Increased Complement Factor B and Bb Levels Are Associated with Mortality in Patients with Severe Aortic Stenosis.

Inflammation is involved in initiation and progression of aortic stenosis (AS). However, the role of the complement system, a crucial component of innate immunity in AS, is unclear. We hypothesized that circulating levels of complement factor B (FB), an important component of the alternative pathway, are upregulated and could predict outcome in patients with severe symptomatic AS. Therefore, plasma levels of FB, Bb, and terminal complement complex were analyzed in three cohorts of patients with severe symptomatic AS and mild-to-moderate or severe asymptomatic AS (population 1, n = 123; population 2, n = 436; population 3, n = 61) and in healthy controls by enzyme immunoassays. Compared with controls, symptomatic AS patients had significantly elevated levels of FB (2.9- and 2.8-fold increase in population 1 and 2, respectively). FB levels in symptomatic and asymptomatic AS patients were comparable (population 2 and 3), and in asymptomatic patients FB correlated inversely with valve area. FB levels in population 1 and 2 correlated with terminal complement complex levels and measures of systemic inflammation (i.e., CRP), cardiac function (i.e., NT-proBNP), and cardiac necrosis (i.e., Troponin T). High FB levels were significantly associated with mortality also after adjusting for clinical and biochemical covariates (hazard ratio 1.37; p = 0.028, population 2). Plasma levels of the Bb fragment showed a similar pattern in relation to mortality. We concluded that elevated levels of FB and Bb are associated with adverse outcome in patients with symptomatic AS. Increased levels of FB in asymptomatic patients suggest the involvement of FB from the early phase of the disease.

Determinants and Outcome of Decision Making Among Patients with Severe Aortic Stenosis.

BACKGROUND AND AIM OF THE STUDY: Aortic valve replacement (AVR) improves survival and quality of life in patients with severe aortic stenosis (AS), but despite clear indications for surgical treatment a significant proportion of patients do not undergo AVR. The study aim was to identify clinical variables associated with the decision to perform AVR, and to assess the prognostic effect of surgery versus medical treatment in patients with severe AS adjusted for significant confounders and effect modifiers. METHODS: A prospective observational study of consenting patients aged >18 years who were under consideration for AVR at the authors' tertiary teaching hospital was conducted. The main outcomes of the study were treatment decisions and survival. RESULTS: Among 480 patients with severe AS who were evaluated, 351 had surgical AVR, 38 had transcatheter AVR, and 91 were declined operative treatment. Typically, non-operated patients were older, were in a lower NYHA class, had fewer symptoms, a lower peak aortic jet velocity, a higher NT-proBNP level, and a lower physical summary score (SF-36). Higher age showed the strongest correlation against AVR (OR 0.91; 95% CI 0.87-0.94). One-, three-, and five-year cumulative survival rates, respectively, were 95%, 87%, and 73% among operated patients, and 82%, 47%, and 27% among non-operated patients. The median survival time was 1,604 days (95% CI 1,554-1,655) in operated patients versus 1,090 days (95% CI 954-1,226) in non-operated patients (p <0.001). The effect of operation on mortality was shown to depend on the interaction with diabetes, when adjusted for significant confounders (i.e., age, atrial fibrillation, NT-proBNP, hs-Troponin T, and NYHA class). An effect of AVR on mortality was found in patients without diabetes (HR 0.29; 95% CI 0.19-0.468; p <0.001), but not among patients with diabetes. CONCLUSIONS: Supplemental and better parameters to improve patient selection are warranted. Surgical AVR shows a greater prognostic effect in patients without diabetes.

Outcomes in asymptomatic, severe aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Patients with asymptomatic, severe aortic stenosis are presumed to have a benign prognosis. In this retrospective cohort study, we examined the natural history of contemporary patients advised against aortic valve replacement due to a perceived lack of symptoms. MATERIALS AND METHODS: We reviewed the medical records of every patient given the ICD-10-code for aortic stenosis (I35.0) at Oslo University Hospital, Rikshospitalet, between Dec 1st, 2002 and Dec 31st, 2016. Patients who were evaluated by the heart team due to severe aortic stenosis were categorized by treatment strategy. We recorded baseline data, adverse events and survival for the patients characterized as asymptomatic and for 100 age and gender matched patients scheduled for aortic valve replacement. RESULTS: Of 2341 patients who were evaluated for aortic valve replacement due to severe aortic stenosis, 114 patients received conservative treatment due to a lack of symptoms. Asymptomatic patients had higher mortality than patients who had aortic valve replacement, log-rank p<0.001 (mean follow-up time: 4.0 (SD: 2.5) years). Survival at 1, 2 and 3 years for the asymptomatic patients was 88%, 75% and 63%, compared with 92%, 83% and 78% in the matched patients scheduled for aortic valve replacement. 28 (25%) of the asymptomatic patients had aortic valve replacement during follow-up. Age, previous history of coronary artery disease and N-terminal pro B-type natriuretic peptide (NT-proBNP) were predictors of mortality and coronary artery disease and NT-proBNP were predictors of 3-year morbidity in asymptomatic patients. CONCLUSIONS: In this retrospective study, asymptomatic patients with severe aortic stenosis who were advised against surgery had significantly higher mortality than patients who had aortic valve replacement.

YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.

BACKGROUND: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS. METHODS: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed. RESULTS: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, P<0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], P<0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice). CONCLUSIONS: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.

Patient-reported outcomes after referral for possible valve replacement in patients with severe aortic stenosis.

OBJECTIVES: Health-related quality of life (HRQoL) is an important outcome after surgical aortic valve replacement (SAVR). To improve interpretation of HRQoL, mean score change and change in terms of minimal important difference (MID) were assessed using validated instruments for measuring patient-reported outcomes in patients with severe aortic stenosis referred for possible SAVR. METHODS: Of the 442 included patients with severe aortic stenosis evaluated for possible SAVR, 351 were referred to SAVR (operated) and 91 to medical treatment (unoperated). At presurgical evaluation and 1 year postoperatively, HRQoL was assessed using SF-36v2 and EQ-5D. Results were compared with outcomes reported in unoperated patients. We explored the association of clinical factors and improvements corresponding to MID. RESULTS: Among the operated patients, statistically significant change was found for EQ-5D scores and SF-36 scale scores for physical functioning, role-physical, bodily pain, general health, vitality and physical summary score. The largest proportion of operated patients achieving change corresponding to at least MID was 61.5% for physical summary score. Change in unoperated patients also related largely to physical scales of the SF-36. However, smaller proportions of unoperated patients reported improvements, and larger proportions reported decline reaching MID. Baseline scores, but no clinical covariates, were consistently associated with improved HRQoL reaching MID across instruments for those referred to SAVR. CONCLUSIONS: This study found improvement in HRQoL 1 year after SAVR for patients with severe aortic stenosis. Results in unoperated patients suggest that HRQoL deteriorates 1 year after evaluation of possible SAVR. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01794832).

Age-dependent morbidity and mortality outcomes after surgical aortic valve replacement.

OBJECTIVES: This study addressed the assumption of increased morbidity and mortality after surgical aortic valve replacement in patients older than 80 years with severe aortic stenosis. METHODS: This prospective study was performed in consecutive patients referred for aortic valve replacement. The age-dependent change in cognitive and physical function, quality of life and rehospitalization and complication rates during the following year and 5-year all-cause mortality were documented. RESULTS: A total of 351 patients underwent surgical aortic valve replacement. The death risk at 5 years was 10%, 20% and 34% in patients aged <70 years, 70-79 years and ≥80 years, respectively. Patients aged 70-79 years and ≥80 years had a hazard ratio of 1.88 [95% confidence interval (95% CI) 0.92-3.83, P = 0.08] and 2.90 [95% CI 1.42-5.92, P = 0.003] for mortality, respectively, when compared with patients aged <70 years. The length of stay and rehospitalization rate during the following year were similar between the groups. Patients ≥80 years of age experienced more delirium and infections, whereas the risks of new pacemaker, transient ischaemic attack (TIA) or stroke, myocardial infarction and heart failure were comparable between the age groups. All groups exhibited reduced New York Heart Association class, improved physical quality of life and unchanged mental scores without any clinically significant Mini Mental Status reduction. CONCLUSIONS: Elderly patients (≥80 years of age) have important gains in health measures and satisfactory 5-year survival with an acceptable complications rate during the year following surgery. Active respiratory mobilization and the removal of an indwelling urethra catheter can prevent adverse effects, and measures should be taken to prevent delirium and confusion in elderly patients. Clinical trial registration: clinicaltrials.gov (NCT 01794832).

Prevalence and prognostic implication of iron deficiency and anaemia in patients with severe aortic stenosis.

