Post-Procedure Monocyte Count Levels Predict Major Adverse Cardiovascular Events (MACE) Following Transcatheter Aortic Valve Implantation (TAVI) for Aortic Stenosis.

BACKGROUND: Aortic stenosis has recently been characterised as having an inflammatory aetiology, beyond the traditional degenerative model. Recruitment of monocytes has been associated with inflammation contributing to progression of calcific aortic-valve disease. Prior research has demonstrated that pre-procedure inflammatory biomarkers do not consistently discriminate poorer outcomes in those with aortic stenosis. It remains, however, unclear if postprocedure inflammatory biomarkers, which are influenced by intraprocedural pro-inflammatory insults, can predict major adverse cardiovascular events (MACE) post transcatheter aortic valve implantation (TAVI). METHOD: All patients with postprocedure monocyte levels undergoing transcatheter aortic valve implantation at The Alfred Hospital, Melbourne, Australia (2008-2019) were included. The highest monocyte count from postprocedure days 1 to 3 was used. Patients were divided into "high" or "low" postprocedure monocyte count groups using the Youden Index. The incidence of 30-day MACE a composite of stroke, acute myocardial infarction, and death) was then compared. RESULTS: In total, 472 patients were included (54% men, median age 84 years). Fourteen (14) patients (3%) suffered a 30-day MACE. Those with high postprocedure monocyte count were more likely to: be hypertensive (p=0.049); have a higher Society of Thoracic Surgeons risk score (p=0.032); and, undergo non-transfemoral access (p=0.018). A high (≥0.975) postprocedure monocyte count was significantly associated with 30-day MACE (odds ratio [OR] 1.16 for each 0.1 increase in monocyte, p=0.025). This association remained present on multivariable analysis adjusted for age, sex, Society of Thoracic Surgeons risk score, and self-expanding valve prosthesis type (OR 1.17, p=0.028). CONCLUSIONS: The association between postprocedure monocytosis and 30-day MACE suggests that minimising peri-procedural inflammatory insults may improve outcomes. This inexpensive and readily available biomarker may also aid in tailored risk stratification for patients.

Acute Kidney Injury Following Transcatheter Aortic Valve Implantation-A Contemporary Perspective of Incidence, Predictors, and Outcomes.

BACKGROUND: Acute kidney injury (AKI) is a known complication following transcatheter aortic valve implantation (TAVI), associated with increased morbidity and mortality. Most of this data relates to higher-risk patients with early-generation TAVI valves. With TAVI now established as a safe and cost-effective procedure for low-risk patients, there is a distinct need for updated analysis. We aimed to assess the incidence, predictors, and outcomes of AKI in a contemporary cohort of TAVI patients, concurrently examining the role of temporal evolution on AKI. METHOD: A total of 2,564 patients undergoing TAVI from 2008-2023 included in the Alfred-Cabrini-Epworth (ACE) TAVI Registry were analysed. Patients were divided into AKI and no AKI groups. Outcomes were reported according to the Valve Academic Research Consortium-3 (VARC-3) criteria. RESULTS: Of 2,564 patients, median age 83 (78-87) years, 57.4% men and a median Society of Thoracic Surgeons score of 3.6 (2.4-5.5), 163 (6.4%) patients developed AKI with incidence falling from 9.7% between 2008-2014 to 6% between 2015-2023 (p=0.022). On multivariable analysis, independent predictors of AKI were male sex (adjusted odds ratio [aOR] 1.89, p=0.005), congestive cardiac failure (aOR 1.52, p=0.048), estimated glomerular filtration rate 30-59 (aOR: 2.79, p<0.001), estimated glomerular filtration rate <30 (aOR 8.65, p<0.001), non-femoral access (aOR 5.35, p<0.001), contrast volume (aOR 1.01, p<0.001), self-expanding valve (aOR 1.60, p=0.045), and bleeding (aOR 2.88, p=0.005). Acute kidney injury was an independent predictor of 30-day (aOR: 6.07, p<0.001) and 12-month (aOR: 3.01, p=0.002) mortality, an association that remained consistent when excluding TAVIs performed prior to 2015. CONCLUSIONS: Acute kidney injury remains a relatively common complication of TAVI, associated with significant morbidity and mortality even in less comorbid, contemporary practice patients.

