Impaired coronary flow reserve in patients with supra-normal left ventricular ejection fraction at rest

Purpose Recently, a “U” hazard ratio curve between resting left ventricular ejection fraction (LVEF) and prognosis has been observed in patients referred for routine clinical echocardiograms. The present study sought to explore whether a similar “U” curve existed between resting LVEF and coronary flow reserve (CFR) in patients without severe cardiovascular disease (CVD) and whether impaired CFR played a role in the adverse outcome of patients with supra-normal LVEF (snLVEF, LVEF ≥ 65%). Methods Two hundred ten consecutive patients (mean age 52.3 ± 9.3 years, 104 women) without severe CVD underwent clinically indicated rest/dipyridamole stress electrocardiography (ECG)-gated 13 N-ammonia positron emission tomography/computed tomography (PET/CT). Major adverse cardiac events (MACE) were followed up for 27.3 ± 9.5 months, including heart failure, late revascularization, re-hospitalization, and re-coronary angiography for any cardiac reason. Clinical characteristics, corrected CFR (cCFR), and MACE were compared among the three groups categorized by resting LVEF detected by PET/CT. Dose–response analyses using restricted cubic spline (RCS) functions, multivariate logistic regression, and Kaplan–Meier survival analysis were conducted to evaluate the relationship between resting LVEF and CFR/outcome. Results An inverted “U” curve existed between resting LVEF and cCFR (p = 0.06). Both patients with snLVEF (n = 38) and with reduced LVEF (rLVEF, LVEF < 55%) (n = 66) displayed a higher incidence of reduced cCFR than those with normal LVEF (nLVEF, 55% ≤ LVEF < 65%) (n = 106) (57.9% vs 54.5% vs 34.3%, p < 0.01, respectively). Both snLVEF (p < 0.01) and rLVEF (p < 0.05) remained independent predictors for reduced cCFR after multivariable adjustment. Patients with snLVEF encountered more MACE than those with nLVEF (10.5% vs 0.9%, log-rank p = 0.01). Conclusions Patients with snLVEF are prone to impaired cCFR, which may be related to the adverse prognosis. Further investigations are warranted to explore its underlying pathological mechanism and clinical significance.

100 Global longitudinal strain by CMR improves prognostic stratification in acute myocarditis presenting with normal LVEF

Aims Prognostic stratification of acute myocarditis (AM) presenting with normal left ventricular (LV) ejection fraction (EF) relies mostly on late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) imaging. In this specific AM population, LV peak global longitudinal strain (LV-GLS) measured by feature tracking (FT) analysis might provide further prognostic information. Methods and results Data of patients undergoing CMR for clinically suspected AM in seven European Centres, between January 2013 and August 2020, were retrospectively analysed. Those patients fulfilling CMR Lake Louise Criteria (LLC) for the diagnosis of AM and presenting with normal LVEF (≥50%) were included. Patients presenting with heart failure (HF) or significant arrhythmic events, LVEF &lt;50% or haemodynamic instability were excluded. CMR-LGE extent (localized vs. diffuse), localization (subepicardial vs. mid-wall), and distribution (anteroseptal vs. inferolateral) were visually assessed. LV-GLS was measured by dedicated software. The primary outcome was the first occurrence of an adverse cardiovascular event (ACE) including a composite of cardiac death, development of heart failure, life-threatening arrhythmias, or development of LVEF &lt;50%. In patients experiencing more than one event, the first one was considered for the outcome analysis. Of 389 patients with clinically suspected AM, 256 (66%) had confirmed AM with LVEF ≥50% and were included. Median age was 36 years, 71% were males, median LVEF was 60%, and median LV-GLS −17.3%. CMR was performed at a median time of 4 (IQR: 2–12) days from hospital admission. At a median follow-up of 27 months, 24 (9%) patients experienced at least one ACE with development of LVEF &lt;50% accounting for 17 [71%]. Compared to the others, patients experiencing ACEs had lower median LV-GLS values at baseline (−13.9% vs. −17.5%, P = 0.001). At Kaplan–Meier analysis, impaired LV-GLS (both considered as &gt;-20% or quartiles), diffuse and mid-wall LGE were associated with a significantly higher rate of ACEs. LV-GLS remained independently associated with ACEs after adjustment for diffuse or mid-wall LGE as covariate at bivariable analysis. Conclusions In AM with LVEF ≥50%, LV-GLS provides independent prognostic value over LGE, improving risk stratification and providing a rationale for further studies of therapy in this cohort. 100 Figure