Objective: The aim of this study was to evaluate the prevalence and prognostic implication of iron deficiency (ID) and anaemia in patients with severe aortic stenosis (AS). Methods: In an observational study of consecutive patients referred for aortic valve replacement (AVR), we assessed a wide range of biomarkers of iron status, including the definition of ID commonly applied in patients with chronic heart failure (ferritin <100 µg/L or ferritin 100-299 µg/L with a transferrin saturation <20%). The endpoints were short-term (one-year) and long-term (median 4.7 years, IQR: 3.8-5.5) mortality and major adverse cardiovascular events (MACE) within the first year after inclusion. Results: 464 patients were included in this substudy. 91 patients (20%) received conservative treatment and 373 patients (80%) received AVR. ID was detected in 246 patients (53%). 94 patients (20%) had anaemia. Patients with ID had an overall worse clinical profile than patients without ID. During follow-up, 129 patients (28%) died. Neither ID as defined above, soluble transferrin receptor nor hepcidin were associated with short-term or long-term mortality or MACE independent on treatment allocation. Anaemia was associated with one-year mortality in conservatively treated patients. Conclusions: ID and anaemia are prevalent in patients with severe AS. In our cohort, ID did not provide independent prognostic information on top of conventional risk factors. More studies are required to determine how to correctly diagnose ID in patients with AS. Trial registration number: NCT01794832.

Associations of brain-natriuretic peptide, high-sensitive troponin T, and high-sensitive C-reactive protein with outcomes in severe aortic stenosis.

OBJECTIVES: Among patients with severe aortic stenosis (AS), we investigated the associations of N-terminal pro-natriuretic peptide (NT-proBNP), high-sensitive troponin T (hsTnT), and high-sensitive C-reactive protein (hs-CRP) with 3-year mortality and major adverse cardiovascular events (MACE) during 1 year. METHODS: This observational cohort study prospectively enrolled 442 patients with severe AS who were referred for evaluation of possible valve replacement. Clinical data was recorded before the decision of whether to operate was made. We studied the prognostic value of assessing biomarkers by serum levels, and tested associations of NT-proBNP, hsTnT, and hs-CRP with clinical outcomes (3-year all-cause mortality and risk of MACE in the year following study inclusion) using adjusted multivariable analysis. RESULTS: Elevated serum levels of these biomarkers at baseline evaluation were associated with increased all-cause 3-year mortality regardless of treatment assignment. Adjusted analysis showed that none of the studied biomarkers (NT-proBNP, hsTnT or hs-CRP) or any other covariates were associated with 3-year all-cause mortality following surgical aortic valve replacement (SAVR). However, adjusted analyses showed that hsTnT (HR, 1.51; 95% CI, 1.11-2.05; P = 0.008) and left ventricular ejection fraction (HR 0.97; 95% CI 0.94-0.97, P = 0.043) was associated with MACE for operated patients. CONCLUSIONS: Whereas NT-proBNP, hsTnT and hs-CRP had no independently prognostic value in relation to all-cause mortality following SAVR, hsTnT was independently associated with MACE following operation. The use of these clinically available biomarkers, in particular hsTnT, should be clarified in larger studies.

Morbidity outcomes after surgical aortic valve replacement.

OBJECTIVE: In patients with mild to moderate operative risk, surgical aortic valve replacement (SAVR) is still the preferred treatment for patients with severe symptomatic aortic stenosis (AS). Aiming to broaden the knowledge of postsurgical outcomes, this study reports a broad set of morbidity outcomes following surgical intervention. METHODS: Our cohort comprised 442 patients referred for severe AS; 351 had undergone SAVR, with the remainder (91) not operated on. All patients were evaluated using the 6-minute walk test (6MWT), were assigned a New York Heart Association class (NYHA) and Canadian Cardiovascular Society class (CCS), with additional scores for health-related quality of life (HRQoL), cognitive function (Mini-Mental State Examination (MMSE)) and myocardial remodelling (at inclusion and at 1-year follow-up). Adverse events and mortality were recorded. RESULTS: Three-year survival after SAVR was 90.0%. SAVR was associated with an improved NYHA class, CCS score and HRQoL, and provoked reverse ventricular remodelling. The 6MWT decreased, while the risks of major adverse cardiovascular events (death, non-fatal stroke/transient ischaemic attack or myocardial infarction) and all-cause hospitalisation (incidence rate per 100 patient-years) were 13.5 and 62.4, respectively. The proportion of cognitive disability measured by MMSE increased after SAVR from 3.2% to 8.8% (p=0.005). Proportion of patients living independently at home, having attained NYHA class I, was met by 49.1% at 1 year. Unoperated individuals had a poor prognosis in terms of any outcome. CONCLUSION: This study provides knowledge of outcomes beyond what is known about the mortality benefit after SAVR to provide insight into the morbidity burden of modern-day SAVR.