Impact of intraventricular haemodynamic forces misalignment on left ventricular remodelling after myocardial infarction

Introduction

Cardiac remodelling following acute myocardial infarction (MI) has been widely described. The single best predictor of adverse left ventricular remodelling (aLVr) is infarct size (IS) determined by cardiac magnetic resonance (CMR) imaging.1 Other known predictors of post-infarction aLVr are anterior localization of infarct,1 the presence of microvascular obstruction (MVO)2 and intra-myocardial haemorrhage (IMH).3 Neurohormonal activation promotes left ventricular remodelling (LVr), and modulation of β-adrenergic and renin-angiotensin pathways is the best known strategy for preventing post-infarct heart failure.4 Recent developments in cardiac fluid-dynamics imaging have heightened the interest about haemodynamic forces (HDFs) patterns associated with cardiac adaptations.5 However, their association with cardiac adaptation after MI has not been investigated. We sought to evaluate HDFs and their influence on post-infarction aLVr in a cohort of patients with reperfused segment elevation MI (STEMI) using a novel technique based on endocardial borders tracking of steady-state free-precession cineMR data sets.

Methods Study population

Forty-nine acute STEMI patients underwent CMR at 1 week (baseline) and 4 months (follow-up) after MI. Inclusion criteria were (i) clinical diagnosis of STEMI according current guidelines (STEMI guidelines), (ii) successful treatment with percutaneous coronary intervention (PCI) within 12 h from symptoms onset and (iii) sinus rhythm. Exclusion criteria were prior MI or revascularization, cardiogenic shock, atrial fibrillation, plasma creatinine > 2 mg/dL and claustrophobia or other contraindications to CMR. Twenty-one non-athletic healthy individuals (HC) underwent CMR as a control group for HDFs assessment. The study was conducted in accordance with the Declaration of Helsinki. Local ethical review boards approved the study, and all patients gave written informed consent.

Cardiovascular magnetic resonance acquisition

Cardiac magnetic resonance studies were performed using a commercial 1.5 T unit (Avanto-Siemens, Erlangen, Germany). Breath-hold steady-state free-precession cineMR images were acquired in cardiac vertical and horizontal long axis and short axis with full coverage of the ventricles. Area at risk (AAR) was assessed using black-blood short tau inversion recovery T2-weighted sequence (T2w imaging) acquired in cardiac long and short axis. After contrast administration, breath-hold, two-dimensional inversion recovery, segmented gradient-echo T1-weighted sequences were used to detect MVO and IS. An intravenous contrast agent dose of 0.1 mmol/kg gadolinium contrast agent (Gadoterate meglumine, Dotarem, Guerbet S.A., France) was used. The presence of MVO and late gadolinium enhancement (LGE) was assessed by early and late post-contrast imaging acquired respectively 2–5 and 10–20 min following contrast administration. Inversion time was individually adapted to suppress the signal of normal remote myocardium (usual range, 220 to 350 ms). At 4 months follow-up, the same CMR protocol was repeated except for T2-weighted sequences.

Image analysis

The following parameters were measured: left ventricular (LV) end-diastolic volume indexed for body surface area (LVEDVi), left ventricular end-systolic volume indexed (LVESVi), left ventricular ejection fraction (LVEF) and LV mass indexed (LVmass/i). On T2-weighted images, AAR was identified as the myocardial tissue with signal intensity (SI) > 2SD above mean SI of remote myocardium; when present, the internal hypointense core reflecting haemorrhagic component was included. Then, AAR was quantified using a semi-automatic approach, and its extent was expressed as percentage of LV mass. On early post-contrast imaging, MVO was defined as the hypoenhanced region within the hyperintense myocardium. On late post-contrast imaging, LV LGE was automatically identified as the myocardium with SI > 5SD mean SI of remote myocardium.6 MVO, when present, was included in LGE area. Infarct location was assigned according to the location of the LGE and/or oedema. Infarction was defined as anterior when at least one of the following segments was involved: basal anteroseptal, mid-anterior, mid-anteroseptal or apical anterior segment.7

Transmural infarction was defined as >75% hyperenhancement of the LV wall thickness in late post-contrast imaging. STEMI patients were divided in two subgroups according to baseline LVEF using a cut-off of 50% (preserved LVEF and reduced LVEF).

