Background

Age-associated inflammation and immune system dysfunction have been implicated as mechanisms that increase risk for adverse long-term procedural outcomes in older adults. The purpose of this study was to investigate relationships between baseline inflammatory and innate antiviral gene expression and outcomes after transcatheter aortic valve replacement (TAVR) in older adults with severe aortic stenosis.

Methods

We performed a retrospective case-control study comparing pre-procedural pro-inflammatory and Type 1 interferon (IFN) gene expression in 48 controls with favorable outcomes (alive 1 year after TAVR with improved quality of life [QoL]) versus 48 individuals with unfavorable outcomes (dead by 1 year or alive at 1 year but with reduced QoL). Gene expression was evaluated in whole blood via (1) pre-defined composite scores of 19 inflammation-associated genes and 34 Type I IFN response genes, and (2) pro-inflammatory and antiviral transcription factor activity inferred from promotor based bioinformatics analyses of genes showing > 25% difference in average expression levels across groups. All analyses were adjusted for age, gender, body mass index, diabetes, immunosuppression, cardiovascular disease (CVD), and frailty.

Results

Relative to controls, those with unfavorable outcomes demonstrated higher expression of the pro-inflammatory gene composite prior to TAVR (p < 0.01) and bioinformatic indicators of elevated Nuclear Factor kB (p < 0.001) and Activator Protein 1 (p < 0.001) transcription factor activity, but no significant differences in Type I IFN-related gene expression.

Conclusions

These results demonstrate that a pro-inflammatory state prior to TAVR, independent of CVD severity and frailty status, is associated with worse long-term procedural outcomes.

The novel coronavirus disease-2019 (COVID-19) pandemic has created uncertainty in the management of patients with severe aortic stenosis. This population experiences high mortality from delays in treatment of valve disease but is largely overlapping with the population of highest mortality from COVID-19. The authors present strategies for managing patients with severe aortic stenosis in the COVID-19 era. The authors suggest transitions to virtual assessments and consultation, careful pruning and planning of necessary testing, and fewer and shorter hospital admissions. These strategies center on minimizing patient exposure to COVID-19 and expenditure of human and health care resources without significant sacrifice to patient outcomes during this public health emergency. Areas of innovation to improve care during this time include increased use of wearable and remote devices to assess patient performance and vital signs, devices for facile cardiac assessment, and widespread use of clinical protocols for expedient discharge with virtual physical therapy and cardiac rehabilitation options.

Aims

Impaired physical function is common in patients undergoing transcatheter aortic valve replacement (TAVR) and associated with worse outcomes. Participation in centre-based cardiac rehabilitation (CR) after cardiovascular procedures is sub-optimal. We aimed to test a home-based mobile health exercise intervention as an alternative or complementary approach.

Methods and results

At five centres, after a run-in period, eligible individuals treated with TAVR were randomized 1:1 at their 1-month post-TAVR visit to an intervention group [activity monitor (AM) with personalized daily step goal and resistance exercises] or a control group for 6 weeks. Among 50 participants, average age was 76 years, 34% were female, average STS score was 2.91.8, and 40% had Short Physical Performance Battery (SPPB) 9. Daily compliance with wearing the AM and performing exercises averaged 8590%. In the intention to treat population, there was no evidence that the intervention improved the co-primary endpoints: daily steps +769 (95% CI 244 to +1783); SPPB +0.68 (0.27 to 1.53); and Kansas City Cardiomyopathy Questionnaire 1.7 (9.1 to 7.1). The intervention did improve secondary physical activity parameters, including moderate-to-intense daily active minutes (P<0.05). In a pre-specified analysis including participants who did not participate in CR (n=30), the intervention improved several measures of physical activity: +1730 (1003360) daily steps; +66 (28105) daily active minutes; +53 (2780) moderate-to-intense active minutes; and 157 (265 to 50) sedentary minutes.

Conclusion

Among selected participants treated with TAVR, this study did not provide evidence that a pragmatic home-based mobile health exercise intervention improved daily steps, physical performance or QoL for the overall cohort. However, the intervention did improve several measures of daily activity, particularly among individuals not participating in CR.

Trial registry

Clinicaltrials.gov NCT03270124.

Background Blood pressure (BP) guidelines for patients with aortic stenosis or a history of aortic stenosis treated with aortic valve replacement (AVR) match those in the general population, but this extrapolation may not be warranted. Methods and Results Among patients enrolled in the Medtronic intermediate, high, and extreme risk trials, we included those with a transcatheter AVR (n=1794) or surgical AVR (n=1103) who were alive at 30 days. The associations between early (average of discharge and 30 day post-AVR) systolic BP (SBP) and diastolic BP (DBP) measurements and clinical outcomes between 30 days and 1 year were evaluated. Among 2897 patients, after adjustment, spline curves demonstrated an association between lower SBP (<120 mm Hg, representing 21% of patients) and DBP (<60 mm Hg, representing 30% of patients) and increased all-cause and cardiovascular mortality and repeat hospitalization. These relationships were unchanged when patients with moderate-to-severe aortic regurgitation post-AVR were excluded. After adjustment, compared with DBP 60 to <80 mm Hg, DBP 30 to <60 mm Hg was associated with increased all-cause (adjusted hazard ratio 1.62, 95% CI 1.23-2.14) and cardiovascular mortality (adjusted hazard ratio 2.13, 95% CI 1.52-3.00), but DBP 80 to <100 mm Hg was not. Similarly, after adjustment, compared with SBP 120 to <150 mm Hg, SBP 90 to <120 mm Hg was associated with increased all-cause (adjusted hazard ratio 1.63, 95% CI 1.21-2.21) and cardiovascular mortality (adjusted hazard ratio 1.81, 95% CI 1.25-2.61), but SBP 150 to <180 mm Hg was not. Conclusions Lower BP in the first month after transcatheter AVR or surgical AVR is common and associated with increased mortality and repeat hospitalization. Clarifying optimal BP targets in these patients ought to be a priority and may improve patient outcomes. Clinical Trial Registration Information URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01586910, NCT01240902.

