Pulmonary 4D-flow MRI imaging in landrace pigs under rest and stress.

4D-flow MRI is a promising technique for assessing vessel hemodynamics. However, its utilization is currently limited by the lack of reference values, particularly for pulmonary vessels. In this work, we have analysed flow and velocity in the pulmonary trunk (PT), left and right pulmonary arteries (LPA and RPA, respectively) in Landrace pigs at both rest and stress through the software MEVISFlow. Nine healthy Landrace pigs were acutely instrumented closed-chest and transported to the CMR facility for evaluation. After rest measurements, dobutamine was administered to achieve a 25% increase in heart rate compared to rest. 4D-flow MRI images have been analysed through MEVISFlow by two independent observers. Inter- and intra-observer reproducibility was quantified using intraclass correlation coefficient. A significant difference between rest and stress regarding flow and velocity in all the pulmonary vessels was observed. Mean flow increased 55% in PT, 75% in LPA and 40% in RPA. Mean peak velocity increased 55% in PT, 75% in LPA and 66% in RPA. A good-to-excellent reproducibility was observed in rest and stress for flow measurements in all three arteries. An excellent reproducibility for velocity was found in PT at rest and stress, a good one for LPA and RPA at rest, while poor reproducibility was found at stress. The current study showed that pulmonary flow and velocity assessed through 4D-flow MRI follow the physiological alterations during cardiac cycle and after stress induced by dobutamine. A clinical translation to assess pulmonary diseases with 4D-flow MRI under stress conditions needs investigation.

Cardiovascular magnetic resonance-derived left ventricular mechanics-strain, cardiac power and end-systolic elastance under various inotropic states in swine.

BACKGROUND: Cardiovascular magnetic resonance (CMR) strain imaging is an established technique to quantify myocardial deformation. However, to what extent left ventricular (LV) systolic strain, and therefore LV mechanics, reflects classical hemodynamic parameters under various inotropic states is still not completely clear. Therefore, the aim of this study was to investigate the correlation of LV global strain parameters measured via CMR feature tracking (CMR-FT, based on conventional cine balanced steady state free precession (bSSFP) images) with hemodynamic parameters such as cardiac index (CI), cardiac power output (CPO) and end-systolic elastance (Ees) under various inotropic states. METHODS: Ten anaesthetized, healthy Landrace swine were acutely instrumented closed-chest and transported to the CMR facility for measurements. After baseline measurements, two steps were performed: (1) dobutamine-stress (Dobutamine) and (2) verapamil-induced cardiovascular depression (Verapamil). During each protocol, CMR images were acquired in the short axisand apical 2Ch, 3Ch and 4Ch views. MEDIS software was utilized to analyze global longitudinal (GLS), global circumferential (GCS), and global radial strain (GRS). RESULTS: Dobutamine significantly increased heart rate, CI, CPO and Ees, while Verapamil decreased them. Absolute values of GLS, GCS and GRS accordingly increased during Dobutamine infusion, while GLS and GCS decreased during Verapamil. Linear regression analysis showed a moderate correlation between GLS, GCS and LV hemodynamic parameters, while GRS correlated poorly. Indexing global strain parameters for indirect measures of afterload, such as mean aortic pressure or wall stress, significantly improved these correlations, with GLS indexed for wall stress reflecting LV contractility as the clinically widespread LV ejection fraction. CONCLUSION: GLS and GCS correlate accordingly with LV hemodynamics under various inotropic states in swine. Indexing strain parameters for indirect measures of afterload substantially improves this correlation, with GLS being as good as LV ejection fraction in reflecting LV contractility. CMR-FT-strain imaging may be a quick and promising tool to characterize LV hemodynamics in patients with varying degrees of LV dysfunction.

Estimation of total collagen volume: a T1 mapping versus histological comparison study in healthy Landrace pigs.

Right ventricular biopsy represents the gold standard for the assessment of myocardial fibrosis and collagen content. This invasive technique, however, is accompanied by perioperative complications and poor reproducibility. Extracellular volume (ECV) measured through cardiovascular magnetic resonance (CMR) has emerged as a valid surrogate method to assess fibrosis non-invasively. Nonetheless, ECV provides an overestimation of collagen concentration since it also considers interstitial space. Our study aims to investigate the feasibility of estimating total collagen volume (TCV) through CMR by comparing it with the TCV measured at histology. Seven healthy Landrace pigs were acutely instrumented closed-chest and transported to the MRI facility for measurements. For each protocol, CMR imaging at 3T was acquired. MEDIS software was used to analyze T1 mapping and ECV for both the left ventricular myocardium (LVmyo) and left ventricular septum (LVseptum). ECV was then used to estimate TCVCMR at LVmyo and LVseptum following previously published formulas. Tissues were prepared following an established protocol and stained with picrosirius red to analyze the TCVhisto in LVmyo and LVseptum. TCV measured at LVmyo and LVseptum with both histology (8 ± 5 ml and 7 ± 3 ml, respectively) and T1-Mapping (9 ± 5 ml and 8 ± 6 ml, respectively) did not show any regional differences. TCVhisto and TCVCMR showed a good level of data agreement by Bland-Altman analysis. Estimation of TCV through CMR may be a promising way to non-invasively assess myocardial collagen content and may be useful to track disease progression or treatment response.

