Background: Frailty is a common condition that significantly affects treatment modality and outcome of patients suffering from severe symptomatic aortic stenosis (AS). Current guidelines consider frailty as a factor favouring TAVR over SAVR. Noteworthy, guidelines recommend the Katz Index to assess frailty, with a maximum score of 6 points indicating complete independence in activities of daily living.  

 

Aims: To assess the impact of frailty on symptom burden and outcome in AS patients and to compare the proteome of frail and non-frail patients

 

Methods: Frailty was assessed retrospectively in 248 consecutive patients undergoing TAVR for severe symptomatic AS at the University Medical Centre Göttingen between 01/2017 and 07/2019. Frailty was defined as Katz-Index of <6 points. In a subset of 168 patients, serum was collected, and proteomic profiling was performed assessing 191 proteins quantitatively. 

 

Results: Frail patients were significantly older (79 vs. 81 years, p=0.01), presented less often with dyslipidaemia (72 vs. 51 %, p=0.003) and suffered significantly more often from coronary artery disease (64 vs. 80 %, p=0.03) and atrial fibrillation (37 vs. 53 %, p=0.03) (table 1). Correspondingly, frail patients exhibited significantly lower functional status and a higher burden of heart failure symptoms (6MWT distance 270 vs. 137 m, p<0.001; MLHFQ 31 vs. 46 points, p<0.001; NT-proBNP 1654.4 vs. 2316.0 ng/l, p=0.04). On echocardiography, frail patients showed significantly lower transaortic gradients (Pmean 39 vs. 33 mmHg, p=0.021) (table 1). Accordingly, we observed a strong trend towards a higher prevalence of low-gradient AS patients in frail patients (p=0.07).

Patients with Katz index < 6 exhibited a significantly higher all-cause mortality after TAVR than non-frail patients (p logrank=0.001, figure 1).





In multivariate analysis, a Katz index <6 proved to be an independent predictor of all-cause mortality, whereas age itself did not (table 2).
  

 

In a first statistical approach, we used Mann-Whitney-U test to compare the proteome of frail and non-frail patients. We identified more than 50 proteins that were expressed differently with a significance level of p<0.001. Noteworthy, 12 of these proteins belonged to the interleukin (IL-4ra, IL1-ra, IL6, IL27, IL2-ra, IL18BP) or the tumor necrosis factor family (TNFRSF10A, TNFRSF11A, TNFRSF13B, TNFRSF14, TNF-R2, TNFR1. Frailty was associated with an activation of inflammatory signalling cascades (IL-1, IL-6, CD4, TNF-α). Induction of pro-inflammatory cytokines are also thought to mediate adverse cardiac remodelling. Deeper statistical analyses and network analyses will have to be performed.

 

Frailty, defined by Katz index < 6 points, is an independent predictor of all-cause mortality after TAVR. Moreover, frail patients exhibit a higher burden of symptomatic heart failure and a greater induction of pro-inflammatory cytokines that also play a role in the pathogenesis of heart failure, regardless of its aetiology. Particularly the induction of pro-inflammatory signalling cascades involving IL-1, IL-6 and TNF-α is thought to mediate adverse cardiac remodelling. Overactive inflammatory responses in frail patients may explain both reduced survival and worse functional status.