The role of Matrix Metalloproteinase-2 and Galectin-3 as predictive biomarkers for all-cause mortality in patients undergoing transfemoral transcatheter aortic valve implantation.

BACKGROUND: Currently available risk scores fail to accurately predict morbidity and mortality in patients with severe symptomatic aortic stenosis who undergo transcatheter aortic valve implantation (TAVI). In this context, biomarkers like matrix metalloproteinase-2 (MMP-2) and Galectin-3 (Gal-3) may provide additional prognostic information. METHODS: Patients with severe aortic stenosis undergoing consecutive, elective, transfemoral TAVI were included. Baseline demographic data, functional status, echocardiographic findings, clinical outcomes and biomarker levels were collected and analysed. RESULTS: The study cohort consisted of 89 patients (age 80.4 ± 5.1 years, EuroScore II 7.1 ± 5.8%). During a median follow-up period of 526 d, 28 patients (31.4%) died. Among those who died, median baseline MMP-2 (alive: 221.6 [170.4; 263] pg/mL vs. deceased: 272.1 [225; 308.8] pg/mL, p < 0.001) and Gal-3 levels (alive: 19.1 [13.5; 24.6] pg/mL vs. deceased: 25 [17.6; 29.5] pg/mL, p = 0.006) were higher than in survivors. In ROC analysis, MMP-2 reached an acceptable level of discrimination to predict mortality (AUC 0.733, 95% CI [0.62; 0.83], p < 0.001), but the predictive value of Gal-3 was poor (AUC 0.677, 95% CI [0.56; 0.79], p = 0.002). Kaplan-Meier and Cox regression analyses showed that patients with MMP-2 and Gal-3 concentrations above the median at baseline had significantly impaired long-term survival (p = 0.004 and p = 0.02, respectively). CONCLUSIONS: In patients with severe aortic stenosis undergoing transfemoral TAVI, MMP-2 and to a lesser extent Gal-3, seem to have additive value in optimizing risk prediction and streamlining decision-making.

Identification of Circulating Inflammatory Proteins Associated with Calcific Aortic Valve Stenosis by Multiplex Analysis.

Calcific aortic valve stenosis (CAVS) is characterized by increasing inflammation and progressive calcification in the aortic valve leaflets and is a major cause of death in the aging population. This study aimed to identify the inflammatory proteins involved in CAVS and provide potential therapeutic targets. We investigated the observational and causal associations of 92 inflammatory proteins, which were measured using affinity-based proteomic assays. Firstly, the case-control cohort identified differential proteins associated with the occurrence and progression of CAVS. Subsequently, we delved into exploring the causal impacts of these associated proteins through Mendelian randomization. This involved utilizing genetic instruments derived from cis-protein quantitative loci identified in genome-wide association studies, encompassing a cohort of over 400,000 individuals. Finally, we investigated the gene transcription and protein expression levels of inflammatory proteins by single-cell and immunohistochemistry analysis. Multivariate logistic regression and spearman's correlation analysis showed that five proteins showed a significant positive correlation with disease severity. Mendelian randomization showed that elevated levels of two proteins, namely, matrix metallopeptidase-1 (MMP1) and sirtuin 2 (SIRT2), were associated with an increased risk of CAVS. Immunohistochemistry and single-cell transcriptomes showed that expression levels of MMP1 and SIRT2 at the tissue and cell levels were significantly higher in calcified valves than in non-calcified control valves. These findings indicate that MMP1 and SIRT2 are causally related to CAVS and open up the possibility for identifying novel therapeutic targets.

Adipokines are possible risk markers for aortic stenosis requiring surgery.

OBJECTIVES: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR). DESIGN: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents. RESULTS: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92-1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08-1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82-1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64-0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI). CONCLUSIONS: The adipokine leptin may promote the development of AS.

Association of B-type natriuretic peptide with rapid progression in patients with aortic stenosis.