Cardiovascular magnetic resonance feature tracking in pigs: a reproducibility and sample size calculation study.

Cardiovascular magnetic resonance feature tracking (CMR-FT) is a novel technique for non-invasive assessment of myocardial motion and deformation. Although CMR-FT is standardized in humans, literature on comparative analysis from animal models is scarce. In this study, we measured the reproducibility of global strain under various inotropic states and the sample size needed to test its relative changes in pigs. Ten anesthetized healthy Landrace pigs were investigated. After baseline (BL), two further steps were performed: (I) dobutamine-induced hyper-contractility (Dob) and (II) verapamil-induced hypocontractility (Ver). Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS) were assessed. This study shows a good to excellent inter- and intra-observer reproducibility of CMR-FT in pigs under various inotropic states. The highest inter-observer reproducibility was observed for GLS at both BL (ICC 0.88) and Ver (ICC 0.79). According to the sample size calculation for GLS, a small number of animals could be used for future trials.

Is enhancing cGMP-PKG signalling a promising therapeutic target for heart failure with preserved ejection fraction?

Heart failure with preserved ejection fraction, i.e. HFpEF, is highly prevalent in ageing populations, accounting for more than 50 % of all cases of heart failure in Western societies, and is closely associated with comorbidities such as obesity, diabetes and arterial hypertension. However, all large multicentre trials of potential HFpEF treatments conducted to date have failed to produce positive outcomes. These disappointing results suggest that a 'one size fits all' strategy may be ill-suited to HFpEF and support the use of tailored, personalised therapeutic approaches with specific treatments designed for specific comorbidity-related HFpEF phenotypes. The accumulation of a multitude of cardiovascular comorbidities over time leads to increased systemic inflammation, oxidative stress and coronary microvascular endothelial inflammation, eventually resulting in degradation of cyclic guanosine monophosphate (cGMP) via multiple pathways, thereby reducing protein kinase G (PKG) activity. The importance of cGMP-PKG pathway modulation is supported by growing evidence that suggests that this pathway may be a promising therapeutic target, evidence that is mainly based on its role in the phosphorylation of the giant cytoskeletal protein titin. This review will focus on the preclinical and early clinical evidence in the field of cGMP-enhancing therapies and PKG activation.

Mild hypothermia induces incomplete left ventricular relaxation despite spontaneous bradycardia in pigs.

AIM: Mild hypothermia (MH) decreases left ventricular (LV) end-diastolic capacitance. We sought to clarify whether this results from incomplete relaxation. METHODS: Ten anaesthetized pigs were cooled from normothermia (NT, 38 °C) to MH (33 °C). LV end-diastolic pressure (LVPed), volume (LVVed) and pressure-volume relationships (EDPVRs) were determined during stepwise right atrial pacing. LV capacitance (i.e. LVVed at LVPed of 10 mmHg, LV VPed10) was derived from the EDPVR. Pacing-induced changes of diastolic indices (LVPed, LVVed and LV VPed10) were analysed as a function of (i) heart rate and (ii) the ratio between diastolic time interval (t-dia) and LV isovolumic relaxation constant τ, which was calculated using a logistic fit (τL ) and monoexponential fit with zero asymptote (τZ ) and nonzero asymptote (τNZ ). RESULTS: Mild hypothermia decreased heart rate (85 ± 4 to 68 ± 3 bpm), increased τL (22 ± 1 to 57 ± 4 ms), τZ (26 ± 2 to 56 ± 5 ms) and τNZ (41 ± 1 to 96 ± 5 ms), decreased t-dia/τ ratios, and shifted the EDPVR leftwards compared to NT (all P < 0.05). During NT, pacing at ≥140 bpm shifted the EDPVR progressively leftwards. During MH, relationships between diastolic indices and heart rate were shifted towards lower heart rates compared to NT. However, relationships between diastolic indices and t-dia/τ during NT and MH were superimposable. CONCLUSION: We conclude that the loss of LV end-diastolic capacitance during MH can be explained at least in part by slowed LV relaxation. MH thereby is an example of incomplete LV relaxation at a spontaneous low heart rate. Caution may be advised, when heart rate is increased in patients treated with MH.