Integrated Diagnostics Characterization of Right Ventricular Diastolic Flow Dynamics in Pulmonary Arterial Hypertension

The adaptive changes that result from chronic pressure overload in pulmonary arterial
hypertension (PAH) lead to myocardial hypertrophy, stiffening, and right ventricular
diastolic dysfunction (RVDD). A growing body of evidence has identified RVDD as an
important prognostic indicator for PAH.1 Diagnosis of RVDD relies upon 1) elevated brain
natriuretic peptide (BNP), which correctly identifies RVDD in the PAH population but remains
a nonspecific marker, and 2) echocardiography, as defined by reduced early (E') tricuspid
annular velocity, elevated ratio of early filling tricuspid inflow peak velocity to E'
(E/E'), and prolonged relaxation time (RT). 2 However, the right ventricle's unusual anatomy
and susceptibility to altered loading conditions have raised questions about the ability of
echo indices to accurately reflect complex diastolic mechanics. The development of a robust
non-invasive application for RV diastolic assessment may improve the understanding,
diagnosis, and management of RVDD and therefore PAH.

Similar to the left ventricle, rheological analysis of right ventricular inflow in canine
models has identified the formation of diastolic vortex rings.3 Vortex rings develop from
high velocity diastolic jet emanating from the valvular annulus interacting with stationary
blood in the ventricle. Vortex ring formation time has successfully identified left
ventricular diastolic dysfunction.4 Numerous additional vortex properties exist, including
depth, transverse position, length, width, and sphericity index, that offer novel and robust
diastolic flow characterization with the potential incremental diagnostic value to existing
echo parameters. Vortex formation and analysis in RVDD has yet to be studied.

Vortex measurement can be performed using dimensional (4D) (time-resolved three-dimensional)
cardiac MRI (CMR). 4D CMR captures the complex multidirectional nature of flow through
volumetric rendering of fluid vectors and velocity using blood flow streamlines and particle
traces. In contrast to echocardiography, 4D CMR is not limited by poor acoustic windows
commonly seen in patients with respiratory disease and PAH, making it an ideal noninvasive
modality for vortex characterization.

The biological adaptations resulting from chronic pressure overload in PAH might be
correlated to the blood levels of different categories of biomarkers. They might play a role
in the screening, diagnosis, monitoring or prognosis of patients with PAH and RVDD. Special
mention can be made to the natriuretic peptides (BNP, NT-proBNP) based on their clinical
value as hemodynamic markers in congestive heart failure. Cardiac markers of necrosis
(asTroponin-I, and particularly the high sensitivity assays) might identify even minimal
areas with such myocardial cell damage. The biological evaluation of cardiac fibrosis, might
be assessed by markers of fibrosis, as Hyaluronic acid (HA), Procollagen III amino terminal
peptide (PIIINP) and Tissue inhibitor of metalloproteinase 1 (TIMP-1). The potential role of
the inflammatory component, can be evaluated with MPO (myeloperoxidase, pro-inflammatory
enzyme), IL-6 (pro-inflammatory cytokine), C-RP (C-reactive protein)

The present study aims to:

1. Characterize and quantify RV vortex flow in normal subjects and PAH subjects with RVDD

2. Assess the feasibility of 4D CMR right ventricular diastolic vortex analysis for
diagnosis of RVDD Hypothesis: 4D CMR vortex analysis accurately identifies RVDD, and
the information provided by biomarkers helps by adding diagnostic information.

Inclusion Criteria:

- previous diagnosis of PH by right heart catheterization

- RV diastolic dysfunction by echo

- normal RV systolic function

- age 18-75 years old

- no contraindication to MRI

Exclusion Criteria:

- absence of PH

- absence of RV diastolic dysfunction by echo

- RV systolic dysfunction

- age < 18 years

- contraindication to MRI

- pregnancy