Comparison of MIS-C Related Myocarditis, Classic Viral Myocarditis, and COVID-19 Vaccine related Myocarditis in Children

Background: Although rare, myocarditis in the pediatric population is a disease process that carries significant morbidity and mortality. Prior to the SARS-CoV-2 related (COVID-19) pandemic, enteroviruses were the most common cause of classic myocarditis. However, since 2020, myocarditis linked to multisystem inflammatory syndrome in children (MIS-C) is now common. In recent months, myocarditis related to COVID-19 vaccines has also been described. This study aims to compare these three different types of myocarditis with regards to clinical presentation, course, and outcomes. Methods: In this retrospective cohort study, we included all patients <21 years of age hospitalized at our institution with classic viral myocarditis from 2015-2019, MIS-C myocarditis from 3/2020-2/2021 and COVID-19 vaccine-related myocarditis from 5/2021-6/2021. We compared demographics, initial symptomatology, treatment, laboratory data, and echocardiogram findings. Results: Of 201 total participants, 43 patients had classic myocarditis, 149 had MIS-C myocarditis, and 9 had COVID-19 vaccine-related myocarditis. Peak troponin was highest in the classic myocarditis group, whereas the MIS-C myocarditis group had the highest recorded brain natriuretic peptide (BNP). There were significant differences in time to recovery of normal left ventricular ejection fraction (LVEF) for the three groups: nearly all patients with MIS-C myocarditis (n=139, 93%) and all patients with COVID-19 vaccine-related myocarditis (n=9, 100%) had normal LVEF at the time of discharge, but a lower proportion of the classic myocarditis group (n=30, 70%) had a normal LVEF at discharge (p<0.001). Three months post-discharge, 18 of 40 children (45%) in the classic myocarditis group still required heart failure treatment, whereas only one of the MIS-C myocarditis patients and none of the COVID-19 vaccine-associated myocarditis patients did. Conclusions: Compared to those with classic myocarditis, those with MIS-C myocarditis had more significant hematologic derangements and worse inflammation at presentation, but had better clinical outcomes, including rapid recovery of cardiac function. Patients with COVID-19 vaccine-related myocarditis had similar clinical presentation to patients with classic myocarditis, but their pattern of recovery was similar to those with MIS-C, with prompt resolution of symptoms and improvement of cardiac function. Long-term follow-up should focus on cardiac and non-cardiac consequences of myocarditis associated with COVID-19 illness and vaccination. Key Words: MIS-C, myocarditis, COVID-19, mRNA vaccine

Myocardial Work by Speckle Tracking Echocardiography Accurately Assesses Left Ventricular Function of Coronary Artery Disease Patients

Objective: Myocardial work (MW) is a novel non-invasive method that uses speckle tracking echocardiography (STE) to assess left ventricular (LV) function. MW incorporates the global longitudinal strain and afterload conditions. Here we aimed to use MW to assess the LV function of patients with coronary artery disease (CAD) with or without heart failure (HF).Methods: We enrolled a total of 150 individuals (50 each) with CAD and a normal LV ejection fraction (LVEF), CAD with HF, and healthy controls. Patients were divided into the hypertension (HTN) and normal blood pressure (no HTN) subgroups. MW was determined from the pressure-strain loop using STE. The relationships between MW indices and conventional echocardiographic parameters were evaluated, and the MW indices were compared among groups.Results: Univariate and multivariate analyses showed that MW indices were strongly correlated with LVEF. The global work index (GWI) was increased in the CAD with normal LVEF subgroup with HTN vs. controls (1,922.3 ± 393.1 vs. 1,639.7 ± 204.6 mmHg%, p &lt; 0.05) and decreased in CAD patients with HF (no HTN: 940.9 ± 380.6 vs. 1,639.7 ± 204.6 mmHg%, p &lt; 0.05; HTN: 857.3 ± 369.3 vs. 1,639.7 ± 204.6 mmHg%, p &lt; 0.05). Global waste work was increased in all CAD subgroups vs. controls. Global constructive work had the same tendency as GWI in patients with CAD. Global MW efficiency was decreased in all patients with CAD.Conclusion: MW using STE accurately quantifies LV function in patients with CAD. It offers additional information about LV function with respect to disease progression, particularly in CAD patients with a normal LVEF.