BACKGROUND: Rapid progression of aortic stenosis (AS) is associated with poor outcomes, and the impact of B-type natriuretic peptide (BNP) on AS progression remains unknown. OBJECTIVES: The purpose of the present study was to investigate the association between BNP level and the AS progression rate. METHODS: From January 2016 to June 2021, 200 AS patients with progression who had at least two transthoracic echocardiograms with a maximum interval of 180 days were retrospectively analyzed. Rapid progression of AS was defined as the annual increase of aortic jet velocity (Vmax) ≥0.3 m/s/year. For analyses, both the log-transformed BNP and the BNP ratio were used. The linear regression and binary logistic regression analyses were used to determine the association between BNP and the AS progression. RESULTS: At a median echocardiographic follow-up of 595 days, the annual median (interquartile) progression of Vmax was 0.26 (0.09-0.58) m/s/year. Patients with rapid progression had higher age, log BNP, and higher percentage of diabetes and male gender. Higher tertiles of log BNP and BNP ratio had more rapid increase in Vmax (p = 0.018 and 0.033, respectively). BNP ratio significantly correlated with Vmax progression in univariate and multivariate linear regression analyses (p < 0.001 and p = 0.001, respectively). Moreover, both the univariate and multivariate binary logistic regression analyses showed that the log BNP and BNP ratio were associated with the rapid progression of AS (p < 0.050 for all). CONCLUSIONS: Higher BNP was independently associated with the rapid progression of AS.

Evaluation of left ventricular diastolic function in patients operated for aortic stenosis.

BACKGROUND: Left ventricular diastolic dysfunction is common in patients with aortic valve stenosis (AS) and reportedly affects prognosis after surgical aortic valve replacement (SAVR). Here we investigated whether and how diastolic function (assessed following the most recent guidelines) was affected by SAVR, and whether preoperative diastolic function affected postoperative outcome. We also examined whether long-term mortality was associated with preoperative NT-proBNP and postoperative heart failure (PHF). METHODS: We performed a prospective observational study of 273 patients with AS who underwent AVR with or without concomitant coronary artery bypass surgery. Of these patients, 247 were eligible for assessment of left ventricular (LV) filling pressure. Preoperatively and at the 6-month postoperative follow-up, we measured N-terminal pro-B type natriuretic peptide (NT-proBNP) in serum and assessed diastolic function with Doppler echocardiography. PHF was diagnosed using prespecified criteria. Multivariable logistic regression was performed to explore variables associated with high LV filling pressure. Cox regression was performed to explore variables associated with mortality, accounting for timeto-event. RESULTS: At the time of surgery, 22% (n = 54) of patients had diastolic dysfunction expressed as high LV filling pressure. Of these 54 patients, 27 (50%) showed postoperative diastolic function improvement. Among the 193 patients with preoperative low LV filling pressure, 24 (12%) showed postoperative diastolic function deterioration. Increased long-term mortality was associated with PHF and high preoperative NT-proBNP, but not with preoperative or postoperative diastolic dysfunction. Cox regression revealed the following independent risk factors for long-term mortality: diabetes, renal dysfunction, preoperative NT-proBNP>960 ng/L, age, and male gender. CONCLUSIONS: Surgery for aortic stenosis improved diastolic function in patients with high LV filling pressure in 50% of the patients. Our results could not confirm the previously suggested role of diastolic dysfunction as a marker for poor long-term survival after SAVR. Our findings showed that both PHF and high preoperative NT-proBNP were associated with long-term mortality.

Lipoprotein(a) and Body Mass Compound the Risk of Calcific Aortic Valve Disease.

BACKGROUND: High plasma lipoprotein(a) and high body mass index are both causal risk factors for calcific aortic valve disease. OBJECTIVES: This study sought to test the hypothesis that risk of calcific aortic valve disease is the highest when both plasma lipoprotein(a) and body mass index are extremely high. METHODS: From the Copenhagen General Population Study, we used information on 69,988 randomly selected individuals recruited from 2003 to 2015 (median follow-up 7.4 years) to evaluate the association between high lipoprotein(a) and high body mass index with risk of calcific aortic valve disease. RESULTS: Compared with individuals in the 1st to 49th percentiles for both lipoprotein(a) and body mass index, the multivariable adjusted HRs for calcific aortic valve disease were 1.6 (95% CI: 1.3-1.9) for the 50th to 89th percentiles of both (16% of all individuals) and 3.5 (95% CI: 2.5-5.1) for the 90th to 100th percentiles of both (1.1%) (P for interaction = 0.92). The 10-year absolute risk of calcific aortic valve disease increased with higher lipoprotein(a), body mass index, and age, and was higher in men than in women. For women and men 70-79 years of age with body mass index ≥30.0 kg/m2, 10-year absolute risks were 5% and 8% for lipoprotein(a) ≤42 mg/dL (88 nmol/L), 7% and 11% for 42-79 mg/dL (89-169 nmol/L), and 9% and 14% for lipoprotein(a) ≥80 mg/dL (170 nmol/L), respectively. CONCLUSIONS: Extremely high lipoprotein(a) levels and extremely high body mass index together conferred a 3.5-fold risk of calcific aortic valve disease. Ten-year absolute risk of calcific aortic valve disease by categories of lipoprotein(a) levels, body mass index, age, and sex ranged from 0.4% to 14%.