Left ventricular adverse remodelling was defined as a relative increase in LVESV of at least 15% compared with baseline (ΔLVESV ≥ 15%).

Cardiac magnetic resonance feature tracking

Left ventricular global longitudinal strain (GLS) and global circumferential strain (GCS) were measured using a CMR feature tracking technique from the same endocardial border traced for HDFs estimation (QStrain Version 1.3.0.79; Medis, Leiden, the Netherlands). Both endocardial (-endo) and transmural (-myo) value were reported in this study.

Left ventricular haemodynamic forces assessment

Left ventricular HDFs were computed from a combination of multiple intersected breath-hold steady-state free-precession cineMR long axis data sets (corresponding to 4, 2 and 3 chamber view), using a dedicated software (QStrain Version 1.3.0.79; Medis, Leiden, the Netherlands). HDFs were estimated using the same endocardial border tracking used for strain calculation. The mathematical model was previously described and validated against 4D flow MRI.8 The endocardial borders were traced at the end-systolic frame from the three apical views and then tracked frame-by-frame. The 3D LV endocardial surface was reconstructed from the long axis borders. The total HDF vector was evaluated by computing the integral balance of momentum inside LV volume. HDFs curves over time and a polar histogram of HDFs' distribution in the LV were generated (Figure 1). As a measure of the overall force amplitude, the dimensionless root mean square of HDFs was computed over the selected period of time: entire cardiac cycle, systole and diastole. In order to compare patients with different LV size, the HDFs were normalized with the LV volume and expressed as a percentage of gravity acceleration. These normalized forces represent the average value of pressure gradients in the LV cavity towards different directions, without a direct dependence on the volume size.

image

From left to right: Cine CMR long axis data sets are used for left ventricular haemodynamic forces estimation. End-systolic and end-diastolic borders are traced and tracked frame-by-frame to allow endocardial border movement reconstruction in a three-dimensional model. Apex-to-base and latero-septal haemodynamic forces are estimated over time and graphically represented as curves. Haemodynamic forces distribution in a selected period of time is represented using a polar plot. 2C, two chamber view; 3C, three chamber view; 3D, three-dimensional; 4C, four chamber view; A, apex; B, base; ED, end-diastole; ES, end-systole; HDFs, haemodynamic forces; L, lateral wall; MR, magnetic resonance; S, septum.

The following parameters are calculated in systole, diastole and over the entire cardiac cycle: ‘apex-to-base’ (A-B, longitudinal) HDFs (%): the normalized entity of HDFs directed in the apex-to-base direction; ‘latero-septal’ (L-S, horizontal) HDFs (%): the normalized entity of HDFs directed in the latero-septal direction; L-S/A-B HDFs ratio (%): the ratio between L-S HDFs and A-B HDFs was used to assess the relative distribution of the HDF directions in the LV; HDFs angle [φ (°)]: the main direction of HDFs over a selected period of time, using a polar coordinate system. φ ranges from 0°, when the HDFs are directed in infero-lateral direction, to 360°, after a circular full turn. Intra-observer and inter-observer variability

Intra-observer and inter-observer variability for measurements of HDFs were assessed in a sample of 10 patients. Two investigators measured blinded the same exam, and one investigator repeated the analysis 1 week later, blinded to the previous measurements.

Statistical analysis

Continuous variables are presented as mean ± SD and were compared using Student's t-test or the Mann–Whitney rank sum test for unpaired and paired comparisons, as appropriate. Comparisons between more than two groups were performed by two-way ANOVA with post-hoc Bonferroni correction. The categorical variables are expressed as counts and percentages and compared by χ2 test or by Fisher's exact, as appropriate. Spearman correlation coefficient (r) was used to test correlation between continuous variables. Univariate logistic analysis was used to determine the association of demographic, CMR and HDFs variables with adverse LV remodelling at follow-up. Then, all significant univariate risk factors were included in two different multivariate logistic models developed for testing separately collinear variables. Interclass correlation coefficients were calculated to assess inter-observer and intra-observer agreement of HDFs measurements. All tests were two-tailed at 5% significance level, except for multiple comparisons. In that case a Bonferroni-corrected alpha level was applied by dividing the alpha value by the number of comparisons (P value = 0.05/18 = 0.0015). Statistical analyses were performed using the Statistical Package for Social Sciences, Version 23.0 (SPSS, Chicago, IL).

