Real-time cardiovascular magnetic resonance imaging for non-invasive characterisation of heart failure with preserved ejection fraction: final outcomes of the HFpEF stress trial

At the time of cardiac imaging, all patients were in stable sinus rhythm. Myocardial function was assessed with conventional ECG triggered cine imaging at rest and free breathing RT-CMR imaging at rest and during physiological exercise. Conventional imaging at rest was performed using balanced steady state free precession (bSSFP) sequences including 2-, 3- and 4- chamber views (CV) as well as a short axis (SA) stack covering the entire heart. Post processing included volumetric analyses and tissue characterisation using Medis (QMass^®, Medical Imaging Systems, Leiden, Netherlands) as well as feature-tracking (FT) deformation imaging using TomTec (2D CPA MR, Cardiac Performance Analysis, TomTec Imaging Systems, Unterschleissheim, Germany) [16]. Global longitudinal strain (GLS) was assessed in long axis views, global circumferential and radial strains (GCS/GRS) were assessed in SA stacks, respectively. Atrial phasic function was analysed in 2 and 4 CV and classified according to reservoir (total strain Es), passive conduit (Ee) and active booster pump (Ea) function [17, 18], Fig. 2. RT-CMR imaging was performed at rest and during exercise-stress using a bSSFP sequence combined with an undersampled radial encoding scheme [13]. Left atrial (LA) and ventricular (LV) long axis strains (LAS) were assessed in the 2 and 4 CV using OsiriX MD (Pixmeo SARL, CH-1233 Bernex, Switzerland) [19, 20].

Tissue characterisation was based on Modified Look-Locker Inversion recovery (MOLLI) sequences (pre- (5(3)3) and post-contrast (4(1)3(1)2) application) including septal and myocardial T1 times in one midventricular SA slice with subsequent calculation of extracellular volume (ECV) [21]. Late gadolinium enhancement (LGE) imaging was performed using inversion-recovery gradient echo sequences. Post-contrast images were obtained 10–20 min after the administration of gadolinium-based contrast agent (0.15 mmol/kg).

Categorical variables are reported as frequencies and corresponding percentages and were compared using the chi-squared test. Continuous variables were tested for normal distribution using the Shapiro–Wilk test, are reported as median with associated interquartile ranges (IQR) and were compared using the nonparametric Mann–Whitney U test. Patients characteristics are reported according to the occurrence of CVE. Predictors for the latter were identified from Cox regression analyses, the results of which are reported as hazard ratios (HR) with 95% confidence intervals (CI), as well as areas under the ROC curve (AUC) analyses reported with 95% CI. AUCs were compared using the method proposed by DeLong et al. [22]. A 2-tailed p value < 0.05 was considered statistically significant. Analyses were performed using SPSS version 26.0 (IBM, Armonk, New York, USA) and MedCalc version 18.2.1 (MedCalc Software bvba, Ostend, Belgium).

The study population consisted of 68 patients (HFpEF n = 34, non-cardiac dyspnea (NCD) n = 34) from the HFpEF Stress Trial as shown in Fig. 1. One patient was lost to follow-up. Fifteen patients with HFpEF (heart failure n = 5, arrhythmia n = 8, hypertension n = 2) and eight with non-cardiac dyspnea (CAD including AMI, PCI and catheterisation n = 4, arrhythmia n = 3, heart failure n = 1) were hospitalised due to cardiovascular reasons (p = 0.059). Two patients had died, one of which due to cardiovascular reasons (heart failure hospitalisation followed by death). Cardiovascular hospitalisation and mortality are both considered in CVE. There were significantly more CVE in overt HFpEF (n = 8/15) compared to NCD (n = 8/26, p = 0.040). Baseline characteristics according to CVE are reported in Table 1. Hospitalised patients were slightly older (71 vs. 67, p = 0.030), while sex and cardiovascular risks factors were similar compared to patients without CVE during follow-up (p ≥ 0.345). Patients with CVE during follow-up had a higher H2FPEF [23] (heavy, 2 or more antihypertensive drugs, atrial fibrillation, pulmonary hypertension, elder age > 60, elevated filling pressures; 5 vs. 3, p < 0.001) but not HFA-PEFF (Heart Failure Association pretest assessment, echocardiography and natriuretic peptide, functional testing, final aetiology; 5 vs. 4, p = 0.103) scores.

On echocardiography patients with CVE showed no difference for E/e’ in echocardiography at rest (p = 0.132), the left atrial volume index (LAVI) was significantly increased (p =  < 0.001) and AF was significantly more frequent in these patients (14/23, 61% with vs. 17/44, 16% without CVE, p < 0.001).

STE, FT- and RT-CMR deformation assessment parameters are reported in Table 2 according to CVE. LV function assessed by STE CMR-FT deformation imaging and RT-CMR LAS revealed no differences comparing patients with and without CVE during follow-up (p ≥ 0.146) with the exception of LV LAS at rest only, being impaired in patients with CVE (p = 0.028).