Long-Term Valve Durability in Patients Undergoing Transcatheter Aortic Valve Implantation.

AIMS: To evaluate the long-term incidence of structural valve deterioration (SVD) in patients who underwent transcatheter aortic valve implantation (TAVI). METHOD AND RESULTS: Between 2008 and 2018, 693 underwent TAVI at two centres. Four hundred and twenty-one (421) patients (mean age 83.6±6.0 yrs) survived for ≥2 years post TAVI and had at least two consecutive transthoracic echocardiographies (TTEs) with the latest TTE no less than 2 years after TAVI, and were therefore included in the analysis for SVD. Median follow-up was 4.7 (3.6-6.0) years and median echocardiography follow-up 3 (3.0-4.0) years. All-cause mortality was 30.9% (130) with a median time to death of 4.1 (3.0-5.6) years. The cumulative incidence of SVD increased from 1.7% (95% CI, 0.4-2.9) at 3 years to 3.5% (95% CI, 1.5-5.8) at 5 years and 4.7% (95% CI, 1.6-7.9) at 10 years. The overall median time to SVD was 3 (2-4) years. Twelve (12) patients demonstrated SVD stage 2, and 1 patient stage 3. No SVD required re-intervention. All other patients showed no significant changes in valve parameters over time. CONCLUSIONS: Structural valve deterioration is an uncommon event, occurring in 5% over a total follow-up of 10 years. Most patients show stable valve parameters. However, the analysis is limited by the loss of follow-up (owing to patient mortality), which renders extrapolation of the data to a younger patient population difficult.

Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial.

BACKGROUND: Inflammation plays a crucial role in clinical manifestations and complications of acute coronary syndromes (ACS). Colchicine, a commonly used treatment for gout, has recently emerged as a novel therapeutic option in cardiovascular medicine owing to its anti-inflammatory properties. We sought to determine the potential usefulness of colchicine treatment in patients with ACS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial involving 17 hospitals in Australia that provide acute cardiac care service. Eligible participants were adults (18-85 years) who presented with ACS and had evidence of coronary artery disease on coronary angiography managed with either percutaneous coronary intervention or medical therapy. Patients were assigned to receive either colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo, in addition to standard secondary prevention pharmacotherapy, and were followed up for a minimum of 12 months. The primary outcome was a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke in a time to event analysis. RESULTS: A total of 795 patients were recruited between December 2015 and September 2018 (mean age, 59.8±10.3 years; 21% female), with 396 assigned to the colchicine group and 399 to the placebo group. Over the 12-month follow-up, there were 24 events in the colchicine group compared with 38 events in the placebo group (P=0.09, log-rank). There was a higher rate of total death (8 versus 1; P=0.017, log-rank) and, in particular, noncardiovascular death in the colchicine group (5 versus 0; P=0.024, log-rank). The rates of reported adverse effects were not different (colchicine 23.0% versus placebo 24.3%), and they were predominantly gastrointestinal symptoms (colchicine, 23.0% versus placebo, 20.8%). CONCLUSIONS: The addition of colchicine to standard medical therapy did not significantly affect cardiovascular outcomes at 12 months in patients with ACS and was associated with a higher rate of mortality. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12615000861550.

Transcatheter Aortic Valve Implantation Represents an Anti-Inflammatory Therapy Via Reduction of Shear Stress-Induced, Piezo-1-Mediated Monocyte Activation.