Results Segment elevation myocardial infarction patients vs. controls

General characteristics and CMR findings of whole STEMI population are depicted in Tables 1 and 2, respectively. STEMI patients were divided in two subgroups according to baseline LVEF and then, compared with HC (Table 3). STEMI patients with reduced LVEF had lower values of HDFs measured along A-B direction during the entire heartbeat and in systole, as compared with HC (A-B HDFs entire heartbeat: 13 ± 6 vs. 22 ± 6; P = 0.001), (systolic A-B HDFs: 19 ± 8 vs. 31 ± 9; P = 0.001). STEMI patients with preserved LVEF showed intermediate A-B HDFs values both in systole and over the entire heartbeat. L-S HDFs were slightly lower in patients with reduced LVEF compared with HC, but without reaching statistical significance. Considering the whole enrolled population, both A-B HDFs and L-S HDFs, calculated over the entire cardiac cycle, showed good linear correlation with LVEF (r = 0.7, P = 0.001 and r = 0.6, P = 0.001 respectively), GLS-endo (r = −0.7, P = 0.001 and r = −0.6, P=0.001 respectively) and GCS-endo (r = −0.6, P = 0.001 and r = −0.5, P = 0.001 respectively). Diastolic L-S/A-B HDF ratio did not differ comparing both STEMI groups with HC.