In contrast, LA function was impaired in patients with CVE. This included STE at rest (p < 0.001) and stress (p = 0.004), phasic function using CMR-FT (Es p < 0.001, Ee p < 0.001, Ea p = 0.002) as well as rest and exercise-stress RT-CMR derived LA EF (rest/stress: p = 0.002) and LA LAS (rest: p < 0.001, exercise-stress p = 0.006).

Hazard ratios for CVE and accuracies to predict CVE are reported in Table 3. An increase in the H2FPEF (HR 1.49, p = 0.006) but not in the HFA-PEFF (HR 1.29, p = 0.075) score was significantly associated with higher CVE rates. Visually, there was no LGE present. Tissue characterisation showed no association to outcome. STE, CMR-FT and RT-CMR LAS showed no significant association between LV function parameters and risk of CVE (p ≥ 0.171, AUC ≤ 0.64) except for LV LAS at rest (HR 0.84, p = 0.029).

Impaired atrial function at rest was associated with increased likelihood for CVE in Cox-regression analyses using STE, CMR-FT and RT-CMR (p ≤ 0.003) and during exercise-stress (p ≤ 0.004). This can further be appreciated from Kaplan–Meier plots after dichotomisation at the median, Fig. 3. These results remained significant in the subgroup of patients with invasively proven HFpEF (p ≤ 0.020). LA functional testing at rest using STE (p = 0.008), CMR-FT LA Es/Ee (p = 0.016/0.017) and RT-CMR derived LAS (p = 0.003) were independent predictors of CVE regardless of the presence of AF.

The highest accuracy for the prediction of CVE was found for LA deformation imaging (AUC STE Es 0.86, CMR-FT Es 0.78, and RT CMR LAS 0.80), Fig. 4.

Subgroup analyses for NCD, masked and overt HFpEF revealed that only STE Es (p = 0.016/0.032) and LA LAS at rest (p = 0.037/0.017) have prognostic implications both in masked and overt HFpEF, Table 4. Prognostic implications remained significant in overt but not masked HFpEF independent of atrial fibrillation; LA LAS (overt HFpEF: HR 0.80, 95% CI 0.67–0.96, p = 0.018, masked HFpEF: HR 0.94, 95% CI 0.83–1.06, p = 0.287) and STE Es (overt HFpEF: HR 0.87, 95% CI 0.76–1.00, p = 0.042, masked HFpEF: HR 0.96, 95% CI 0.87–1.05, p = 0.334).

CMR offers a comprehensive and non-invasive approach for the assessment of cardiac pathophysiology in HFpEF using tissue characterisation and function quantification [24‐26]. The STIFFMAP Trial [27] demonstrated that CMR derived tissue characterisation independently predicts invasively assessed LV stiffness by pressure–volume loops. CMR deformation imaging allows the assessment of myocardial contractility and relaxation. CMR-FT derived LV GLS has been shown to correlate with invasively assessed LV relaxation Tau [28] and is associated with heart failure hospitalisation and mortality [29]. LA function has also been shown to be a sensitive imaging-biomarker for cardiac remodelling in HFpEF [30, 31] independent of atrial size [32] and associated with cardiovascular outcome [33]. CMR-FT atrial assessments offer differentiation of the three phases of atrial physiology, which can be attributed to atrial elasticity (reservoir and to some extent conduit function) and function parameters that contribute to LV filling (booster pump and to some extent conduit function) [17]. These phases have been shown to carry distinct physiological information with direct clinical and prognostic information. Atrial reservoir function, representing the collection of venous return during ventricular systole and elasticity of the atrium, is associated with cardiovascular mortality; for example, following acute myocardial infarction independent of ventricular function and tissue composition [34]. Passive atrial restoring forces and early diastolic ventricular filling are quantified by atrial passive conduit strain which has been shown to be associated with exercise intolerance in HFpEF [35] independent of LV stiffness and relaxation. LA active contractility (booster pump strain) has been reported to compensate for LV heart failure [36]. The finding that LA reservoir strain by both STE and CMR-FT provides high prognostic information regarding CVE may indicate that atrial elasticity by reducing pulmonary venous hypertension has stronger prognostic impact than LA function parameters contributing to LV filling (booster pump strain and to some extent conduit strain). We speculate of a prominent role of active atrial contractility during exercise as well as elasticity at rest in HFpEF pathophysiology. While exercise induced impaired active atrial contractility can precisely identify patients with HFpEF, impaired elasticity at rest identifies those patients at risk for hospitalisation due to congestion at rest or minimal levels of exercise at later disease stages. This is paralleled by data from Melenovsky et al. [37] who demonstrated that echocardiography derived active atrial contractility as defined by A’ from tissue velocity mapping during exercise was impaired and so a potential mechanism of cardio pulmonary congestion in HFpEF. Indeed, exercise-stress testing emerged as a cornerstone in the early diagnosis of HFpEF [6, 7]. Advances in CMR imaging introduced in the HFpEF Stress Trial [12, 13] demonstrated that RT-CMR imaging allows the transition of exercise-stress testing into the already broad spectrum of CMR imaging. Although RT-CMR does not allow for detailed deformation imaging assessment of the three atrial phases, our results show that it accurately reflects LA longitudinal function (and potentially increased active contractility during exercise), which allows for the identification of early stage HFpEF based on surrogate estimation (LV/LA LAS) of global LV and LA longitudinal strains [20]. This allows the translation of longitudinal deformation imaging to physiological exercise-stress assessments [12].