Forward Left Ventricular Ejection Fraction as a Predictor of Postoperative Left Ventricular Dysfunction in Patients with Degenerative Mitral Regurgitation

Background: Left ventricular dysfunction (LVD) can occur immediately after mitral valve repair (MVr) for degenerative mitral regurgitation (DMR) in some patients with normal preoperative left ventricular ejection fraction (LVEF). This study investigated whether forward LVEF, calculated as left ventricular outflow tract stroke volume divided by left ventricular end-diastolic volume, could predict LVD immediately after MVr in patients with DMR and normal LVEF. Methods: Echocardiographic and clinical data were retrospectively evaluated in 234 patients with DMR ≥ moderate and preoperative LVEF ≥ 60%. LVD and non-LVD were defined as LVEF < 50% and ≥50%, respectively, as measured by echocardiography after MVr and before discharge. Results: Of the 234 patients, 52 (22.2%) developed LVD at median three days (interquartile range: 3–4 days). Preoperative forward LVEF in the LVD and non-LVD groups were 24.0% (18.9–29.5%) and 33.2% (26.4–39.4%), respectively (p < 0.001). Receiver operating characteristic (ROC) analyses showed that forward LVEF was predictive of LVD, with an area under the ROC curve of 0.79 (95% confidence interval: 0.73–0.86), and an optimal cut-off was 31.8% (sensitivity: 88.5%, specificity: 58.2%, positive predictive value: 37.7%, and negative predictive value: 94.6%). Preoperative forward LVEF significantly correlated with preoperative mitral regurgitant volume (correlation coefficient [CC] = −0.86, p < 0.001) and regurgitant fraction (CC = −0.98, p < 0.001), but not with preoperative LVEF (CC = 0.112, p = 0.088). Conclusion: Preoperative forward LVEF could be useful in predicting postoperative LVD immediately after MVr in patients with DMR and normal LVEF, with an optimal cut-off of 31.8%.

Speckle-Tracking Echocardiography With Novel High Frame-Rate Imaging

Background: global longitudinal strain (GLS) measures myocardial deformation and is a sensitive modality for detecting subclinical myocardial dysfunction and predicting cardiac outcomes. The accuracy of speckle-tracking echocardiography (STE) is dependent on temporal resolution. A novel software enables relatively high frame rate (Hi-FR) (~200 fps) echocardiographic images acquisition which empowers us to investigate the impact of Hi-FR imaging on GLS analysis. The goal of this pilot study was to demonstrate the feasibility of Hi-FR for STE. Methods: In this prospective study, we acquired echocardiographic images using clinical scanners on patients with normal left ventricular systolic function using Hi-FR and conventional frame rate (Reg-FR) (~50 FPS). GLS values were evaluated on apical 4-, 2- and 3-chamber images acquired in both Hi-FR and Reg-FR. Inter-observer and intra-observer variabilities were assessed in Hi-FR and Reg-FR. Results: There were 143 resting echocardiograms with normal LVEF included in this study. The frame rate of Hi-FR was 190 &plusmn; 25 and Reg-FR was 50 &plusmn; 3, and the heart rate was 71 &plusmn; 13. Strain values measured in Hi-FR were significantly higher than those measured in Reg-FR (all p &lt; 0.001). Inter-observer and intra-observer correlations were strong in both Hi-FR and Reg-FR. Conclusions: We demonstrated that strain values were significantly higher using Hi-FR when compared with Reg-FR in patients with normal LVEF. It is plausible that higher temporal resolution enabled the measurement of myocardial strain at desired time point. The result of this study may inform clinical adoption of the novel technology. Further investigations are necessary to evaluate the value of Hi-FR to assess myocardial strain in stress echocardiography in the setting of tachycardia.