BACKGROUND: Aortic valve stenosis is an increasingly prevalent degenerative and inflammatory disease. Transcatheter aortic valve implantation (TAVI) has revolutionized its treatment, thereby avoiding its life-threatening/disabling consequences. Whether aortic valve stenosis is accelerated by inflammation and whether it is itself a cause of inflammation are unclear. We hypothesized that the large shear forces exerted on circulating cells, particularly on the largest circulating cells, monocytes, while passing through stenotic aortic valves result in proinflammatory effects that are resolved with TAVI. METHODS: TAVI provides a unique opportunity to compare the activation status of monocytes under high shear stress (before TAVI) and under low shear stress (after TAVI). The activation status of monocytes was determined with a single-chain antibody, MAN-1, which is specific for the activated ß2-integrin Mac-1. Monocyte function was further characterized by the adhesion of myocytes to stimulated endothelial cells, phagocytic activity, uptake of oxidized low-density lipoprotein, and cytokine expression. In addition, we designed a microfluidic system to recapitulate the shear rate conditions before and after TAVI. We used this tool in combination with functional assays, Ca2+ imaging, siRNA gene silencing, and pharmacological agonists and antagonists to identify the key mechanoreceptor mediating the shear stress sensitivity of monocytes. Last, we stained for monocytes in explanted stenotic aortic human valves. RESULTS: The resolution of high shear stress through TAVI reduces Mac-1 activation, cellular adhesion, phagocytosis, oxidized low-density lipoprotein uptake, and expression of inflammatory markers in monocytes and plasma. Using microfluidics and pharmacological and genetic studies, we could recapitulate high shear stress effects on isolated human monocytes under highly controlled conditions, showing that shear stress-dependent calcium influx and monocyte adhesion are mediated by the mechanosensitive ion channel Piezo-1. We also demonstrate that the expression of this receptor is shear stress dependent and downregulated in patients receiving TAVI. Last, we show monocyte accumulation at the aortic side of leaflets of explanted aortic valves. CONCLUSIONS: We demonstrate that high shear stress, as present in patients with aortic valve stenosis, activates multiple monocyte functions, and we identify Piezo-1 as the mainly responsible mechanoreceptor, representing a potentially druggable target. We demonstrate an anti-inflammatory effect and therefore a novel therapeutic benefit of TAVI.

Short- and Long-Term Outcomes After Transcatheter Aortic Valve Implantation in Public and Private Hospital Settings: A Propensity-Matched Analysis.

OBJECTIVES: To compare short- and long-term outcomes after transcatheter aortic valve implantation (TAVI) in the public and private hospital setting. DESIGN: Propensity-matched, retrospective analysis of a prospective registry. SETTING AND PARTICIPANTS: Patients with severe aortic stenosis who underwent TAVI at a tertiary public hospital (n=507) and an experienced private hospital (n=436). MAIN OUTCOME MEASURES: The primary endpoint was all-cause mortality. RESULTS: Patients that underwent TAVI in the public hospital were younger than patients in the private hospital (82±8 years vs 84±6 years, p<0.001), with lower estimated short-term mortality risk (Society of Thoracic Surgeons Predicted Risk of Mortality [STS-PROM] score >4.0%: 43% vs 56%, p<0.001). There was no difference between public and private hospitals in 30-day mortality (1.5% vs 1.2%, p=1.0), and the rate of complications was similar. Long-term survival was similar in propensity-matched public (n=344) and private (n=344) patient cohorts. The 1-year, 2-year, 5-year and 7-year survival rates were 95%, 90%, 67% and 47% in public patients, and 92%, 86%, 67% and 51% in private patients (p=0.94). In multivariable analysis, the hospital setting was not a predictor of mortality. CONCLUSION: Despite increased age and predicted mortality in private hospital patients, short- and long-term outcomes after TAVI were comparable between public and private hospital settings. This study demonstrates the feasibility of performing TAVI in a private hospital with a dedicated and experienced team and questions the current restricted access to TAVI in the private sector.

Transcatheter aortic valve-in-valve implantation for failed surgical bioprosthetic valves. A minimalist approach without contrast aortography or echocardiographic guidance.

