The main findings of this study investigating elderly symptomatic patients with severe AS undergoing TAVR are: 1) LVEF was preserved in 60% of the patients despite advanced symptoms in contrast to LVGLS that was abnormal in 75% (>-18%) and at least moderately decreased (>-14%) in approximately half of the patients; 2) a highly significant correlation between LVGLS and all-cause mortality was identified; 3) LVGLS >-14% was identified as an independent predictor of all-cause mortality and patients with a LVGLS > -14% had reduced long-term survival as compared to patients with LVGLS ≤-14%; 4) patients with high gradient AS with preserved LVEF but LVGLS >-14% had reduced survival as compared to patients with LVGLS ≤-14%.
The main factors that determine the timing for SAVR or TAVR intervention according the current AHA/ESC guidelines are symptoms and/or LV systolic dysfunction in terms of LVEF < 50% [4, 5]. In recent years TAVR treatment of severe AS is routinely offered in many centres to elderly patients with intermediate to high - and in some cases also patients at low preoperative risk. The population of patients above 75 years with severe AS treated with TAVR is increasing and, according to the Danish Heart Registry, accounts for two-thirds of all aortic valve interventions in 2018. The interpretation of symptoms in the elderly with co-morbidities and decreased physical activity level can be challenging and may result in failure to recognise symptoms or late reporting of symptoms . Evaluation of LV systolic function is therefore of particular interest and importance in order to refer the patient for timely valve intervention before potential irreversible LV dysfunction occurs. In both asymptomatic and symptomatic severe AS the progressive AVA reduction leads to increasing afterload, which is usually accompanied by compensatory LV hypertrophy. This LV remodelling process tends to normalize the LV wall stress and maintenance of LVEF. A normal LVEF is often present until late in the disease stage. At this stage a mismatch develops between afterload and inadequate LV hypertrophy response, which is independent of symptom status as seen in the present study where 60% of the all patients had preserved LVEF but severe symptoms (78% were in NYHA class III or IV). In contrast to LVEF, myocardial strain analysis including assessment of LVGLS has been demonstrated to be able to detect subclinical myocardial dysfunction in a wide range of AS severities with LVEF ≥ 60% . The LV systolic dysfunction determined by LVGLS seems to appear first in the subendocardial layer and progresses transmurally with increasing severity of AS independent of LVEF . In addition, patients with symptoms seem to have more impaired levels of LVGLS as compared to asymptomatic patients. Recently, a meta-analysis of LVGLS in 1067 asymptomatic AS patients with LVEF ≥ 50% (median LVEF 63,5%) and AVAI of 0.49 cm2 demonstrated an average LVGLS of -16,2% . From other studies LVGLS in severe AS with preserved LVEF has been reported to be -15% on average and with lower absolute values if symptoms were present and/or LVEF was < 50% [8, 11, 16]. In our study we noted a lower mean LVGLS of -14.0%, which might be explained by a higher degree of AS severity determined by AVA/AVAI, a lower mean LVEF of 50% and presence of more advanced symptoms as compared to the aforementioned studies. The majority of AS patients in our study had an abnormal LVGLS >-18% in contrast to normal LVGLS ≤-20% which was found in only 15% of the patients. Preserved LVGLS is most often seen in patients with aortic valve sclerosis or mild AS and is noted in less than 15% of patients with severe asymptomatic AS with preserved LVEF [11, 15].
Overall, assessment of LVGLS seems to be a suitable tool for monitoring LV systolic function in AS enabling detection of early myocardial contractile dysfunction. Furthermore, LVGLS relates to both AS severity and progression of the AS severity in contrast to LVEF. LVGLS is easily calculated, has a good feasibility and has an inter-and intra-variability of 8% and 5% that is even better than bi-plane LVEF analysis of 10% and 8%, respectively .
Abnormal and worsening LVGLS in AS is likely to reflect several factors such as inadequate compensatory LV hypertrophy, subendocardial ischemia, neurohumoral up-regulation, myocyte degeneration and replacement fibrosis [17–19]. Increased interstitial myocardial fibrosis has been reported in AS with preserved LVEF but with impaired longitudinal systolic function . Presence of increased myocardial fibrosis detected by staining of LV biopsies taken during SAVR operation was associated with significantly higher serum Nt-pro-brain natriuretic peptide (NT-pro-BNP), higher LV mass index and impaired LVGLS . Late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) imaging detects myocardial fibrosis and a positive LGE-CMR has been shown to be present in 49% of patients with AS. Myocardial fibrosis identified by LV biopsy staining or LGE-CMR independently predicts mortality [20–22]. Recently, co-existing transthyretin wild type cardiac amyloidosis (ATTRwt) has been demonstrated in AS patients undergoing TAVR with a prevalence of 16% . Myocardial amyloid deposition impairs LV longitudinal systolic function and an apical-basal strain pattern is often present. The presence of ATTRwt in AS reduces LVGLS and is likely to affect prognosis after AVR.
Marwick et al. have previously demonstrated that LVGLS is an independent predictor of death or AV replacement in asymptomatic severe AS patients with LVEF ≥50%. Baseline LVGLS >-15% was associated with significantly increased mortality . In a recent meta-analysis by Magne et al. it was demonstrated that impaired LVGLS (>-14.7%) was associated with reduced survival in patients with significant asymptomatic AS with LVEF ≥50% and even in patients with LVEF ≥60% . Impaired LVGLS (>-18.2%) has been shown to predict disease progression with development of symptoms and need for AV replacement in a population with asymptomatic severe AS with preserved LVEF . In two studies including asymptomatic as well as symptomatic patients with a wide range of AS severities and preserved LVEF, LVGLS was identified as a strong independent predictor of all-cause mortality. Patients with LVGLS >-14% had a reduced survival [8, 25]. In addition, LVEF did not show any predictive value in terms of all-cause mortality, AV replacement or development of cardiac symptoms in the studies referred to above. The lack of predictive value of LVEF of all-cause mortality in asymptomatic AS patients has previously been documented in a larger series of AS patients with prolonged follow-up .
LVGLS >-14% was an independent predictor of all-cause mortality and a strong association between severity of LVGLS impairment and mortality was noted. A risk model demonstrated additive prognostic value of LVGLS to clinical characteristics, AVA and LVEF. LVGLS seems a more reliable parameter than LVEF for evaluating myocardial function and prognosis in both asymptomatic and symptomatic AS patients with a wide range of severities and ages. Assessment of LVGLS in AS patients could potentially contribute to a more optimal decision process against a SAVR or TAVR, and the current published data on the subject should be considered implemented in future guidelines.
The present study is limited by its retrospective design and because it was performed as a single centre study in a tertiary cardiovascular referral centre. The latter might induce selection bias as the included patients only account for patient referred for AV replacement evaluation at our institution. Furthermore, patients selected for conservative treatment are not included in the analysis.
LVGLS may be influenced by a variety of pathologies including myocardial ischemia, previous myocardial infarction, diabetes mellitus, hypertension and amyloidosis. We do not report data on the specific extent of coronary artery disease. No systematic screening or investigations for ATTRwt was performed. Although, LVGLS does not detect the specific cause of the myocardial dysfunction, the parameter is not limited to being an independent marker of adverse risk in AS.