Table 1. General characteristic of the STEMI population Parameter STEMI Pts, n = 49 Adverse remodelling, n = 18 (37%) Non-adverse remodelling, n = 31 (63%) P Age (years) 57 ± 10 59 ± 11 56 ± 10 0.726 Weight (kg) 80 ± 10 79 ± 11 81 ± 9 0.811 Height (cm) 172 ± 6 173 ± 5 172 ± 7 0.593 BMI (kg/m2) 27 ± 3 26 ± 3 25 ± 2 0.689 cTnI peak (ng/L) 44 ± 75 44 ± 86 44 ± 71 0.754 SBP pre-PCI (mmHg) 124 ± 17 120 ± 19 126 ± 16 0.725 DBP pre-PCI (mmHg) 76 ± 9 72 ± 12 77 ± 7 0.411 HR pre-PCI (bpm) 73 ± 9 71 ± 8 74 ± 9 0.434 Door-to-balloon (min) 184 ± 286 135 ± 174 212 ± 334 0.471 Time-to-PCI (min) 248 ± 837 274 ± 246 247 ± 1,000 0.754 Male sex, n (%) 46 (94%) 17 (94%) 29 (94%) 0.679 Diabetes, n (%) 6 (12%) 5 (28%) 2(6%) 0.08 Hypertension, n (%) 31 (63%) 8 (44%) 24 (77%) 0.047 Family history for CAD, n (%) 27 (55%) 10 (56%) 16 (52%) 0.74 Active smoker, n (%) 25 (51%) 8 (44%) 17 (55%) 0.69 Dyslipidaemia, n (%) 26 (53%) 6 (33%) 17(55%) 0.188 Prodromal angina, n (%) 9 (18%) 6 (33%) 3 (10%) 0.065 Killip class 1, n (%) 42 (86%) 16 (89%) 25 (81%) 0.311 Killip class 2, n (%) 7 (14%) 1 (5%) 6 (19%) Anterior STEMI, n (%) 31 (63%) 13 (72%) 18 (58%) 0.305 Non-anterior STEMI, n (%) 18 (37%) 5 (28%) 13 (42%) RCA dominant, n (%) 26 (53%) 15 (83%) 29 (94%) 0.362 TIMI flow grade 0/1 pre-PCI, n (%) 48 (98%) 18 (100%) 29 (94%) 0.745 TIMI flow grade 2/3 pre-PCI, n (%) 1 (2%) 0 (0%) 2 (6%) TIMI flow grade 0/1 post-PCI, n (%) 0 (0%) 0 (0%) 0 (0%) 0.99 TIMI flow grade 2/3 post-PCI, n (%) 49 (100%) 18 (100%) 31 (100%) BMI, body mass index; CAD, coronary artery disease; CKMB, creatine kinase MB; cTnI, cardiac Troponin I; DPB, diastolic blood pressure; HR, heart rate; PCI, percutaneous coronary intervention; RCA, right coronary artery; SBP, systolic blood pressure; STEMI, segment elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction. Table 2. CMR parameter baseline and at 4 months follow-up Parameters STEMI Pts, n = 49 Baseline LVEF (%) 48 ± 10 LVEDVi (mL/m2) 67 ± 13 ESVi (mL/m2) 36 ± 12 SVi (mL/m) 33 ± 6 LVmass/i (g/m2) 62 ± 12 AAR (%) 26 ± 21 IS (%) 18 ± 13 MVO, n (%) 22 (45%) Transmural MI (%) 19 (39%) 4 months FU LVEF (%) 50 ± 10 EDVi (mL/m2) 74 ± 22 ESVi (mL/m2) 38 ± 20 SVi (mL/m2) 36 ± 6 LVmass/i (g/m2) 58 ± 11 IS (%) 14 ± 12 AAR, area at risk; EDVi, end-diastolic volume index; ESVi, end-systolic volume index; IS, infarct size; LVEDVi, left ventricular end-diastolic volume indexed; LVEF, left ventricular ejection fraction; LVmass/i, left ventricular mass index; MI, myocardial infarction; MVO, microvascular obstruction; SVi, stroke volume index. Table 3. Feature tracking and haemodynamic forces analysis: STEMI patients and reduced EF vs. STEMI patients and preserved EF vs. healthy controls STEMI EF < 50%, n = 21 STEMI EF > 50%, n = 28 Healthy controls, n = 21 P Post-hoc analysis Pa Pb Pc Feature tracking analysis EF (%) 41 ± 5 57 ± 6 63 ± 3 0.001 0.001 0.001 0.020 GLS-endo (%) −9 ± 2 −17 ± 3 −21.7 ± 2 0.001 0.008 0.001 0.001 GLS-myo (%) −9 ± 2 −14 ± 8 −21 ± 2 0.001 0.890 0.001 0.003 GCS-endo (%) −20 ± 3 −28 ± 3 −31 ± 2 0.001 0.001 0.001 0.284 GCS-myo (%) −13 ± 1 −20 ± 3 −20 ± 1 0.001 0.001 0.001 0.890 GRS (%) 36 ± 12 55 ± 10 65 ± 14 0.001 0.03 0.001 0.076 Haemodynamic forces: entire heart cycle A-B (%) 13 ± 6 15 ± 4 22 ± 6 0.001 0.958 0.001 0.002 L-S (%) 2.6 ± 1.3 2.6 ± 0.6 3.6 ± 0.6 0.002 0.980 0.002 0.003 L-S/A-B HDF ratio (%) 20 ± 6 18 ± 4 16 ± 4 0.051 0.244 0.059 0.970 Angle φ (°) 73 ± 3 75 ± 3 74 ± 3 0.016 0.014 0.267 0.469 Haemodynamic forces: systole A-B (%) 19 ± 8 23 ± 5 31 ± 9 0.001 0.391 0.001 0.014 L-S (%) 3.3 ± 1.9 3.6 ± 1 4 ± 1 0.046 0.962 0.053 0.268 L-S/A-B HDF ratio (%) 18 ± 6 16 ± 4 15 ± 5 0.229 0.908 0.271 0.987 Impulse angle φ (°) 74 ± 4 76 ± 7 76 ± 4 0.173 0.394 0.267 0.965 Haemodynamic forces: diastole A-B (%) 9 ± 7 10 ± 6 13 ± 4 0.038 0.965 0.052 0.176 L-S (%) 2 ± 1.5 1.8 ± 0.7 3 ± 0.9 0.002 0.985 0.010 0.002 L-S/A-B HDF ratio (%) 25 ± 13 20 ± 6 23 ± 7 0.227 0.363 0.985 0.777 Impulse angle φ (°) 72 ± 6 76 ± 4 72 ± 5 0.059 0.111 0.9886 0.096 A-B, apex-base; EF, ejection fraction; GCS-endo, endocardial global circumferential strain; GCS-myo, transmural global circumferential strain; GLS-endo, endocardial global longitudinal strain; GLS-myo, transmural global longitudinal strain; GRS, global radial strain; HDFs, haemodynamic forces; L-S, latero-septal; STEMI, segment elevation myocardial infarction. Location and extension of myocardial infarction