OBJECTIVES: To demonstrate safety, feasibility and short-term clinical outcomes after transcatheter aortic valve-in-valve (ViV) implantation under local anesthesia without contrast aortography or echocardiographic guidance. BACKGROUND: Transcatheter ViV implantation is an emerging treatment modality for patients with degenerative surgical bioprostheses. Given the radiopaque properties of the surgical aortic valve (SAV) frame, ViV procedures can often be performed with fluoroscopic guidance alone. METHODS: ViV implantation was performed in 37 patients with SAV failure under local anesthesia without contrast aortography. Clinical and echocardiographic data were obtained at baseline, discharge, and 30 days. RESULTS: Mean age was 74 ± 10 years and STS predicted risk of mortality was 5.6 ± 2.4%. Mean transaortic gradient decreased from 39.4 ± 15.5 mmHg to 13 ± 6.3 mmHg at discharge (p < .001), and 20 ± 7.5 mmHg at 30 days (p < .001 compared to baseline), aortic valve area increased from 0.9 ± 0.3 cm2 to 1.2 ± 0.4 cm2 at 30 days (p = .007). No patient had more than mild aortic regurgitation. Hospital discharge occurred at a median of 2.6 ± 4.4 days. At 30-day follow-up there were no deaths, myocardial infarctions, strokes, repeat hospital admissions for heart failure, or renal failure. One patient (2.7%) required a new pacemaker. 93% of the patients were in New York Heart Association functional class I or II. CONCLUSIONS: Transcatheter aortic ViV implantation for selected patients with degenerative surgical bioprostheses under local anesthesia without aortography or echocardiographic guidance is feasible and safe.

Comparison of Early Outcomes in Patients at Estimated Low, Intermediate and High Risk Undergoing Transcatheter Aortic Valve Implantation: A Multicentre Australian Experience.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been shown to be a safe and effective alternative to surgical aortic valve replacement (SAVR) in high- and intermediate-risk patients with severe aortic stenosis. TAVI for patients at lower risk of periprocedural mortality has not been extensively investigated. We aimed to describe outcomes in low-, intermediate- and high-risk patients undergoing TAVI in a multicentre Australian study. METHODS: We evaluated data from 601 patients who underwent TAVI at two hospitals in Melbourne, from August 2008 to February 2018. Patients were stratified according to low risk (STS <4%), intermediate risk (Society for Thoracic Surgeons [STS] 4.0-7.9%) and high risk (STS >8%). Outcomes were reported according to Valve Academic Research Consortium-2 (VARC-2) criteria. RESULTS: Mean age was 84±5 years and 49% were female. Two hundred and eighty-five (285) (47%) patients were low-risk, 243 (40%) were intermediate risk and 73 (12%) were high risk. Thirty-day (30-) mortality was low in all three groups (1.1%, 1.7% and 1.4%, respectively, p=0.8). Similarly, patients had a low risk of disabling stroke (0.4%, 1.3%, 0%, p=0.8). Rates of post-procedural permanent pacemaker were also similar (21%, 27%, 26%, p=0.5). At least moderate aortic regurgitation occurred in 9% of patients at discharge with no significant differences between groups. CONCLUSIONS: In this large Australian multicentre cohort of TAVI patients, 30-day mortality, and post-procedural outcomes were excellent and similar across the patient-risk spectrum. Our study offers further support for the safety of TAVI in low-risk populations and demonstrates the limitations of the STS score.

Incidence, Predictors, and Outcomes of Nonhome Discharge Following Transcatheter Aortic Valve Implantation: A Multicenter Australian Experience-The NHD TAVI Study.