Background Left ventricular hypertrophy (LVH) is associated with increased mortality risk and rehospitalization after transcatheter aortic valve replacement among those with severe aortic stenosis. Whether cardiac troponin (cTnT) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) risk stratify patients with aortic stenosis and without LVH is unknown. Methods and Results In a multicenter prospective registry of 923 patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, we included 674 with core-laboratory-measured LV mass index, cTnT, and NT-proBNP. LVH was defined by sex-specific guideline cut-offs and elevated biomarker levels were based on age and sex cut-offs. Adjusted Cox proportional hazards models evaluated associations between LVH and biomarkers and all-cause death out to 5 years. Elevated cTnT and NT-proBNP were present in 82% and 86% of patients with moderate/severe LVH, respectively, as compared with 66% and 69% of patients with no/mild LVH, respectively (P<0.001 for each). After adjustment, compared with no/mild LVH, moderate/severe LVH was associated with an increased hazard of mortality (adjusted hazard ratio [aHR], 1.34; 95% CI 1.01-1.77, P=0.043). cTnT and NT-proBNP each risk stratified patients with moderate/severe LVH (P<0.05). In a model with both biomarkers and LVH included, elevated cTnT (aHR, 2.08; 95% CI 1.45-3.00, P<0.001) and elevated NT-proBNP (aHR, 1.46; 95% CI 1.00-2.11, P=0.049) were each associated with increased mortality risk, whereas moderate/severe LVH was not (P=0.15). Conclusions Elevations in circulating cTnT and NT-proBNP are more common as LVH becomes more pronounced but are also observed in those with no/minimal LVH. As measures of maladaptive remodeling and cardiac injury, cTnT and NT-proBNP predict post-transcatheter aortic valve replacement mortality better than LV mass index. These findings may have important implications for risk stratification and treatment of patients with aortic stenosis.

Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.

Background The neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic inflammation has been associated with worse prognosis in several chronic disease states, including heart failure. However, few data exist on the prognostic impact of elevated baseline NLR or change in NLR levels during follow-up in patients undergoing transcatheter or surgical aortic valve replacement (TAVR or SAVR) for aortic stenosis. Methods and Results NLR was available in 5881 patients with severe aortic stenosis receiving TAVR or SAVR in PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials/registries (median [Q1, Q3] NLR, 3.30 [2.40, 4.90]); mean NLR, 4.10; range, 0.5-24.9) and was evaluated as continuous variable and categorical tertiles (low: NLR ≤2.70, n=1963; intermediate: NLR 2.70-4.20, n=1958; high: NLR ≥4.20, n=1960). No patients had known baseline infection. High baseline NLR was associated with increased risk of death or rehospitalization at 3 years (58.4% versus 41.0%; adjusted hazard ratio [aHR], 1.39; 95% CI, 1.18-1.63; P<0.0001) compared with those with low NLR, irrespective of treatment modality. In both patients treated with TAVR and patients treated with SAVR, NLR decreased between baseline and 2 years. A 1-unit observed decrease in NLR between baseline and 1 year was associated with lower risk of death or rehospitalization between 1 year and 3 years (aHR, 0.86; 95% CI, 0.82-0.89; P<0.0001). Conclusions Elevated baseline NLR was independently associated with increased subsequent mortality and rehospitalization after TAVR or SAVR. The observed decrease in NLR after TAVR or SAVR was associated with improved outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00530894, NCT0134313, NCT02184442, NCT03225001, NCT0322141.

Background Global longitudinal strain (GLS) is a sensitive measure of left ventricular function and a risk marker in severe aortic stenosis. We sought to determine whether biomarkers of cardiac damage (cardiac troponin) and stress (NT-proBNP [N-terminal pro-B-type natriuretic peptide]) could complement GLS to identify patients with severe aortic stenosis at highest risk. Methods and Results From a multicenter prospective cohort of patients with symptomatic severe aortic stenosis who underwent transcatheter aortic valve implantation, we measured absolute GLS (aGLS), cardiac troponin, and NT-proBNP at baseline in 499 patients. Left ventricular ejection fraction <50% was observed in 19% and impaired GLS (aGLS <15%) in 38%. Elevations in cardiac troponin and NT-proBNP were present in 79% and 89% of those with impaired GLS, respectively, as compared with 63% and 60% of those with normal GLS, respectively (P<0.001 for each). aGLS <15% was associated with increased mortality in univariable analysis (P=0.009), but, in a model with both biomarkers, aGLS, and clinical covariates included, aGLS was not associated with mortality; elevation in each biomarker was associated with an increased hazard of mortality (adjusted hazard ratio, >2; P≤0.002 for each) when the other biomarker was elevated, but not when the other biomarker was normal (interaction P=0.015). Conclusions Among patients with symptomatic severe aortic stenosis undergoing transcatheter aortic valve implantation, elevations in circulating cardiac troponin and NT-proBNP are more common as GLS worsens. Biomarkers of cardiac damage and stress are independently associated with mortality after transcatheter aortic valve implantation, whereas GLS is not. These findings may have implications for risk stratification of asymptomatic patients to determine optimal timing of valve replacement.