Segment elevation myocardial infarction population was divided according to infarct location in anterior STEMI (63%) and non-anterior STEMI (37%) (Supporting Information, Tables S1 and S2). Anterior STEMI had larger IS (32 ± 21 vs. 14 ± 13; P = 0.012) and AAR (22 ± 14 vs. 11 ± 10; P = 0.016) at baseline and greater values of IS at 4 months FU. Feature tracking analysis showed that anterior STEMI had lower values of GLS (GLS-endo: −12 ± 4 vs. −18 ± 3; P = 0.001 and GLS-myo: −12 ± 4 vs. −13 ± 5; P = 0.02) while no significant differences in GCS and GRS were detected. Anterior STEMI had lower values of L-S HDF measured both in systole (2.8 ± 0.9 vs. 3.9 ± 1; P = 0.01) and during the entire cardiac cycle (2.2 ± 0.6 vs. 2.8 ± 0.6; P = 0.01). Interestingly, patients with IS over the median (15%) had significantly higher diastolic L-S/A-B HDF ratio (25 ± 10 vs. 20 ± 10; P = 0.028) while difference in L-S HDF did not reach statistical significance (2.9 ± 1.5 vs. 3.5 ± 0.7; P = 0.074).

Adverse left ventricular remodelling

Clinical characteristics of patients with and without aLVr are reported in Table 1. CMR findings comparing patients with and without adverse LV remodelling at 4 months FU are summarized in Table 4. We observed greater value of IS (23 ± 16 vs. 15 ± 11; P = 0.03) in patients with adverse remodelling, while AAR did not reach statistical significance (32 ± 23 vs. 22 ± 18; P = 0.07). In patients with aLVr at FU, baseline systolic L-S HDFs were lower (2.7 ± 0.9 vs. 3.6 ± 1; P = 0.027) while diastolic L-S/A-B HDF ratio was significantly higher (28 ± 14 vs. 19 ± 6; P = 0.03) (Table 5) (Figure 2). Accordingly, impulse diastolic HDF angle was lower in patients with adverse remodelling (71 ± 7 vs. 75 ± 4; P = 0.03).

Table 4. CMR findings comparing patient with vs. without adverse remodelling STEMI, n = 49 Adverse remodelling, n = 18 (37%) Non-adverse remodelling, n = 31 (63%) P Baseline EF (%) 48 ± 11 47 ± 9 0.868 EDVi (mL/m2) 68 ± 13 70 ± 13 0.427 ESVi (mL/m2) 35 ± 13 37 ± 13 0.471 SV/i (mL/m2) 32 ± 6 33 ± 6 0.726 LVmass/i (g/m2) 59 ± 11 64 ± 13 0.289 AAR (%) 32 ± 23 22 ± 18 0.070 IS (%) 23 ± 16 15 ± 11 0.030 MVO, n (%) 7 (39%) 17 (54%) 0.462 Transmurality, n (%) 10 (56%) 9 (29%) 0.09 4 months FU LVEF (%) 45 ± 11 53 ± 8 0.060 EDV/i (mL/m2) 87 ± 27 66 ± 15 0.053 ESV/i (mL/m2) 50 ± 25 31 ± 12 0.005 SV/i (mL/m2) 37 ± 7 36 ± 6 0.726 LVmass/i (g/m2) 54 ± 11 60 ± 11 0.326 IS (%) 16 ± 14 12 ± 10 0.580 AAR, area at risk; EDVi, end-diastolic volume index; ESVi, end-systolic volume index; IS, infarct size; LVEF, left ventricular ejection fraction; LVmass/i, left ventricular mass index; MVO, microvascular obstruction; SVi, stroke volume index; STEMI, segment elevation myocardial infarction. Table 5. Feature tracking and haemodynamic forces analysis comparing patient with vs. without adverse remodelling STEMI, n = 49 Adverse remodelling, n = 18 (37%) Non-adverse remodelling, n = 31 (63%) P Feature tracking analysis GLS-endo (%) −13 ± 5 −15 ± 5 0.308 GLS-myo (%) −13 ± 5

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