Relation of Preprocedure Platelet-to-Lymphocyte Ratio and Major Adverse Cardiovascular Events Following Transcatheter Aortic Valve Implantation for Aortic Stenosis.

The platelet-to-lymphocyte ratio (PLR) is a novel inflammatory biomarker that has prognostic value in patients presenting with acute coronary syndrome. Transcatheter aortic valve implantation (TAVI) treats the inflammatory disease of aortic stenosis. However, the utility of preprocedure PLR in predicting major adverse cardiovascular events (MACE) after TAVI is not clear. Our study population included 470 patients who underwent TAVI at The Alfred Hospital in Melbourne, Australia from August 2008, to January 2019. Patients were divided into 4 groups based on PLR quartiles. The incidence of 30-day MACE (a composite of stroke, myocardial infarction, and death) was then compared. Outcomes were reported according to the Valve Academic Research Consortium-2 criteria. Of 470 patients, median age 84 years, 54% men, and median Society of Thoracic Surgeons score of 3.5%, 14 (3%) suffered a MACE within 30 days. Rates of MACE were low in all 4 groups (1.7%, 2.5%, 2.6%, 5.1%, respectively) with no statistically significant difference in the different PLR groups (p = 0.46). This nonsignificant association was supported by univariate logistic regression analysis of PLR as a continuous variable (odds ratio 1.01, p = 0.55). Using multivariable logistic regression analysis accounting for age, gender, self-expanding valve, and procedural risk, a higher PLR did not correlate with MACE (odds ratio 1.01, p = 0.60). In this study of a large cohort of TAVI patients, elevated preprocedure PLR was not independently associated with MACE after TAVI. This is a novel finding in comparison with previous studies.

Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk.

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

Differential systemic inflammatory responses after TAVI: The role of self versus balloon expandable devices.

OBJECTIVE: Transcatheter aortic valve implantation (TAVI) provokes early injury response, represented in part by dynamic changes in the inflammatory markers. The association of self-expanding valves (SEVs) and balloon-expandable valves (BEVs) with the consequent inflammatory response remains uncertain. MATERIALS AND METHODS: Patients with severe symptomatic aortic stenosis who underwent transfemoral TAVI: SEVs or BEVs, from January 2010 to December 2019 were enrolled. Whole white blood cells (WBC) and subpopulation dynamics as well the neutrophil to lymphocyte ratio (NLR) were evaluated. RESULTS: Three-hundred seventy consecutive patients (mean age 81.75 ± 6.8 years, 199 women's) were enrolled. In the entire population, significant kinetic changes in the WBC response (p <0.0001) between admission and first 24 hours post procedure, with a significant increase in total WBC (7.46 ± 2.26 to 10.08 ± 3.55) and absolute neutrophil count (4.97 ± 2.06 to 8.19 ± 3.43), NL ratio (3.72 ± 2.8 to 9.76 ± 7.29), and a meaningful decrease in absolute lymphocytes count (1.67 ± 1.1 to 1.1 ± 0.76). When compared between the types of valves, SEVs were associated with a more pronounced inflammatory response than BEVs, with total WBC (10.44 ± 3.86 vs. 9.45 ± 3.19) neutrophils (8.56 ± 3.75 vs. 7.55 ± 3.06) with p 0.016 and 0.012 respectively. CONCLUSION: This is the first description of a differential inflammatory response between the two leading delivery systems. SEV appears to trigger a more robust inflammatory response as compared to BEV. Clinical studies are warranted to assess the long term effect of our findings.