Patients who undergo transcatheter aortic valve implantation (TAVI) commonly experience nonhome discharge (NHD), a phenomenon associated with increased health care expenditure and possibly poorer outcomes. Despite its clinical relevance in TAVI, the incidence and predictors of NHD and its impact on the quality of life remain poorly characterized. Also unknown is the proportion of patients who undergo TAVI that require long-term residential care after initial NHD. Therefore, we aimed to address these questions using a large, multicenter Australian cohort. A total of 2,229 patients who underwent TAVI from 2010 to 2023 included in the Alfred-Cabrini-Epworth TAVI Registry were analyzed. The median age was 82 (interquartile range 78 to 86) years and 41% were women. A total of 257 patients (12%) were not discharged home after TAVI, with the incidence falling over time (R2 = 0.636, p <0.001). A multivariable logistic regression model for NHD prediction was developed with excellent calibration and discrimination (C-statistic = 0.835). The independent predictors of NHD were postprocedural stroke (adjusted odds ratio [aOR] 11.05), procedure at a private hospital (aOR 3.01), living alone (aOR 2.35), vascular access site complications (aOR 2.09), frailty (aOR 1.89), age >80 years (aOR 1.82), hypoalbuminemia (aOR 1.76), New York Heart Association III to IV (aOR 1.74), and hospital length of stay (aOR 1.13) (all p <0.05). NHD was not associated with mortality at 30 days and <1% of all patients required longer-term residential care. In conclusion, although common after TAVI, NHD does not predict short-term mortality, most patients successfully return home within 30 days, and when used appropriately, NHD may serve as a brief and effective method of optimizing functional status without compromising long-term independence.

Periprocedural Myocardial Injury and Coronary Artery Disease in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND/PURPOSE: PPMI and CAD are common in patients undergoing TAVR. Despite several studies evaluating their interaction as well as the influence these factors play on outcomes, there remains no consensus. We sought to evaluate the impact of peri-procedural myocardial injury (PPMI) and incidental coronary artery disease (iCAD) on outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS/MATERIALS: We analyzed prospective data from 400 patients undergoing TAVI for severe aortic stenosis between 2008 and 2018 to determine rates of PPMI (troponin 15× the upper limit of normal) and iCAD (≥50% stenosis) and their impact on long-term mortality. RESULTS: Mean age was 83 ± 6 years; 45% were female. PPMI was observed in 65% (254/400). On multivariable logistic regression analysis, higher left ventricular ejection fraction (LVEF) (OR 1.04, 95%CI 1.01-1.06, p = 0.002), and first generation valves (OR 3.00, 95%CI 1.75-5.15, p < 0.001) were independently associated with PPMI, while oral anticoagulation was inversely associated (OR 0.48, 95%CI 0.28-0.82, p = 0.007). PPMI was not associated with 30-day, 1-year or long-term mortality. After excluding previous bypass grafting, iCAD was observed in 40% (129/324). In patients with iCAD, PCI was associated with reduced long-term mortality compared to medical management in adjusted analysis (OR 0.37, 95%CI 0.16-0.88, p = 0.03). CONCLUSIONS: PPMI and iCAD in patients undergoing TAVR are common. PPMI is associated with older generation valves and higher LVEF rather than traditional cardiovascular risk factors. In our study, PPMI was not associated with long-term mortality. However, in patients with iCAD, PCI was associated with reduced long-term mortality compared to medical management.

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.

Impact of Gender on Transcatheter Aortic Valve Implantation Outcomes.

Previous studies indicate that women who underwentwho underwent transcatheter aortic valve implantation (TAVI) have poorer 30-day outcomes compared with men. However, the effect of gender as a prognostic factor for long-term outcomes following TAVI remains unclear. Between 2008 and 2018, all patients (n = 683) who underwent TAVI in 2 centres in Melbourne, Australia were prospectively included in a registry. The primary end-point was long-term mortality. The secondary end points were Valve Academic Research Consortium-2 (VARC-2) in-hospital complications and mortality at 30-days and 1-year. Of 683 patients, 328 (48%) were women. Women had a higher mean STS-PROM score (5.2 ± 3.1 vs 4.6 ± 3.5, p < 0.001) but less co-morbidities than men. Women had a significantly higher in-hospital bleeding rates (3.3% vs 1.0%, Odds Ratio 4.21, 95% confidence interval [CI] 1.16 to15.25, p = 0.027) and higher 30-day mortality (2.4% vs 0.3%, hazard ratio [HR] 8.75, 95% CI 1.09 to 69.6, p = 0.040) than men. Other VARC-2 outcomes were similar between genders. Overall mortality rate was 36% (246) over a median follow up of 2.7 (interquartile rang [IQR] 1.7 to 4.2) years. Median time to death was 5.3 (95% CI 4.7 to 5.7) years. One-year mortality was similar between genders (8.3% vs 7.8%), as was long-term mortality (HR = 0.91, 95% CI 0.71 to 1.17, p = 0.38). On multivariable analysis, female gender was an independent predictor for 1-year mortality (HR = 2.33, 95% CI 1.11 to 4.92, p = 0.026), but not long-term mortality (HR = 0.78, 95% CI 0.54 to 1.14, p = 0.20). In the women only cohort, STS-PROM was the only independent predictor of long-term mortality (HR 1.88, 95% CI 1.42 to 2.48, p < 0.001). In conclusion, women had higher rates of peri-procedural major bleeding and 30-day mortality following TAVI. However, long-term outcomes were similar between genders.

