Kwon, Deborah

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

This retrospective propensity-matched cohort study assessed the association between sodium-glucose co-transporter-2 inhibitor (SGLT2i) use and cardiovascular outcomes in patients with acute myocardial infarction (AMI) without a history of heart failure. Using the TriNetX U.S. Collaborative Network, we identified 1440 matched patients (720 SGLT2i+ vs 720 SGLT2i−) with preserved ejection fraction and no prior heart failure. Nearly 90% of patients had diabetes. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of MI, stroke, heart failure, and all-cause mortality. At 1 year, MACE occurred in 17.4% of SGLT2i+ versus 22.0% of SGLT2i− patients (odds ratio [OR] 0.746, 95% CI 0.574-0.969; P = .028), and all-cause mortality occurred in 3.1% versus 7.6%, respectively (OR 0.389, 95% CI 0.234-0.645; P < .001). SGLT2i use was also associated with lower risks of major bleeding. Findings were consistent over long-term follow-up. While the observed associations suggest potential cardioprotective effects of SGLT2i post-MI in patients without heart failure, residual confounding cannot be excluded. The observed reduction in bleeding events is novel and warrants further investigation in prospective studies.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated benefits in heart failure with preserved ejection fraction (HFpEF), but their impact following acute myocardial infarction (AMI) is less well understood. Using the TriNetX Research Network (TriNetX) multi-center registry (2014–2022), we identified patients with heart failure with preserved ejection fraction (HFpEF)—defined as left ventricular ejection fraction (LVEF) >50% and New York Heart Association (NYHA) class II–IV—not previously treated with sodium-glucose co-transporter 2 inhibitors (SGLT2i) who experienced an acute myocardial infarction (AMI). Patients who initiated SGLT2i within 1-year post-AMI were compared with those who did not. Propensity score matching was used to balance cohorts ( n = 20,423 each; mean age 68.3 ± 11.0 years; 54.5% female) for demographics, comorbidities, and treatment variables. The primary outcome was a composite of major adverse cardiovascular events (MACE), including all-cause mortality, recurrent AMI, acute heart failure, and stroke. Secondary outcomes included cardiac arrest and major bleeding. SGLT2i use was associated with lower rates of MACE (3.7% vs 6.1%; P = .0005), all-cause mortality (0.9% vs 5.6%; P < .0001), and other adverse events at both 30 days and 1 year. In this large, propensity-matched cohort, SGLT2i use post-AMI in HFpEF patients was associated with favorable cardiovascular outcomes. Further studies are needed to confirm these associations.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

BACKGROUND: Defining qualitative grades of echocardiographic metrics of right heart chamber size and function is critical for screening, clinical assessment, and measurement of therapeutic response in individuals with pulmonary vascular disease (PVD). In a population enriched for PVD, we sought to establish qualitative grades and prognostic value of right heart chamber size and function. METHODS: We investigated 1053 study participants in PVDOMICS (Redefining Pulmonary Hypertension Through the PVD Phenomics Program) to determine clinical and echocardiographic differences associated with increasing pulmonary vascular resistance severity. Right heart chamber size and function were qualitatively assessed using a percentile-based approach above the median values to create a clinical grading system for right heart adaptation. The relationship between echocardiographic categories and all-cause mortality was examined using survival analyses adjusted for potential confounders. RESULTS: A stepwise increase in adverse right heart remodeling was observed with a concomitant decrease in functional parameters by pulmonary vascular resistance strata ( P <0.001 for all). Mild, moderate, and severe categories of right heart chamber size and dysfunction were defined using a percentile-based approach across the spectrum of PVD. During a median follow-up of 2.07 years (interquartile range, 1.23–3.01 years), 130 participants died (11.4%). Progressive pulmonary vascular resistance increase and 2DE evidence of right heart dysfunction inclusive of fractional area change, and right ventricular global longitudinal strain were independently associated with increased all-cause mortality risk in multivariate analysis adjusted for age, disease duration, and male sex. CONCLUSIONS: In this well-characterized sample of adults with diverse etiologies and varying PVD severity, we define categories of abnormal right heart chamber size and function. Further, we demonstrate a stepwise relationship between these categories of abnormal morphology and function and all-cause mortality. Defining grades of right ventricular dysfunction in individuals with known PVD has important clinical implications for monitoring disease progression and response to therapies.