Whole blood viscosity in patients with aortic stenosis.

Whole blood viscosity (WBV) may promote endothelial shear stress, inflammation, and can accelerate the atherosclerotic process. We aimed to evaluate the relationship between WBV and aortic stenosis. The study included 209 participants of whom 49 patients had severe aortic stenosis, 98 patients had mild-to-moderate aortic stenosis and 62 patients served as control. WBV values were significantly higher for high shear rate (HSR) (P = 0.001) and for low shear rate (LSR) (P = 0.002) in severe aortic stenosis group. HSR and LSR were correlated with mean systolic transaortic gradient (P < 0.001 and P < 0.001, respectively). WBV for both LSR and HSR were found to be independent predictors for the aortic stenosis severity (P = 0.034 and P = 0.049, respectively). We found a significant relationship between WBV and aortic stenosis.

Baseline pro-inflammatory gene expression in whole blood is related to adverse long-term outcomes after transcatheter aortic valve replacement: a case control study.

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.

JCL Roundtable: Global Think Tank on Lipoprotein(a).

Lipoprotein(a) operates in causal pathways to promote atherosclerosis, arterial thrombosis, and aortic stenosis. It has been associated with rare cases of nonatherosclerotic arterial thrombotic stroke at any age. Inherited variation of lipoprotein(a) levels substantially increases cardiovascular risk in 20% of people worldwide. Recent progress in identifying the risk associated with lipoprotein(a) and in pursuing effective treatment has led to a recent Global Think Tank including representatives from the European Atherosclerosis Society, American Heart Association, Preventive Cardiovascular Nurses Association, National Lipid Association, and other groups. The need for standardized laboratory measurement in nanomoles per liter met with unanimous consensus. Atherosclerotic risk is linearly associated with plasma lipoprotein(a) levels, so that persons with the highest levels may have risk similar to other severe inherited lipoprotein disorders. Universal once-in-lifetime screening has been recommended by European and Canadian cardiovascular societies, but not by U.S. organizations. Current pharmacologic therapies are limited to 20-30% lowering of lipoprotein(a) levels, and no pharmacologic treatment for lowering lipoprotein(a) has yet been proven to reduce risk in a cardiovascular outcomes trial. Treatment for high-risk patients focuses on reducing low density lipoprotein cholesterol and other risk factors. New therapies targeting messenger RNA for apolipoprotein(a) can achieve 80-90% reduction of lipoprotein(a) levels. One such therapy using a liver-directed antisense oligonucleotide is currently being tested in a large cardiovascular outcomes trial. Increased recognition of lipoprotein(a)-associated risk and emergence of potentially effective therapy together lead to a mandate for a unified global effort on education, standardization, and clinical management.

Coagulation derangement and risk factors for valve thrombosis following transcatheter aortic valve implantation.

AIMS: Durability of transcatheter aortic valve implantation (TAVI) is key to its expansion. We sought to identify incidence of valve thrombosis and predictors of valve thrombosis in our single centre with associated coagulation testing pre-TAVI and post-TAVI. METHODS AND RESULTS: This single-centre observational study comprised patients undergoing transfemoral TAVI discussed in the Heart Team meeting . Patients were followed up with echocardiography at 120 days to identify incidence of elevated transvalvular gradient and multivariable analysis was performed to identify factors associated with an increased odds of developing valve thrombosis. In addition, 11 patients underwent baseline, day 1 and day 120 post-TAVI coagulation testing. Between August 2017 and August 2019, 437 consecutive patients underwent transfemoral TAVI. Of these patients, 207/437 (47.4%) had 3-month follow-up echo data available and were analysed. Of these patients, 26/207 (12.6%) had elevated transvalvular gradients. These patients tended to be younger (80±14 vs 83±6 years; p=0.047) with a lower ejection fraction (49±13 vs 54%±11%; p=0.021), with a greater proportion of the population experiencing atrial fibrillation (14/21, 54% vs 68/181, 38%; p=0.067). Following multivariable analysis, there remained a trend towards higher eccentricity index associated with elevated gradients. Baseline (pre-TAVI) elevation of thrombin antithrombin levels (56±63; reference range 1.0-4.1 ng/L) and PF 1+2 (791±632; reference range 69-229 ng/mL) normalised at 120 days post-TAVI CONCLUSION: This study demonstrated that in the cohort of patients undergoing transfemoral TAVI in our centre: younger age, poor ejection fraction, atrial fibrillation and increased baseline eccentricity of the aortic valve annulus were present to a greater extent in patients exhibiting elevated transvalvular gradients at 3-month follow-up. Further work is required to delineate the extent of coagulation derangement and confirm predictors of thrombosis.

