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. 2023 Dec 5;12(23):e031746.
doi: 10.1161/JAHA.123.031746. Epub 2023 Nov 28.

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension

Neil J Kelly  1   2   3 , David Newhouse  1 , Himal Chapagain  4 , Ashish Patel  2 , Yicheng Tang  1 , Ato Howard  5 , Anna Kirillova  1 , Hee-Jung J Kim  1 , Haris Rahman  1 , Wadih El Khoury  1   2 , Seyed Mehdi Nouraie  5 , Gavin Hickey  2   3 , Leyla Elif Sade  2 , Sandeep Jain  2 , Stephen Y Chan  1   2
Affiliations

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension

Neil J Kelly et al. J Am Heart Assoc. .

Abstract

Background: Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods.

Methods and results: Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance.

Conclusions: Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.

Keywords: atrial fibrillation; left atrium; pulmonary hypertension; pulmonary vascular resistance.

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Figures

Figure 1
Figure 1. CpcPH is associated with increased mortality rate compared with IpcPH.
A, Patient selection flow diagram. B, Kaplan–Meier curve of 5‐year mortality rate in IpcPH and CpcPH. # Deaths indicates cumulative deaths at each year of follow‐up from the time of RHC. C, Cox proportional hazards for 5‐year mortality rate from the time of RHC. BMI indicates body mass index; CpcPH, combined pre‐ and postcapillary pulmonary hypertension; CTEPH, chronic thromboembolic pulmonary hypertension; eGFR, estimated glomerular filtration rate; FPVR, pulmonary vascular resistance by indirect Fick method; HR, hazard ratio; IpcPH, isolated postcapillary pulmonary hypertension; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PH, pulmonary hypertension; RHC, right heart catheterization; and TPVR, pulmonary vascular resistance by thermodilution method.
Figure 2
Figure 2. Omics‐level associations of vitamin K antagonist use and atrial fibrillation with CpcPH.
Volcano plot of (A) ATC class associations and (B) phecodes with CpcPH shows a significant omics‐level associations of Vitamin K antagonist use and atrial fibrillation, respectively, with CpcPH in an unadjusted logistic regression model. ATC indicates Anatomic Therapeutic Class; CpcPH, combined pre‐ and postcapillary pulmonary hypertension; IpcPH, isolated postcapillary pulmonary hypertension; and OR, odds ratio.
Figure 3
Figure 3. Left atrial assessment in CpcPH.
Left atrial enlargement was more common in CpcPH by both (A) semiquantitative and (B) quantitative measures, regardless of the presence of AF. P values were calculated by 2‐way ANOVA with Sidak's multiple comparisons test. (C) Mediation analysis was performed to quantify the mediation of the AF and CpcPH relationship by LADi. (D) LADi exerted a significant average causal mediation effect (ACME) on the AF‐CpcPH relationship. ADE indicates average direct effect; AF, atrial fibrillation; CpcPH, combined pre‐ and postcapillary pulmonary hypertension; LADi, left atrial diameter indexed to body surface area.
Figure 4
Figure 4. Correlation of longitudinal changes in left atrial size and pulmonary vascular resistance.
A, Longitudinal patient population flow diagram. Longitudinal correlation of LADi with (B) TPVR and (C) FPVR. CTEPH indicates chronic thromboembolic pulmonary hypertension; FPVR, pulmonary vascular resistance by indirect Fick method; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; r: Pearson correlation coefficient; RHC, right heart catheterization; and TPVR, pulmonary vascular resistance by thermodilution method. P values are calculated from Pearson correlation (P) or time‐adjusted linear regression (Adj. P).
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