Abstract Aims In the Phase 3 trial, RHAPSODY, rilonacept effectively resolved active pericarditis recurrences, and long-term treatment led to sustained pericarditis recurrence risk reduction. Prior analysis suggested association between higher late gadolinium enhancement (LGE) at baseline and more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. This subgroup analysis assessed the utility of longitudinal serial cardiac magnetic resonance (CMR) imaging for tracking clinical improvement and predicting post-treatment cessation outcomes to help guide clinical decision-making. Methods and results At an 18-month decision milestone (18MDM) in the RHAPSODY long-term extension, investigators decided if patients would continue rilonacept, suspend rilonacept for off-treatment observation, or discontinue the study. Pericardial thickness, pericardial oedema (T2-short tau inversion recovery, T2-STIR), and LGE were determined at baseline and 18MDM by an imaging core lab blinded to clinical data, and pericarditis recurrence was investigator-assessed. CMR results in patients with data at both baseline and 18MDM (n = 13) showed that pericardial thickness, T2-STIR, and LGE were reduced during rilonacept treatment. Among patients with CMR data who suspended rilonacept at the 18MDM (n = 7), five (71%) had a pericarditis recurrence within 1–4 months of rilonacept suspension, despite all having had none/trace LGE (n = 7) and negative T2-STIR (n = 7) at the 18MDM and two having received prophylactic colchicine. Conclusion Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial oedema, and resolution of LGE. However, none/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup.

Introduction: The right ventricle [RV] adapts to pulmonary hypertension [PH] by increasing contractility to maintain RV-PA coupling. With increased afterload, RV contractility cannot compensate, resulting in RV failure. TAPSE/RVSP ratio is a non-invasive measure of RV-PA coupling. We aim to assess TAPSE/RVSP ratio for predicting PH severity and survival across a spectrum of PH in the PVDOMICS cohort. Methods: PVDOMICS subjects from the 5 World Symposium PH groups and comparators were evaluated. TAPSE/RVSP ratio, in mm/mmHg, was derived for each group. PH subjects were stratified by TAPSE/RVSP ratio into low < 0.19, intermediate ≥ 0.19 to < 0.32, and high ratio > 0.32. The relationship between the ratio and RHC parameters (mean PA pressure [mPAP] and pulmonary vascular resistance [PVR]), and between-group differences were evaluated by one-way ANOVA. Kaplan-Meier curves and log-rank tests were used to characterize and compare survival between groups. Results: Data were available for 514 PH subjects (58 ± 15 yrs, 64% female) and 179 comparators (61 ± 13 yrs, 59% female). Mean TAPSE/RVSP ratio was 0.35 ± 0.18 in PH vs 0.63 ± 0.26 in comparators (p < 0.001). Mean TAPSE/RVSP across the PH groups 1-5 were similar, 0.33 ± 0.19, 0.33 ± 0.16, 0.37 ± 0.15, 0.41 ± 0.21 and 0.43 ± 0.29 (p=NS). Within PH subjects, 99 (19.2%) had low, 173 (33.7%) had intermediate and 242 (47.1%) had high ratio. Those with low ratio had higher mPAP (53.6 ± 11.8 mmHg), compared to intermediate (44.6 ± 11.7 mmHg) and high ratio (34.1 ± 10.2 mmHg) [p < 0.001]. Those with low ratio had higher PVR (10.1 ± 5.1 WU), compared to intermediate (6.8 ± 4.1 WU) and high ratio (4.1 ± 2.1 WU) [p < 0.001]. Survival was significantly higher for those with high TAPSE/RVSP ratio compared to those with low ratio (p < 0.001) [Figure]. Discussion: TAPSE/RVSP ratio correlates well with invasive markers to predict PH severity. This useful measure of RV-PA coupling also enables stratification for outcome, with ratio > 0.32 having the best survival rates.