Impact of Comorbidities and Antiplatelet Regimen on Platelet Reactivity Levels in Patients Undergoing Transcatheter Aortic Valve Implantation.

ABSTRACT: The aim of our study is to assess the impact of anemia, chronic kidney disease, and diabetes mellitus on platelet reactivity (PR) in patients with severe aortic stenosis, both at baseline and after transcatheter aortic valve implantation (TAVI). This study is a prespecified subanalysis of the REAC-TAVI prospective, multicenter trial that included patients pretreated with aspirin + clopidogrel before TAVI. PR was measured at baseline and at 5 different time points after TAVI with the VerifyNow assay (Accriva Diagnostics, San Diego, CA), over a 3-month follow-up period. Patients with high PR (HPR) at baseline, before TAVI (n = 48) were randomized to aspirin + clopidogrel or aspirin + ticagrelor for 3 months, whereas those with normal PR (NPR) (n = 20) were continued on aspirin + clopidogrel. A "raiser response" in PR was defined as an increase in PR units >20% of baseline after TAVI. Patients with HPR before TAVI presented concomitant anemia and chronic kidney disease more frequently than their counterparts with NPR. Anemia and higher body mass index were independently associated with HPR to clopidogrel at baseline. Moreover, anemic patients with baseline HPR who were continued on clopidogrel presented higher PR after TAVI than patients with HPR switched to ticagrelor. All patients with baseline NPR presented a "raiser response" after TAVI, which was nonexistent among patients with HPR managed with ticagrelor. In summary, anemia seems as a relevant factor associated with baseline HPR and higher PR after TAVI in patients with baseline HPR randomized to clopidogrel, whereas ticagrelor proved more effective than clopidogrel at attaining sustained reductions in PR during follow-up, regardless of baseline comorbidities.

Incidence and Impact of Routine Inflammatory Parameters on Outcome after Transcatheter Aortic Valve Replacement.

BACKGROUND: Previous research reported adverse clinical outcomes in association with systemic inflammation (SI) after transcatheter aortic valve replacement (TAVR). However, data characterizing the impact of SI, as reflected by postprocedural routine inflammatory parameters (pRIP), on clinical outcome of patients undergoing TAVR are sparse. OBJECTIVES: In light of this, the present work aimed to analyze incidence and clinical significance of pRIP after transapical (TA) and transfemoral (TF)-TAVR. METHODS AND RESULTS: Data of 81 high-risk consecutive patients undergoing TAVR in our center from 2017 to 2018 were analyzed in a retrospective manner. 40 out of 81 patients (49, 4%) were treated via TF access (group A) and 41 patients via TA access (group B). Incidence, cause, and amplitude of pRIP were analyzed in relation to pre- and peri-interventional data. Assessment of outcomes was conducted according to the valve academic research consortium (VARC-2). Postprocedural C-reactive protein (pCRP) and leucocytes (pL) were significantly increased in patients undergoing TA-TAVR (group B) vs. TF-TAVR (group A; 12.1 ± 9.7 vs. 22.1 ± 7.9 mg/dl, p < 0.001 and 12.8 ± 4.0 vs. 14.2 ± 3.8/nl, p = 0.002); however, there was no significant difference regarding incidence of postprocedural fever (pF) ≥38.0°C (12.5% vs. 22%, p = 0.37). Furthermore, we observed a vast (though insignificant) trend towards a longer fever duration in group B vs. group A (9.9 ± 14.9 vs. 3.2 ± 5.9 hours, p = 0.06). Further analysis identified pCRP >30 mg/dl (hazard ratio (HR) 3.15, confidence interval (CI) 1.22-8.14, p = 0.018) and European System for Cardiac Operative Risk Evaluation (logistic EuroSCORE I (ES)) >20% (HR 2.95, CI 1.17-7.47, p = 0.02) as predictors of mortality; in this context, we also discovered a marginally significant trend for pL > 14/nl (HR 2.44, CI 0.97-6.14, p = 0.05). Multivariate analysis by use of the fisher`s exact test revealed a significant association between pCRP >30 mg/dl and ES >20% (p < 0.001). CONCLUSION: pRIP are significantly increased in patients undergoing TA-TAVR. pCRP >30 mg/dl, ES>20%, and pL > 14/nl are hallmark of adverse prognosis and require further investigation.