Long-Term Outcomes Stratified by Body Mass Index in Patients Undergoing Transcatheter Aortic Valve Implantation.

Transcatheter aortic valve implantation (TAVI) is emerging as the default strategy for older patients with severe, symptomatic, and trileaflet aortic stenosis. Increased body-mass index (BMI) is associated with a protective effect in patients undergoing percutaneous coronary intervention. We assessed whether elevated BMI was associated with a similar association in TAVI. We evaluated prospectively collected data from 634 patients who underwent TAVI at 2 centers from August 2008 to April 2019. Patients were stratified as normal weight (BMI 18.5 to 24.9 kg/m2, n = 214), overweight (25 to 29.9 kg/m2, n = 234), and obese (>30 kg/m2, n = 185). Outcomes were reported according to VARC-2 criteria. Mortality was assessed using Cox proportional hazards regression analysis (median follow-up 2 years). Kaplan-Meier analysis was used to estimate cumulative mortality. Baseline differences were seen in age (85 vs 84 vs 82, p <0.001), STS-PROM score (4.3 vs 3.4 vs 3.6, p <0.001), sex (50% vs 36% vs 55% female, p <0.001), clinical frailty score (p = 0.02), diabetes (21% vs 29% vs 40%, p <0.001), and presence of chronic obstructive pulmonary disease (COPD) (13% vs 13% vs 23%, p = 0.009). On multivariable analysis there was no mortality difference between normal and obese patients (hazard ratio [HR] 0.70, confidence interval [CI] 0.46 to 1.1 p = 0.11), however overweight patients had significantly lower mortality (HR 0.56 CI 0.38 to 0.85, p = 0.006). Variables independently associated with increased mortality were increasing age, male sex, COPD, previous balloon valvuloplasty, and higher STS-PROM. In conclusion, overweight patients have lower long-term mortality when compared with normal weight and obese patients undergoing TAVI.

Successful renal denervation decreases the platelet activation status in hypertensive patients.

AIMS: To determine whether renal denervation (RDN) in hypertensive patients affects the platelet activation status. METHODS AND RESULTS: We investigated the effect of RDN on the platelet activation status in 41 hypertensive patients undergoing RDN. Ambulatory blood pressure (BP), plasma sympathetic neurotransmitter Neuropeptide Y, and platelet activation markers were measured at baseline, at 3 months, and 6 months after RDN. RDN significantly decreased BP at 3 months (150.6 ± 11.3/80.9 ± 11.4 mmHg to 144.7 ± 12.0/77.1 ± 11.1 mmHg; P < 0.01) and at 6 months (144.3 ± 13.8/78.3 ± 11.1 mmHg; P < 0.01). Plasma levels of the sympathetic neurotransmitter Neuropeptide Y, an indicator of sympathetic nerve activity, were significantly decreased at 3 months (0.29 ± 0.11 ng/mL to 0.23 ± 0.11 ng/mL; P < 0.0001) and at 6 months (0.22 ± 0.12 ng/mL; P < 0.001) after RDN. This was associated with a reduction in platelet membrane P-selectin expression (3 months, P < 0.05; 6 months, P < 0.05), soluble P-selectin (6 months, P < 0.05), circulating numbers of platelet-derived extracellular vesicles (EVs) (3 months, P < 0.001; 6 months, P < 0.01), and phosphatidylserine expressing EVs (3 months, P < 0.001; 6 months, P < 0.0001), indicative of a reduction in platelet activation status and procoagulant activity. Only patients who responded to RDN with a BP reduction showed inhibition of P-selectin expression at 3 months (P < 0.05) and 6 months (P < 0.05) as well as reduction of glycoprotein IIb/IIIa activation at 3 months (P < 0.05). Notably, 13 patients who took aspirin did not show significant reduction in platelet P-selectin expression following RDN. CONCLUSION: Our results imply a connection between the sympathetic nervous system and the platelet activation status and provide a potential mechanistic explanation by which RDN can have favourable effects towards reducing cardiovascular complications.

