Heart failure can be roughly categorized into heart failure with preserved ejection fraction [HFpEF with left ventricular ejection fraction (LVEF) ≥ 50%], heart failure with midrange ejection fraction (HFmrEF with LVEF between 40 and 49%), and heart failure with reduced ejection fraction (HFrEF with LVEF < 40%). Early diagnosis is critical for effective treatment and may differ for each category depending on the underlying etiology [
1‐
3]. Because clear clinical signs or symptoms are often absent in the early phases of the disease, a straightforward diagnosis of HFpEF remains difficult and requires objective evidence of cardiac structural and functional alterations [
2,
4]. The heterogeneous pathophysiology of HFpEF includes impaired diastolic filling, stiffening of the myocardium, atrial dysfunction, and pulmonary hypertension [
5], which can be related to renal disease[
5,
6], type 2 diabetes mellitus [
5,
7] and hypertension [
5,
8].
Cardiac magnetic resonance (CMR) imaging has emerged as a versatile translational imaging modality for the characterization of HFpEF, offering a variety of cardiac structural and functional outcome measures with comparable protocols for humans and small animals [
12]. Recent developments in CMR acquisition and post-processing methods such as feature tracking and advanced flow modeling have even created new opportunities to quantitatively assess cardiac function in HFpEF beyond LVEF. Specifically, clinical studies have already shown feature tracking to have good reproducibility for the assessment of cardiac strain [
13‐
15], which has shown diagnostic and prognostic potential in HFpEF patients [
16‐
18]. Lower absolute values for global longitudinal strain (GLS) were observed despite preserved LVEF values, potentially due to compensatory changes in global circumferential strain (GCS), wall thickness, or diameter of the left ventricle [
19]. Intracardiac hemodynamic forces have also shown potential to assess cardiac function beyond LVEF, and can be estimated in humans with a mathematical model using feature tracking on conventional LV 2-, 3- and 4-chamber CINE MR images [
20]. The hemodynamic force represents the force exchange between ventricular blood and surrounding myocardium and is a global measure of the interventricular pressure gradient integrated over the LV volume [
20]. Alterations in hemodynamic forces over the cardiac cycle indicate an alteration in blood-tissue interaction, possibly both a cause and effect of the progression of structural remodeling [
21]. Lapinskas et al
. recently demonstrated the use of hemodynamic forces to distinguish patients with normal LVEF, HFpEF, HFmEF and HFrEF [
22]. Lower hemodynamic forces in patients with HFpEF compared to healthy volunteers were observed, without a significant difference in LVEF or GLS. As such, hemodynamic forces can be an important marker for cardiac functional changes in the early phases of myocardial dysfunction in HFpEF [
22‐
24]. Recently, our group demonstrated the feasibility of calculating hemodynamic forces in mice using conventional LV 2-,3- and 4-chamber CINE CMR images in combination with clinically validated software that implements this mathematical model [
25]. However, the feasibility to use this parameter for preclinical studies in HFpEF has never been assessed before.
In order to study possible distinct temporal behavior of several cardiac functional parameters during early development of heart failure, we therefore applied a comprehensive preclinical CMR protocol for longitudinal characterization of cardiac LV dysfunction. Specifically, we compared changes in LV functional parameters between healthy control mice and a diabetic mouse model (db/db mice) treated with the antibiotic doxycycline. The db/db mice are a known model for diastolic dysfunction with preserved ejection fraction thus mimicking aspects of human HFpEF [
26]. Recently we observed that administration of doxycycline exacerbates development of diastolic dysfunction in db/db mice accelerating the progression of HFpEF [
27], due to metabolic and mitochondrial dysfunction [
27,
28]. As such, we deemed that this model provided us with a feasible intervention that accelerated HFpEF disease progression, better than for instance a myocardial infarction that leads to obvious, rapid and widespread alterations in the LVEF and hence GLS and/or hemodynamic forces. For our experimental setup, we hypothesized that db/db mice would exhibit early changes in GLS and/or hemodynamic force parameters, with distinct temporal behavior from healthy controls.