Lipoprotein(a) is robustly associated with aortic valve calcium.

OBJECTIVES: To investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC. METHODS: We included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC. RESULTS: The prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (ß 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase). CONCLUSIONS: Lp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.

Transcatheter Aortic Valve Implantation Induces Transient Drop in Platelet Reactivity.

ABSTRACT: Although recent studies described platelet reactivity (PR) changes in days after transcatheter aortic valve implantation (TAVI), precise time course and duration of these changes have not been fully investigated. The aim of this study was to investigate PR pattern during and after TAVI in multiple time points. Study included 40 consecutive patients undergoing TAVI. All patients underwent the procedure on dual antiplatelet therapy. PR was measured in 7 time points: before induction of anesthesia (T1), after heparin administration (T2), 10 minutes after initial valve implantation (T3), at the end of procedure (T4), and on 3rd, 6th, and 30th postoperative day (T5-T7). PR was measured using impedance aggregometer using 3 different platelet aggregation agonists (arachidonic acid in ASPItest, adenosine diphosphate in ADPtest and thrombin receptor activating peptide 6 in TRAPtest). All patients underwent successful TAVI procedure. Mean PR on T1 was 22.9 ± 23.0 U for ASPItest, 40.5 ± 23.7 U for ADPtest and 91.7 ± 32.5 U for TRAPtest. There was no significant difference in PR on T2. On T3, significant reduction of PR in all 3 tests was observed [ASPI 10.4 ± 11.6 U (P = 0.001), ADP 24.2 ± 14.1 U (P < 0.001) and TRAP 69.3 ± 26.6 U (P < 0.001)]. PR nadir for all tests was reached on T5, with subsequent PR incline. PR values in all tests returned to baseline levels on T7. Our results show that successful TAVI procedure induces transient decrease in PR regardless of the platelet activation pathway.

Evaluation of latest viscoelastic coagulation assays in the transcatheter aortic valve implantation setting.

BACKGROUND: Point of care viscoelastic measures with thromboelastography (TEG; Haemonetics Corporation, Switzerland) and thromboelastometry (ROTEM, Tem Innovations GmbH, Germany) now supersede laboratory assays in the perioperative assessment and management of coagulation. To the best of our knowledge, this sophisticated coagulation assessment has not been performed to characterise thrombotic changes in the transcatheter aortic valve implantation (TAVI) setting, nor have the two latest iteration cartridge-based systems been directly compared in the elective perioperative period. METHODS: Patients undergoing TAVI were prospectively recruited. Samples (n=44) were obtained at four timepoints (postinduction of anaesthesia, postheparin (100 IU/kg), postprotamine (1 mg/100 IU heparin) and 6 hours postoperatively). Each sample was concurrently assessed with standard laboratory tests (prothrombin time/international normalised ratio, activated partial thromboplastin time, thrombin clotting time, platelet count and direct fibrinogen, ROTEMSigma and TEG6s). RESULTS: Clot strength showed a statistically significant increase postheparin/TAVI deployment. When considering the subgroup of samples taken following the administration heparin, the heparinase channel of the TEG6s did not yield clotting strength results in 55% of samples and clotting time exceeded the upper limit of normal in 70% of samples. It was retrospectively recognised that the arachidonic acid channel of the TEG6s Platelet Mapping Cartridge had been decommissioned prohibiting assessment of aspirin effect. CONCLUSIONS: This study demonstrated a small intraprocedural prothrombotic change of uncertain clinical importance during the transcatheter aortic valve procedure. Further comparison with percutaneous coronary intervention and aortic valve replacement cohorts are needed to assess the merits of current antithrombotic guidelines, which are extrapolated from the PCI setting. The heparin effect was more consistently quantified by ROTEM.