Background:
Degenerative aortic stenosis is characterized by processes that, similarly to atherosclerosis, significantly impact vascular function, cardiac autonomic function, and systemic inflammation. Transcatheter aortic valve implantation (TAVI) has become the treatment of choice for patients over 75 years of age at high operative risk. Importantly, exercise capacity of patients undergoing TAVI is significantly reduced both before and after the intervention.
Our aim was i) to assess changes in vascular function, cardiac autonomic function, and inflammation in patients undergoing TAVI (including the prognostic impact of inflammation on long-term outcomes) and ii) to evaluate the impact of exercise training after TAVI on physical performance, vascular function, biomarkers, and health-related quality of life.
Hypothesis:
1. Exercise training after TAVI improves vascular function (i.e., pulse wave velocity and flow-mediated vasodilation).
2. Exercise training after TAVI improves specific biomarkers (i.e., NT-proBNP and lipid status).
3. Exercise training after TAVI improves exercise capacity (i.e., peak oxygen consumption during exertion).
4. Exercise training after TAVI improves health-related quality of life.
Research design and methods:
Consecutive patients referred for TAVI by the local Heart Team were included in two prospective studies. In the first, observational study, endothelial function (assessed using flow-mediated vasodilatation, FMD), cardiac autonomic function (assessed by high resolution ECG-derived heart rate variability parameters), and systemic inflammation (assessed by serum levels of specific biomarkers, i.e., hsCRP, IL-1β, TNF-α, IL-2, IL-10, sST2/IL-33, and IFN-gamma) were determined at three different time-points: before TAVI, 24 hours after TAVI, and 3-6 months after TAVI. Patients were followed up to 5 years. In the second, randomized controlled trial, patients TAVI were randomized after three months to either i) the intervention group (8-12 weeks of supervised, combined exercise training program, consisting of aerobic training and muscle strength exercises) or a control group (unsupervised care, which included home exercise recommendations and regular monitoring). Exercise capacity and vascular function were measured at beginning and the end of the intervention period using cardiopulmonary exercise testing (CPET), FMD and arterial stiffness. Blood samples were withdrawn to determine specific blood markers. Quality of life was assessed with SF-36 and EQ-5D-5L questionnaires.
Results:
In the observational study (vascular function, cardiac autonomic function, and systemic inflammation after TAVI), we included 43 and 63 patients in each analysis. Endothelial function, measured with FMD, significantly improved in patients after TAVI (from 2,8 ± 1,5% to 4,7 ± 2,7%; p <0,001). There were no changes on follow-up after 3-6 months (4,8 ± 2,7%; p = 0,936). On the contrary, heart rate variability parameters remained unchanged immediately after TAVI and improved at follow-up. Improvement was detected in two Poincare diagram parameters (SD2/SD1 increased from 0,682 to 0,906 ms2 (p <0,001) and SDRR from 9,6 to 23,9 ms (p = 0,001)) and in the high-frequency parameter HF (from 5231 ± 1783 to 6507 ± 1789 ms2; p = 0,029). A significant dynamic was observed in specific blood markers hsCRP, TNF-α, sST2/IL-33, IL-10 and IL-2, regardless of patients’ characteristics and intervention. Almost half of the patients (45%) developed systemic inflammatory response syndrome, which had a significant impact on long-term outcomes—rehospitalization or death (hazard ratio, HR, 2,9 [95% confidence interval, 95%CI, 1,36; 6,47]). After Cox multivariate analysis, baseline hsCRP and IFN-gamma values independently predicted long-term outcomes after TAVI (HR 1,27 [95%CI 1,08; 1,48] and HR 1,20 [95%CI 0,98; 1,40], respectively).
In the second, interventional trial (impact of exercise training after TAVI), we included 23 patients. A total of 13 patients (33%) withdrew from the study due to the COVID-19 pandemic. Exercise capacity improved in both groups (intervention and control): VO2 peak increased by 0,09 ml/min/kg ([95%CI 0,01; 0,16]; p = 0,02), workload by 8,2 Watts ([95%CI 0,6; 15,8]; p = 0,034) and cumulative exercise time by 47 seconds ([95%CI 5,0; 89,6]; p = 0,029). Vascular function, measured with FMD, significantly improved in the supervised compared to the unsupervised group (4,49% [95%CI [2,35; 6,63]; p <0,001). There were no differences between groups after comparing specific blood markers and quality of life questionnaires.
Conclusions:
Endothelial function (assessed with FMD) and autonomic function (assessed with heart rate variability parameters) significantly improved after TAVI. The immediate improvement in endothelial function most likely reflects hemodynamic changes after the intervention, whereas the delayed improvement in autonomic function likely reflects gradual adaptations following cardiac remodeling. The procedure itself is also accompanied by a significant dynamic in inflammation biomarkers and systemic inflammatory response syndrome, which had a significant impact on long-term prognosis. Detection of specific biomarkers (eg, hsCRP and IFN-gamma) pre-TAVI independently predicts long-term outcomes and could therefore improve risk-assessment of patients undergoing TAVI. Both supervised and unsupervised exercise training programs significantly improved exercise capacity in patients after TAVI; conversely, supervised exercise training significantly improves vascular function. Further research is needed to demonstrate a potential effect on rehospitalizations and mortality.
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