Abnormal myocardial work in children with Kawasaki disease

Kawasaki disease (KD) can be associated with high morbidity and mortality due to coronary artery aneurysms formation and myocardial dysfunction. Aim of this study was to evaluate the diagnostic performance of non-invasive myocardial work in predicting subtle myocardial abnormalities in Kawasaki disease (KD) children with coronary dilatation (CADL). A total of 100 patients (age 8.7 ± 5 years) were included: 45 children with KD and CADL (KD/CADL) (Z-score > 2.5), 45 age-matched controls (CTRL) and, finally, an additional group of 10 children with KD in absence of coronary dilatation (KD group). Left ventricular (LV) systolic function and global longitudinal strain (GLS) were assessed. Global myocardial work index (MWI) was calculated as the area of the LV pressure-strain loops. From MWI, global Constructive Work (MCW), Wasted Work (MWW) and Work Efficiency (MWE) were estimated. Despite normal LV systolic function by routine echocardiography, KD/CADL patients had lower MWI (1433.2 ± 375.8 mmHg% vs 1752.2 ± 265.7 mmHg%, p < 0.001), MCW (1885.5 ± 384.2 mmHg% vs 2175.9 ± 292.4 mmHg%, p = 0.001) and MWE (994.0 ± 4.8% vs 95.9 ± 2.0%, p = 0.030) compared to CTRL. Furthermore, MWI was significantly reduced in children belonging to the KD group in comparison with controls (KD: 1498.3 ± 361.7 mmHg%; KD vs CTRL p = 0.028) and was comparable between KD/CADL and KD groups (KD/CADL vs KD p = 0.896). Moreover, KD/CADL patients with normal GLS (n = 38) preserved significant differences in MWI and MCW in comparison with CTRL. MWI, MCW and MWE were significantly reduced in KD children despite normal LVEF and normal GLS. These abnormalities seems independent from CADL. Thus, in KD with normal LVEF and normal GLS, estimation of MWI may be a more sensitive indicator of myocardial dysfunction.

CMR feature tracking strain patterns and their association with circulating cardiac biomarkers in patients with hypertrophic cardiomyopathy

Aims CMR feature tracking strain (CMR-FT) provides prognostic information. However, there is a paucity of data in hypertrophic cardiomyopathy (HCM). We sought to analyze global CMR-FT parameters in all four cardiac chambers and to assess associations with NT-proBNP and cardiac troponin T (hsTnT) in patients with HCM. Methods This retrospective study included 144 HCM patients and 16 healthy controls with CMR at 1.5 T. Analyses were performed on standard steady-state free precession cine (SSFP) CMR data using a commercially available software. Global left ventricular (LV) strain was assessed as longitudinal (LVLAX-GLS), circumferential (LVLAX-GCS) and radial strain (LVLAX-GRS) on long -axis (LAX) and as LVSAX-GCS and LVSAX-GRS on short- axis (SAX). Right ventricular (RV-GLS), left atrial (LA-GLS) and right atrial (RA-GLS) strain were assessed on LAX. Results We found LVLAX-GLS [− 18.9 (− 22.0, − 16.0), − 23.5 (− 25.5, − 22.0) %, p = 0.0001), LVSAX-GRS [86.8 (65.9–115.5), 119.6 (91.3–143.7) %, p = 0.001] and LALAX-GLS [LA2CH-GLS 29.2 (19.1–37.7), LA2CH-GLS 38.2 (34.3–47.1) %, p = 0.0036; LA4CH-GLS 22.4 (14.6–30.7) vs. LA4CH-GLS 33.4 (28.4–37.3) %, p = 0.0033] to be impaired in HCM compared to healthy controls despite normal LVEF. Furthermore, LV and LA strain parameters were impaired in HCM with elevated NT-proBNP and/or hsTnT, despite preserved LVEF compared to HCM with normal biomarker levels. There was a moderate correlation of LV and LA CMR-FT with levels of NT-proBNP and hsTnT. Conclusion CMR-FT reveals LV and LA dysfunction in HCM despite normal LVEF. The association between impaired LV strain and elevated NT-proBNP and hsTnT indicates a link between unapparent functional abnormalities and disease severity in HCM. Graphic abstract Typical CMR-FT findings in patients with hypertrophic cardiomyopathy