Comparison of Outcomes of Transcatheter Aortic Valve Implantation in Patients Aged >90 Years Versus <90 Years.

Limited data exist regarding transcatheter aortic valve implantation (TAVI) in nonagenarians. This study evaluates the short- and mid-term outcomes of nonagenarians after TAVI. Between 2008 and 2017, all patients who underwent TAVI in 2 centers in Australia were prospectively included in a registry and followed-up for 5 years. Outcomes were based on VARC-2 criteria. Additionally, the patient's reliance on daily living support at 1 year was evaluated. Of the 588 patients, 71 (12.1%) were ≥90 years old (mean age 92.2 ± 2 vs 83.2 ± 6 years in <90-year-old patients), with a median STS-PROM score of 5.7 (vs 3.9 in <90-year-old patients, odds ratio [OR] 1.07, 95% confidence interval 1.01 to 1.13, p = 0.02) and a median clinical frailty score of 4 (vs 4 <90-year-old patients, OR 0.88, p = 0.44). Mortality was 0% in ≥90-year-old patients at 30 days (vs 1.4% in <90-year-old patients; p = 0.82) and 12% at 1 year (vs 7.4%, in <90-year-old patients; hazard ratio 1.64, p = 0.20). There were no significant differences in periprocedural complications and mortality at 5 years between the 2 groups. At 1 year, nonagenarians were significantly more likely to live in an aged-care facility compared with <90-year-old patients (25% vs 16%, OR 5.99, 95% confidence interval 2.62 to 13.67, p <0.001). In conclusion, carefully selected nonagenarians have excellent short- and mid-term outcomes post-TAVI and should therefore not be refused based on age alone. Nevertheless, the significantly higher rate of transfer to an aged-care facility highlights the importance of a more refined frailty assessment before TAVI than the currently widely used clinical frailty score.

Lysophosphatidylcholine is a Major Component of Platelet Microvesicles Promoting Platelet Activation and Reporting Atherosclerotic Plaque Instability.

BACKGROUND: Microvesicles (MVs) are small cell-derived vesicles, which are mainly released by activated cells. They are part of a communication network delivering biomolecules, for example, inflammatory molecules, via the blood circulation to remote cells in the body. Platelet-derived MVs are known to induce vascular inflammation. Research on the mediators and mechanisms of their inflammatory effects has attracted major interest. We hypothesize that specific lipids are the mediators of vascular inflammation caused by platelet-derived MVs. METHODS AND RESULTS: Liquid chromatography electrospray ionization-tandem mass spectrometry was used for lipid profiling of platelet-derived MVs. Lysophosphatidylcholine (LPC) was found to be a major component of platelet-derived MVs. Investigating the direct effects of LPC, we found that it induces platelet activation, spreading, migration and aggregation as well as formation of inflammatory platelet-monocyte aggregates. We show for the first time that platelets express the LPC receptor G2AR, which mediates LPC-induced platelet activation. In a mouse model of atherosclerotic plaque instability/rupture, circulating LPC was detected as a surrogate marker of plaque instability. These findings were confirmed by matrix-assisted laser desorption ionization imaging, which showed that the LPC concentration of human plaques was highest in vulnerable plaque regions. CONCLUSION: LPC is a major component of platelet-derived MVs and via its interaction with G2AR on platelets contributes to platelet activation, spreading, migration and aggregation and ultimately to vascular inflammation. Circulating LPC reports on atherosclerotic plaque instability in mice and is significantly increased in unstable areas of atherosclerotic plaques in both mice and humans, linking LPC to plaque instability.

