and right ventricular systolic function LVEF, % 64.90 (3.65) 65.57 (2.82) 64.33 (3.61) 63.72 (3.77) 1.79 (0.84 to 2.75) <0.001†LV GLS, % (IQR)‡§-21.50 (1.72)-22.67 (1.84)-21.49 (1.63)-21.67 (1.74)-1.19 (-0.65 to -1.72) <0.001†TAPSE, cm 2.52 (0.39) 2.26 (0.35) 2.58 (0.41) 2.30 (0.42)-0.02 (-0.13 to 0.09) 0.690 RV free wall S', cm/s 14.67 (2.40) 12.91 (2.14) 14.83 (2.48) 12.68 (1.96) 0.26 (-0.33 to 0.85) 0.383 Left ventricular diastolic function E/A ratio 1.28 (0.27) 1.31 (0.29) 1.31 (0.33) 1.30 (0.36) 0.02 (-0.06 to 0.11) 0.592 E deceleration time, s 0.16 (0.03) 0.17 (0.02) 0.16 (0.03) 0.18 (0.03)-0.01 (-0.02 to 0.001) 0.057 Average E' 12.60 (2.04) 12.33 (2.19) 12.64 (2.17) 11.79 (2.38) 0.56 (-0.03 to 1.15) 0.064 Average E/Eʹ 7.93 (1.83) 6.05 (1.38) 8.08 (2.09) 6.61 (1.86)-0.52 (-0.97 to -0.06) 0.024†Medial E/E' 9.22 (2.45) 7.05 (1.86) 9.45 (2.61) 7.96 (2.67)-0.84 (-1.47 to -0.20) 0.009†Cardiac remodeling LVIDd, cm 4.81 (0.38) 4.61 (0.32) 4.85 (0.40) 4.66 (0.36)-0.02 (-0.09 to 0.04) 0.514 PWd, cm 0.94 (0.13) 0.62 (0.11) 0.92 (0.13) 0.76 (0.09)-0.14 (-0.17 to -0.12) <0.001†SWd, cm 1.02 (0.12) 0.67 (0.10) 1.00 (0.12) 0.84 (0.09)-0.18 (-0.21 to -0.16) <0.001†RWT (ASE) 0.39 (0.06) 0.27 (0.05) 0.38 (0.06) 0.33 (0.04)-0.06 (-0.07 to -0.05) <0.001†LAVi, mL/m2 31.66 (6.39) 21.74 (3.19) 31.26 (6.19) 25.98 (5.20)-4.36 (-5.52 to -3.21) <0.001†EDVi, mL/m2 69.92 (10.04) 59.03 (7.18) 69.74 (10.54) 63.68 (8.77)-4.74 (-6.23 to -3.26) <0.001†ESVi, mL/m2 24.49 (4.93) 20.31 (3.07) 25.16 (4.99) 23.26 (4.03)-2.69 (-3.57 to -1.81) <0.001†Parametric: mean (SD). ASE indicates American Society of Echocardiography model for RWT assessment (ie, 2×PWd/LVIDd)21; CO, cardiac output; E/A, ratio of early to late mitral inflow velocity; EDVi, end diastolic volume indexed to body surface area; E/E', ratio of early mitral inflow velocity and early mitral annular diastolic velocity; ESVi, end systolic volume indexed to body surface area; GLS, global longitudinal strain; HR, heart rate; IQR, interquartile range;LAVi, left atrial volume indexed to body surface area; LV, left ventricular; LVEF, LV ejection fraction; LVIDd, LV internal diameter in diastole; PWd, posterior wall diameter in diastole; RV, right ventricle; RWT, relative wall thickness; SV, stroke volume; SVR, systemic vascular resistance calculated as mean arterial pressure/CO; SWd, septal wall diameter in diastole; TAPSE, tricuspid annular plane systolic excursion; and V, visit. *All regressions were performed on measurements at 9 months with the baseline measurement included in the model. †95% CI does not cross 0. ‡Nonparametric: median (IQR). The nonparametric GLS and CO were analyzed by Mann-Whitney U test. §Baseline intervention n=98, usual care n=86, V4 intervention n=96, usual care = 77 (numbers for GLS less because the image quality required for strain led to more cases being excluded). Downloaded from http://ahajournals.org by on January 16, 2025 ORIGINAL RESEARCH ARTICLE Circulation. 2024;149:529-541. DOI: 10.1161/CIRCULATIONAHA.123.067597 February 13, 2024 535 Kitt et al POP-HT Cardiac Imaging Substudy and Figure 2) confirmed the differences identified with echocardiography. Left ventricular mass, both absolute and indexed to body size, was lower in the intervention group by 6.37 g/m2 (95% CI, -7.99 to -4.74; P<0.001). Left ventricular wall thickness was a mean -1.26 mm lower in the intervention arm (95% CI, -1.49 to -1.06; P<0.001). Left ventricular end diastolic and systolic vol umes were also lower by 3.87 mL/m2 (95% CI, -6.77 to -0.98; P=0.009) and 3.25 mL/m2 (95% CI, -4.87 to -1.63; P<0.001), respectively. These changes were con sistent with greater concentric remodeling, demonstrat ed by a lower left ventricular mass to left ventricular end diastolic volume in the intervention arm of -0.09 g/mL/ m2 (95% CI, -0.11 to -0.07; P<0.001). Left ventricular systolic function assessed as ejection fraction was high er in the intervention group by 2.61% (95% CI, 1.31 to 3.92; P<0.001). In addition, CMR identified an increased right ventricular systolic function by 2.76% (95% CI, 1.44 to 4.09; P<0.001). Addit

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