Even in the presence of exertional dyspnea, euvolemic HFpEF patients may present with normal natriuretic peptides and cardiac filling pressures at rest [6]. Exercise-stress induces atrial failure and congestion unmasking pathology in early stages of cardiac remodelling [38], thus allowing for the diagnosis of HFpEF. The HFpEF Stress Trial demonstrated assessment of exercise-induced atrial failure using LA LAS as the most precise parameter for the non-invasive identification of invasively proven HFpEF [12]. In the present study, atrial phasic function at rest, specifically reservoir function, and LA LAS at rest were identified as powerful predictors of CVE. Indeed, patients with advanced stages of cardiac remodelling and impaired atrial function at rest were more likely to be hospitalised during medium-term follow-up of 4 years. Based upon the presented data, for prognostic implications only, e.g., in known HFpEF, a shortened protocol for atrial function quantification including either conventional breath-hold bSSFP, novel free-breathing real-time CMR or echocardiography-based deformation imaging could be employed.

Importantly, in the present population, atrial function assessment (STE Es, CMR-FT Es/Ee and RT-CMR LA LAS) was associated with CVE independently of known AF in the medical history. Indeed, increased preload in diastolic dysfunction leads to atrial remodelling, dilatation and fibrillation [39]. AF burden further promotes atrial remodelling inducing progressive deterioration of atrial mechanics with subsequent worsening of cardiac haemodynamics [40, 41]. The distinct role of AF is also reflected in the H2FPEF score, with AF being the only factor accounting for 3 points [23]. Notwithstanding, atrial dysfunction is not limited to AF, the term atrial cardiomyopathy [42] has recently been introduced to describe intrinsic atrial dysfunction in cardiovascular diseases.

In our cohort at an early disease stage, 56% of HFpEF patients were identified by PCWP exercise-stress thresholds only [12]. Left atrial reservoir and conduit functions had higher diagnostic accuracy for CVE compared to booster (contractility) function. Indeed, reports in HFpEF indicate that changes in conduit function precede reduced atrial contractility, which initially shows an increase in active contractility in the early stages of diastolic dysfunction, compensating for increased LV filling pressures [43]. At later stages the contractility decreases as the disease progresses [44]. Notwithstanding, the assessment of a surrogate for global atrial function (LA LAS) on one hand side reliably detects an exercise induced atrial failure allowing the diagnosis of HFpEF and on the other hand side allows accurate risk stratification in the 4-year follow-up of our trial. The 2-year follow-up of the present population [14] had shown that a more in-depth assessment of the relative phasic function at rest provided the highest diagnostic accuracy. Indeed, as HFpEF tends to have slower progression of symptoms and disease severity compared to HFrEF, impaired phasic function may reflect atrial functional failure more accurately and thus may have the better short-term prognostic accuracy as these patients may suffer from CVE in the nearer future. For a long-term prognosis, overall atrial longitudinal function provides high diagnostic and prognostic accuracy. Importantly, to date, new therapeutic approach for HFpEF has demonstrated significant morbidity reduction [4], while it is important to note that delayed diagnosis may negate prognostic benefits [5, 45]. Atrial functional failure represents a composite of innate atrial functional loss [42] and the burden of LV congestion with increased filling pressures [46], the latter being closely related to symptom onset in HFpEF [47] highlighting its role in HFpEF.

In the current trial, an even longer period of follow-up (or higher patient numbers) may have led to a larger number of CVEs, and possibly a higher value for LV analyses for long-term prognosis prediction as previously demonstrated by Park et al. [29]. LV LAS at rest was the only ventricular parameter associated with CVE. This may again be due to the fact that patients included were at an early disease stage. This also highlights that progress in cardiac remodelling, once apparent in the LV, would significantly increase the risk of CVE. Future research, including a larger cohort of HFpEF patients further down the line of cardiac remodelling with a longer follow-up period, is required to fully understand the clinical significance and the prognostic impact of CMR-derived left atrial and ventricular function at rest and during exercise-stress. For the time being, the atrium reflects the ideal chamber for early diagnostic and prognostic assessments.