Early-stage heart failure with preserved ejection fraction in the pig: a cardiovascular magnetic resonance study

Abstract

BackgroundThe hypertensive deoxy-corticosterone acetate (DOCA)-salt-treated pig (hereafter, DOCA pig) was recently introduced as large animal model for early-stage heart failure with preserved ejection fraction (HFpEF). The aim of the present study was to evaluate cardiovascular magnetic resonance (CMR) of DOCA pigs and weight-matched control pigs to characterize ventricular, atrial and myocardial structure and function of this phenotype model.MethodsFive anesthetized DOCA and seven control pigs underwent 3 T CMR at rest and during dobutamine stress. Left ventricular/atrial (LV/LA) function and myocardial mass (LVMM), strains and torsion were evaluated from (tagged) cine imaging. 4D phase-contrast measurements were used to assess blood flow and peak velocities, including transmitral early-diastolic (E) and myocardial tissue (E’) velocities and coronary sinus blood flow. Myocardial perfusion reserve was estimated from stress-to-rest time-averaged coronary sinus flow. Global native myocardial T1 times were derived from prototype modified Look-Locker inversion-recovery (MOLLI) short-axis T1 maps. After in-vivo measurements, transmural biopsies were collected for stereological evaluation including the volume fractions of interstitium (VV(int/LV)) and collagen (VV(coll/LV)). Rest, stress, and stress-to-rest differences of cardiac and myocardial parameters in DOCA and control animals were compared by t-test.ResultsIn DOCA pigs LVMM (p < 0.001) and LV wall-thickness (end-systole/end-diastole, p = 0.003/p = 0.007) were elevated. During stress, increase of LV ejection-fraction and decrease of end-systolic volume accounted for normal contractility reserves in DOCA and control pigs. Rest-to-stress differences of cardiac index (p = 0.040) and end-diastolic volume (p = 0.042) were documented. Maximal (p = 0.042) and minimal (p = 0.012) LA volumes in DOCA pigs were elevated at rest; total LA ejection-fraction decreased during stress (p = 0.006). E’ was lower in DOCA pigs, corresponding to higher E/E’ at rest (p = 0.013) and stress (p = 0.026). Myocardial perfusion reserve was reduced in DOCA pigs (p = 0.031). T1-times and VV(int/LV) did not differ between groups, whereas VV(coll/LV) levels were higher in DOCA pigs (p = 0.044).ConclusionsLA enlargement, E’ and E/E’ were the markers that showed the most pronounced differences between DOCA and control pigs at rest. Inadequate increase of myocardial perfusion reserve during stress might represent a metrics for early-stage HFpEF. Myocardial T1 mapping could not detect elevated levels of myocardial collagen in this model.Trial registrationThe study was approved by the local Bioethics Committee of Vienna, Austria (BMWF-66.010/0091-II/3b/2013).

A porcine model of heart failure with preserved ejection fraction: magnetic resonance imaging and metabolic energetics

“…DOCA‐salt pigs demonstrated significant increases in LV mass and wall thickness and also left atrial volumes at rest compared with control pigs . During dobutamine stress, changes in LVEF and LVESV demonstrated normal contractile reserve but there were differences in cardiac index and LVEDV compared to normal pigs indicating inadequate increase in myocardial perfusion reserve during dobutamine stress perhaps indicating early‐stage HFpEF but there was no change in T1 mapping of fibrosis . When DOCA‐induced hypertension is combined with high salt, fat, cholesterol, and sugar diet, pigs develop concentric LVH and left atrial dilation with no change in LVEF or HF symptoms at rest .…”

“…The traditional rodent deoxy‐corticosterone acetate (DOCA)–salt model has been upscaled to pigs, with variable results . DOCA‐salt pigs demonstrated significant increases in LV mass and wall thickness and also left atrial volumes at rest compared with control pigs . During dobutamine stress, changes in LVEF and LVESV demonstrated normal contractile reserve but there were differences in cardiac index and LVEDV compared to normal pigs indicating inadequate increase in myocardial perfusion reserve during dobutamine stress perhaps indicating early‐stage HFpEF but there was no change in T1 mapping of fibrosis .…”

Review of Journal of Cardiovascular Magnetic Resonance (JCMR) 2015-2016 and transition of the JCMR office to Boston

“…A hypertensive deoxy-corticosterone acetate salt-treated pig model of early stage heart failure with preserved ejection fraction (HFpEF). Reiter and colleagues [ 189 ] studied 5 HFpEF swine and 6 controls with dobutamine stress at 3 T. They found the HFpEF swine had increased left ventricular (LV) mass and wall thickness along with increase left atrial volume. Myocardial perfusion reserve was decreased in the HFpEF swine.…”

A transmural gradient of myocardial remodeling in early‐stage heart failure with preserved ejection fraction in the pig

“…However, due to the complexity of HFpEF, its chronic character and the anatomy of the heart, large animal models are superior to rodent models in terms of representativeness of the human disease (Conceição et al ). Recently, a pig model of arterial hypertension – based on the implantation of deoxy‐corticosterone acetate (DOCA) pellets in combination with a high‐salt, high‐sugar and high‐fat diet (Schwarzl et al ) or a high‐salt and high‐sugar diet (Reiter et al ) was introduced which mimics several pathophysiological features of HFpEF, including concentric left ventricular hypertrophy, increased left ventricular end‐diastolic pressure, a shift towards the stiffer titin isoform N2B and uncoupled NOS activity (Schwarzl et al ; Reiter et al ).…”

“…Since this animal model represents an early disease stage, the present study was carried out on material obtained during the study of Reiter et al () to characterize the morphological alterations more precisely, and at an early stage of disease development. Specifically, the hypothesis was tested that myocardial remodeling in HFpEF differs between the different layers of the left ventricular wall.…”