Impact of Aortic Root Anatomy and Geometry on Paravalvular Leak in Transcatheter Aortic Valve Replacement With Extremely Large Annuli Using the Edwards SAPIEN 3 Valve.

OBJECTIVES: The aim of this study was to determine factors affecting paravalvular leak (PVL) in transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN 3 (S3) valve in extremely large annuli. BACKGROUND: The largest recommended annular area for the 29-mm S3 is 683 mm2. However, experience with S3 TAVR in annuli >683 mm2 has not been widely reported. METHODS: From December 2013 to July 2017, 74 patients across 16 centers with mean area 721 ± 38 mm2 (range: 684 to 852 mm2) underwent S3 TAVR. The transfemoral approach was used in 95%, and 39% were under conscious sedation. Patient, anatomic, and procedural characteristics were retrospectively analyzed. Valve Academic Research Consortium-2 outcomes were reported. RESULTS: Procedural success was 100%, with 2 deaths, 1 stroke, and 2 major vascular complications at 30 days. Post-dilatation occurred in 32%, with final balloon overfilling (1 to 5 ml extra) in 70% of patients. Implantation depth averaged 22.3 ± 12.4% at the noncoronary cusp and 20.7 ± 9.9% at the left coronary cusp. New left bundle branch block occurred in 17%, and 6.3% required new permanent pacemakers. Thirty-day echocardiography showed mild PVL in 22.3%, 6.9% moderate, and none severe. There was no annular rupture or coronary obstruction. Mild or greater PVL was associated with larger maximum annular and left ventricular outflow tract (LVOT) diameters, larger LVOT area and perimeter, LVOT area greater than annular area, and higher annular eccentricity. CONCLUSIONS: TAVR with the 29-mm S3 valve beyond the recommended range by overexpansion is safe, with acceptable PVL and pacemaker rates. Larger LVOTs and more eccentric annuli were associated with more PVL. Longer term follow-up will be needed to determine durability of S3 TAVR in this population.

Prediction of acute coronary syndromes by urinary proteome analysis.

Identification of individuals who are at risk of suffering from acute coronary syndromes (ACS) may allow to introduce preventative measures. We aimed to identify ACS-related urinary peptides, that combined as a pattern can be used as prognostic biomarker. Proteomic data of 252 individuals enrolled in four prospective studies from Australia, Europe and North America were analyzed. 126 of these had suffered from ACS within a period of up to 5 years post urine sampling (cases). Proteomic analysis of 84 cases and 84 matched controls resulted in the discovery of 75 ACS-related urinary peptides. Combining these to a peptide pattern, we established a prognostic biomarker named Acute Coronary Syndrome Predictor 75 (ACSP75). ACSP75 demonstrated reasonable prognostic discrimination (c-statistic = 0.664), which was similar to Framingham risk scoring (c-statistics = 0.644) in a validation cohort of 42 cases and 42 controls. However, generating by a composite algorithm named Acute Coronary Syndrome Composite Predictor (ACSCP), combining the biomarker pattern ACSP75 with the previously established urinary proteomic biomarker CAD238 characterizing coronary artery disease as the underlying aetiology, and age as a risk factor, further improved discrimination (c-statistic = 0.751) resulting in an added prognostic value over Framingham risk scoring expressed by an integrated discrimination improvement of 0.273 ± 0.048 (P < 0.0001) and net reclassification improvement of 0.405 ± 0.113 (P = 0.0007). In conclusion, we demonstrate that urinary peptide biomarkers have the potential to predict future ACS events in asymptomatic patients. Further large scale studies are warranted to determine the role of urinary biomarkers in clinical practice.