Left ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity

Background Immune checkpoint inhibitors (ICIs) are highly effective in treating cancer; however, cardiotoxicity can occur, including myocarditis. Cardiac magnetic resonance (CMR) imaging is useful for evaluation of myocarditis, although it has not been well studied in ICI cardiotoxicity. Methods We identified patients referred for CMR evaluation of ICI cardiotoxicity from September 2015 through September 2019. We assessed structural and functional parameters, feature tracking (FT) left ventricular and atrial strain, T2- weighted ratios and quantitative late gadolinium enhancement (LGE). We also applied the Updated Lake Louise Criteria for diagnosis of myocarditis. Results Of the 20 patients referred, the median left ventricular ejection fraction (LVEF) was 52.5% ± 19.1 and 50% had a normal LVEF (≥53%). FT strain analysis revealed an average abnormal global longitudinal strain (GLS) of −9.8%± 4.2%. In patients with a normal LVEF, the average GLS remained depressed at −12.3%± 2.4%. In all patients, GLS demonstrated a significant negative correlation with LVEF (rs = −0.64, p 0.002). Sixteen patients (80%) had presence of LGE (14 non-ischemic pattern and 2 ischemic). Percent LGE did not correlate with any CMR parameters and notably did not correlate with LVEF (rs = −0.29, p = 0.22) or GLS (rs = 0.10, p = 0.67), highlighting the value of tissue characterization beyond functional assessment. Nine patients (45%) met full Updated Lake Louise Criteria and 85% met at least one criterion, suggestive of myocarditis in the correct clinical context. Thirteen patients (65%) were treated for ICI-associated myocarditis and, of these, 54% (n = 7) had recovery of LVEF to normal. There was no correlation between LVEF (p = 0.47), GLS (0.89), or % LGE (0.15) and recovery of LVEF with treatment. Conclusion In patients with suspected ICI cardiotoxicity, CMR is an important diagnostic tool, even in the absence of overt left ventricular dysfunction, as abnormalities in left ventricular strain, T2 signal and LGE can identifying disease.

Essential hypertension worsens left ventricular contractility in systemic sclerosis

Objective Primary cardiac involvement in systemic sclerosis (SSc) is prevalent and morbid, however the influence of traditional cardiovascular risk factors such as essential hypertension (HTN) are unclear. In the present study, we sought to understand the effects of HTN on left ventricular (LV) contractility in SSc patients using echocardiographic speckle-derived global longitudinal strain (GLS). Methods 56 SSc patients with HTN (SSc+HTN+) and 82 SSc patients without HTN (SSc+ HTN-) were compared with 40 non-SSc controls with HTN (SSc-HTN+) and 40 non-SSc controls without HTN (SSc-HTN-), matched by age and sex. All HTN patients were on stable antihypertensive therapies. Echocardiographic measures included LV ejection fraction (LVEF), left atrial volume index (LAVi), and LV diastolic function. LV contractility was assessed by GLS, averaged across the 18 LV segments. Results SSc patients had diminished GLS regardless of HTN status when compared to both control groups despite normal LVEF, p<0.001. SSc+HTN+ had the highest prevalence of diastolic dysfunction with significantly higher septal E/e’, a marker of LV filling pressures (p<0.05), as well as the largest reduction in GLS compared to SSc+HTN- and both control groups. Conclusion Speckle-derived strain revealed diminished LV contractility in SSc patients despite normal LVEF. SSc+HTN+ had more prominent reductions in GLS associated with evidence of LV remodeling and worsened diastolic function. Our findings demonstrate the presence of subclinical LV contractile dysfunction in SSc that is further exacerbated by concomitant HTN, thereby identifying HTN as an important modifiable cardiovascular risk factor that should be managed aggressively in this at-risk population.