Introduction: Assessment of right ventricular (RV) size and function by echo is challenging due to complex RV anatomy and requires integration of multiple measurements. We sought to compare accuracy of echo measures of RV size and function with cardiac MRI (CMR) in pulmonary hypertension (PH). Methods: We included patients with PH from the PVDOMICS Study who underwent both echo and CMR. Echo measures of RV size (basal dimension, area, 3D volume) and function (fractional area change [FAC], 3D RV ejection fraction [EF], RV global longitudinal strain [GLS], S’, TAPSE, Tei index) were compared to CMR derived RV volumes and RVEF. Agreement was assessed using Bland-Altman (BA) plots and Lin’s concordance correlation coefficients (ρ c ). Predictive trends were evaluated using linear regression. Results: The cohort included 446 subjects (58 ± 15 yrs, 36% male). Echo measures of RV size showed poor agreement with CMR, but substantial linear associations, when comparing CMR end diastolic volume (EDV) with: echo basal dimension (ρ c = 0.002; β = 60, R 2 = 0.47), end-diastolic area (ρ c = 0.04, β = 6.4, R 2 = 0.64), and 3D EDV (bias = 106, limits of agreement [LOA]: -14.1 to 225); and also when comparing CMR end-systolic volume (ESV) with: end-systolic area (ρ c = 0.08; β = 6.8, R 2 = 0.74) and 3D ESV (bias = 67.3, LOA: -31.8 to 166). Select echo measures of RV function demonstrated better agreement with CMR RVEF including: 3D RVEF (bias -0.23, LOA -17.9 to 17.5) and FAC (ρ c = 0.55; β = 0.89, R 2 = 0.50). Others exhibited modest or poor agreement including: RV GLS (ρ c = 0.11; β = -1.5, R 2 = 0.40), along with S’, TAPSE, and Tei index (ρ c ≤ 0.02; R 2 ≤ 0.19 for all). [Figure] Discussion: In this largest comparison of echo vs CMR measures of RV assessment in PH, echo measures of RV size agreed poorly with CMR, especially at larger RV volumes. RV functional assessment was best with echo 3D RVEF and FAC, which should be preferentially used for echo RV functional assessment. Consider CMR for more accurate volume assessment of RV size.

Introduction: Rilonacept treatment in RHAPSODY resolved active pericarditis recurrences, and long-term treatment led to sustained risk reduction. Prior analysis linked greater baseline Late Gadolinium Enhancement (LGE), with more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. Serial cardiac magnetic resonance (CMR) imaging (T2-STIR, LGE) enabled longitudinal assessment for tracking clinical improvement, guiding decision-making, and predicting patient outcomes after treatment cessation. Methods: At the long-term extension (LTE) 18-month decision milestone (18MDM), investigators chose, based on clinical status, to continue rilonacept, suspend rilonacept/observe, or discontinue the LTE. An imaging core lab blinded to clinical data measured pericardial thickness and graded pericardial edema (T2-STIR) and LGE at baseline and 18MDM. Pericarditis recurrence was assessed clinically following rilonacept suspension. Results: Baseline and 18MDM CMRs were available for 13 patients. Reductions in pericardial thickness, T2-STIR, and LGE from baseline to 18MDM while on treatment are provided in Figure . CMRs were obtained in 7/8 patients suspending rilonacept at 18MDM: LGE was none/trace, and T2-STIR was negative; yet, 5/7 (71%) had pericarditis recurrence within 1-4 months of rilonacept suspension despite prophylactic colchicine (n=2). Conclusions: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema on T2-STIR, and resolution of LGE. Negative/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup. Larger prospective studies examining CMR parameters in guiding RP treatment duration decisions and informing associated clinical outcomes are warranted.

Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. Methods: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO 2peak )>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance. Results: A drop in RV end-diastolic volume of −15 mL best defined RVFnRec (area under the curve, 0.87; P =0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P =0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64–0.88]; P =0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise. Conclusions: RVFnRec defined by RV end-diastolic volume therapeutic decrease of −15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise.