Major threats to early safety after transcatheter aortic valve implantation in a contemporary cohort of real-world patients.

INTRODUCTION: Despite considerable advances in the last decade, major adverse events remain a concern after transcatheter aortic valve implantation (TAVI). The aim of this study was to provide a detailed overview of their underlying causes and contributing factors in order to identify key domains for quality improvement. METHODS: This observational, prospective registry included all patients undergoing TAVI between 31 December 2015 and 1 January 2020 at the St. Antonius Hospital in Nieuwegein and the University Medical Centre in Utrecht. Outcomes of interest were all-cause mortality, stroke, major bleeding, life-threatening or disabling bleeding, major vascular complications, myocardial infarction, severe acute kidney injury and conduction disturbances requiring permanent pacemaker implantation within 30 days after TAVI, according to the Valve Academic Research Consortium­2 criteria. RESULTS: Of the 1250 patients who underwent TAVI in the evaluated period, 146 (11.7%) developed a major complication. In 54 (4.3%) patients a thromboembolic event occurred, leading to stroke in 36 (2.9%), myocardial infarction in 13 (1.0%) and lower limb ischaemia in 11 (0.9%). Major bleeding occurred in 65 (5.2%) patients, most frequently consisting of acute cardiac tamponade (n = 25; 2.0%) and major access-site bleeding (n = 21; 1.7%). Most complications occurred within 1 day of the procedure. Within 30 days a total of 54 (4.3%) patients died, the cause being directly TAVI-related in 30 (2.4%). Of the patients who died from causes that were not directly TAVI-related, 14 (1.1%) had multiple hospital-acquired complications. CONCLUSION: A variety of underlying mechanisms and causes form a wide spectrum of major threats affecting early safety in 11.7% of patients undergoing TAVI in a contemporary cohort of real-world patients.

Direct comparison of predictive performance of PRECISE-DAPT versus PARIS versus CREDO-Kyoto: a subanalysis of the ReCre8 trial.

BACKGROUND: Multiple scores have been proposed to guide risk stratification after percutaneous coronary intervention. This study assessed the performance of the PRECISE-DAPT, PARIS and CREDO-Kyoto risk scores to predict post-discharge ischaemic or bleeding events. METHODS: A total of 1491 patients treated with latest-generation drug-eluting stent implantation were evaluated. Risk scores for post-discharge ischaemic or bleeding events were calculated and directly compared. Prognostic performance of both risk scores was assessed with calibration, Harrell's c­statistics net reclassification index and decision curve analyses. RESULTS: Post-discharge ischaemic events occurred in 56 patients (3.8%) and post-discharge bleeding events in 34 patients (2.3%) within the first year after the invasive procedure. C­statistics for the PARIS ischaemic risk score was marginal (0.59, 95% confidence interval (CI) 0.51-0.68), whereas the CREDO-Kyoto ischaemic risk score was moderate (0.68, 95% CI 0.60-0.75). With regard to post-discharge bleeding events, CREDO-Kyoto displayed moderate discrimination (c-statistic 0.67, 95% CI 0.56-0.77), whereas PRECISE-DAPT (0.59, 95% CI 0.48-0.69) and PARIS (0.55, 95% CI 0.44-0.65) had a marginal discriminative capacity. Net reclassification index and decision curve analysis favoured CREDO-Kyoto-derived bleeding risk assessment. CONCLUSION: In this contemporary all-comer population, PARIS and PRECISE-DAPT risk scores were not resilient to independent testing for post-discharge bleeding events. CREDO-Kyoto-derived risk stratification was associated with a moderate predictive capability for post-discharge ischaemic or bleeding events. Future studies are warranted to improve risk stratification with more focus on robustness and rigorous testing.

Twelve years of circulatory extracorporeal life support at the University Medical Centre Utrecht.

INTRODUCTION: Circulatory extracorporeal life support (ECLS) has been performed at the University Medical Centre Utrecht for 12 years. During this time, case mix, indications, ECLS set-ups and outcomes seem to have substantially changed. We set out to describe these characteristics and their evolution over time. METHODS: All patients receiving circulatory ECLS between 2007 and 2018 were retrospectively identified and divided into six groups according to a 2-year period of time corresponding to the date of ECLS initiation. General characteristics plus data pertaining to comorbidities, indications and technical details of ECLS commencement as well as in-hospital, 30-day, 1­year and overall mortality were collected. Temporal trends in these characteristics were examined. RESULTS: A total of 347 circulatory ECLS runs were performed in 289 patients. The number of patients and ECLS runs increased from 8 till a maximum of 40 runs a year. The distribution of circulatory ECLS indications shifted from predominantly postcardiotomy to a wider set of indications. The proportion of peripheral insertions with or without application of left ventricular unloading techniques substantially increased, while in-hospital, 30-day, 1­year and overall mortality decreased over time. CONCLUSION: Circulatory ECLS was increasingly applied at the University Medical Centre Utrecht. Over time, indications as well as treatment goals broadened, and cannulation techniques shifted from central to mainly peripheral approaches. Meanwhile, weaning success increased and mortality rates diminished.

Rationale for catheter-based therapies in acute pulmonary embolism.

Pulmonary embolism (PE) is a common disease resulting in significant morbidity and mortality. High-risk features of PE are hypotension or shock, and early reperfusion is warranted to unload the strained right ventricle and improve clinical outcomes. Currently, systemic thrombolysis (ST) is the standard of care but is associated with bleeding complications. Catheter-based therapies (CDT) have emerged as a promising alternative having demonstrated to be equally effective while having a lower risk of bleeding. Several CDT are currently available, some combining mechanical properties with low-dose thrombolytics. Recent guidelines suggest that CDT may be considered in patients with high-risk PE who have high bleeding risk, after failed ST, or in patients with rapid haemodynamic deterioration as bail-out before ST can be effective, depending on local availability and expertise. In haemodynamically stable patients with right ventricular (RV) dysfunction (intermediate-risk PE), CDT may be considered if clinical deterioration occurs after starting anticoagulation and relative contraindications for ST due to bleeding risk exist. Decision on treatment modality should follow a risk-benefit analysis on a case by case base, weighing the risk of PE-related complications; i.e. haemodynamic deterioration vs. bleeding. As timely initiation of treatment is warranted to prevent early mortality, bleeding risk factors should be assessed at an early stage in all patients with acute PE and signs of RV dysfunction. To ensure optimal management of complex cases of PE and assess a potential CDT strategy, a multidisciplinary approach is recommended. A dedicated Pulmonary Embolism Response Team may optimize this process.

Appropriate use criteria for optical coherence tomography guidance in percutaneous coronary interventions : Recommendations of the working group of interventional cardiology of the Netherlands Society of Cardiology.

INTRODUCTION: Optical coherence tomography (OCT) enables detailed imaging of the coronary wall, lumen and intracoronary implanted devices. Responding to the lack of specific appropriate use criteria (AUC) for this technique, we conducted a literature review and a procedure for appropriate use criteria. METHODS: Twenty-one of all 184 members of the Dutch Working Group on Interventional Cardiology agreed to evaluate 49 pre-specified cases. During a meeting, factual indications were established whereupon members individually rated indications on a 9-point scale, with the opportunity to substantiate their scoring. RESULTS: Twenty-six indications were rated 'Appropriate', eighteen indications 'May be appropriate', and five 'Rarely appropriate'. Use of OCT was unanimously considered 'Appropriate' in stent thrombosis, and 'Appropriate' for guidance in PCI, especially in distal left main coronary artery and proximal left anterior descending coronary artery, unexplained angiographic abnormalities, and use of bioresorbable vascular scaffold (BVS). OCT was considered 'Rarely Appropriate' on top of fractional flow reserve (FFR) for treatment indication, assessment of strut coverage, bypass anastomoses or assessment of proximal left main coronary artery. CONCLUSIONS: The use of OCT in stent thrombosis is unanimously considered 'Appropriate' by these experts. Varying degrees of consensus exists on the appropriate use of OCT in other settings.

Haemodynamic and functional consequences of the iatrogenic atrial septal defect following Mitraclip therapy.

Percutaneous MitraClip placement for treatment of severe mitral regurgitation in high surgical risk patients is a commonly performed procedure and requires a transseptal puncture to reach the left atrium. The resulting iatrogenic atrial septal defect (iASD) is not routinely closed, yet the haemodynamic and functional consequences of a persisting defect are not fully understood. Despite positive effects such as acute left atrial pressure relief, persisting iASDs are associated with negative consequences, namely significant bidirectional shunting and subsequent worse clinical outcome. Percutaneous closure of the iASD may therefore be desirable in selected cases. In this review we discuss the available literature on this matter.

Effect of body mass index on clinical outcome and all-cause mortality in patients undergoing transcatheter aortic valve implantation.

OBJECTIVES: To assess the effect of body mass index (BMI) on outcome among patients with severe aortic stenosis (AS) admitted for transcatheter aortic valve implantation (TAVI). BACKGROUND: Being overweight or obese is associated with improved outcome following certain medical treatments, suggesting the existence of a BMI paradox. However, the relationship between BMI and mortality after TAVI remains controversial. METHODS: Patients were classified according to World Health Organisation criteria such as normal weight, overweight, or obesity according to their BMI (18.5 to 24.9 kg/m2, 25.0 to 29.9 kg/m2, and ≥30.0 kg/m2, respectively). RESULTS: A total of 549 consecutive patients (age: 80.2 ± 7.5 years; logistic European system for cardiac operative risk evaluation [EuroSCORE]: 17.3 ± 9.9%) who underwent TAVI for AS were included. Of these patients, 43% (n = 237) had normal weight, 36% (n = 200) were overweight, and 20% (n = 112) were obese. There were no differences in peri-operative bleeding or vascular complication rates between the groups. All-cause mortality after 30 days, and 1 year, were higher in normal weight patients compared with overweight and obese patients (7% vs. 5 and 4%, p = 0.383, and 19% vs. 9 and 10%, p = 0.006, respectively). After adjustment for several confounding factors, overweight was associated with a decreased 30-day and 1­year all-cause mortality outcome (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.47-0.99, and HR 0.65; 95% CI 0.45-0.94, respectively). CONCLUSIONS: Despite the well-documented adverse effects of increased body weight on health, being overweight is associated with improved survival following TAVI when compared with normal weight.

Classical determinants of coronary artery disease as predictors of complexity of coronary lesions, assessed with the SYNTAX score.

BACKGROUND: We need new biomarkers that can predict cardiovascular disease to improve both diagnosis and therapeutic strategies. The CIRCULATING CELLS study was designed to study the role of several cellular mediators of atherosclerosis as biomarkers of coronary artery disease (CAD). An objective and reproducible method for the quantification of CAD extension is required to establish relationships with these potential biomarkers. We sought to analyse the correlation of the SYNTAX score with known CAD risk factors to test it as a valid marker of CAD extension. METHODS AND RESULTS: A subgroup of 279 patients (67.4% males) were included in our analysis. Main exclusion criteria were a history of previous percutaneous coronary intervention or surgical revascularisation that prevent an accurate assessment of the SS. Diabetes mellitus, smoking, renal insufficiency, body mass index and a history of CAD and myocardial infarction were all positively and strongly associated with a higher SYNTAX score after adjustment for the non-modifiable biological factors (age and sex). In the multivariate model, age and male sex, along with smoking and renal insufficiency, remain statistical significantly associated with the SYNTAX score. CONCLUSION: In a selected cohort of revascularisation-naive patients with CAD undergoing coronary angiography, non-modifiable cardiovascular risk factors such as advanced age, male sex, as well as smoking and renal failure were independently associated with CAD complexity assessed by the SYNTAX score. The SYNTAX score may be a valid marker of CAD extension to establish relationships with potential novel biomarkers of coronary atherosclerosis.

Current MitraClip experience, safety and feasibility in the Netherlands.

PURPOSE: Data on MitraClip procedural safety and efficacy in the Netherlands are scarce. We aim to provide an overview of the Dutch MitraClip experience. METHODS: We pooled anonymised demographic and procedural data of 1151 consecutive MitraClip patients, from 13 Dutch hospitals. Data was collected by product specialists in collaboration with local operators. Effect on mitral regurgitation was intra-procedurally assessed by transoesophageal echocardiography. Technical success and device success were defined according to modified definitions of the Mitral Valve Academic Research Consortium (MVARC). RESULTS: Median age was 76 (interquartile range 69-82) years and 59% were males. Patients presented with ≥moderate mitral regurgitation and a predominance of functional mitral regurgitation (72%). Overall, 611 (53%) patients were treated with one Clip, 486 (42%) with ≥2 Clips and 54 (5%) received no Clip. The number of patients with ≥2 Clips increased from 22% in 2009 to 52% in 2016. Device success and technical success were 91 and 95%, respectively, and were consistent over the years. Significant reduction of mitral regurgitation by MitraClip was achieved in 94% of patients and was observed more often in patients with functional mitral regurgitation (95% vs. 91%, p = 0.025). Device time declined from 145 min in 2009 to 55 min in 2016. CONCLUSION: MitraClip experience in the Netherlands is growing with excellent technical success and device success. Over the years, device time decreased and more patients were treated with ≥2 Clips.

Coronary vasospasm induced by painful compression of the brachial artery following coronary angiography.

We report the occurrence of coronary vasospasm following forceful compression of the brachial artery after coronary angiography.

Initiation of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock during out of hours versus working hours is not associated with increased mortality.

BACKGROUND: Initiation of veno-arterial (VA) Extracorporeal Membrane Oxygenator (ECMO) is associated with severe complications. It is unknown whether these adverse consequences occur more often after initiations during out of hours service compared to working hours. METHODS: All patients receiving VA-ECMO for cardiogenic shock between 2009 and 2020 were categorized into a working hours group (between 8 am and 5 pm on weekdays) and an out of hours service group (between 5 pm and 8 am, or between Friday 5 pm and Monday 8 am). Primary outcome was all-cause mortality at 30 days. Secondary outcomes included vascular complications (including limb ischemia and/or bleeding), bloodstream infections and length of ICU stay. Propensity scores were used to adjust for potential confounding effects. RESULTS: Among 250 patients (median (IQR) age 56 (42-64) years) receiving VA-ECMO (median duration 3.5 (1.0-9.0) days), 160 (64%) runs were initiated between 5 pm and 8 am whereas the remainder (36%) started during working hours. Characteristic did not differ between the working hours- and out of hours-group. By day 30, 37 (41.1%), and 68 (42.5%) patients in either group had died, respectively (p = 0.831). VA-ECMO support duration and length of stay on the ICU did not differ significantly in both crude and adjusted analyses. More complications occurred during out of hours service (p = 0.039). CONCLUSIONS: Out of hours- versus working hours-initiation of VA-ECMO for cardiogenic shock was not associated with higher mortality, longer VA-ECMO support duration, or longer length of stay on the intensive care. Vascular complications were more common in the out of hours group.

Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis.

OBJECTIVE: A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet. METHODS AND RESULTS: No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. CONCLUSIONS: Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability.

CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms.

BACKGROUND: Chemokines play an important role in atherogenesis and in ischemic injury and repair; however, prospective data on individual chemokines in unstable angina pectoris (UAP) are scarce. Therefore, we assessed chemokine patterns in a prospective cohort of patients with UAP. METHODS AND RESULTS: Plasma samples of 54 patients with Braunwald class IIIB UAP were examined at baseline for 11 chemokines and 5 inflammatory mediators via multiplex analysis. Levels of CC chemokine ligand (CCL)-5 (also known as RANTES [regulated on activation, normally T-cell expressed, and secreted]; 32.7 versus 23.1 ng/mL, P=0.018) and CCL18 (also known as PARC [pulmonary and activation-regulated chemokine]; 104.4 versus 53.7 ng/mL, P=0.011) were significantly elevated in patients with refractory ischemic symptoms versus stabilized patients. Temporal monitoring by ELISA of CCL5, CCL18, and soluble CD40 ligand (sCD40) levels revealed a drop in CCL5 and sCD40L levels in all UAP patients from day 2 onward (CCL5 12.1 ng/mL, P<0.001; sCD40L 1.35 ng/mL, P<0.05), whereas elevated CCL18 levels were sustained for at least 2 days, then were decreased at 180 days after inclusion (34.5 ng/mL, P<0.001). Peripheral blood mononuclear cells showed increased protein expression of chemokine receptors CCR3 and CCR5 in CD3+ and CD14+ cells at baseline compared with 180 days after inclusion, whereas mRNA levels were downregulated, which was attributable in part to a postischemic release of human neutrophil peptide-3-positive neutrophils and in part to negative feedback. Finally, elevated CCL5 and CCL18 levels predicted future cardiovascular adverse events, whereas C-reactive protein and sCD40L levels did not. CONCLUSIONS: We are the first to report that CCL18 and CCL5 are transiently raised during episodes of UAP, and peak levels of both chemokines are indicative of refractory symptoms. Because levels of both chemokines, as well as of cognate receptor expression by circulating peripheral blood mononuclear cells, are increased during cardiac ischemia, this may point to an involvement of CCL5/CCL18 in the pathophysiology of UAP and/or post-UAP responses.

Reduced leucocyte cholesteryl ester transfer protein expression in acute coronary syndromes.

OBJECTIVE: Cholesterol ester transfer protein (CETP) plays an important role in HDL cholesterol metabolism. Leucocytes, including monocyte-derived macrophages in the arterial wall synthesize and secrete CETP, but its role in atherosclerosis is unclear. The aim of the current study was to investigate the effect of acute coronary syndromes (ACS) on leucocyte CETP expression. RESEARCH DESIGN: Peripheral blood mononuclear cells (PBMCs) were freshly isolated from hospitalized ACS patients displaying Braunwald class IIIB unstable angina pectoris (UAP) on admission (t = 0) and at 180 days post inclusion (t = 180) for analysis of CETP expression. In addition, to prove the potential correlation between leucocyte CETP and ACS the effect of acute myocardial infarction on leucocyte CETP expression was studied in CETP transgenic mice. RESULTS: Upon admission, UAP patients displayed approximately 3-6 fold (P < 0.01) lower CETP mRNA and nearly absent CETP protein expression in PBMCs, as compared to healthy age-/sex-matched controls. Interestingly, CETP mRNA and protein levels were significantly elevated in PBMCs isolated from UAP patients (both stabilized and refractory) at t = 180 as compared to t = 0 (P < 0.01), which was correlated with a reduced inflammatory status after medical treatment. In agreement with the data obtained in UAP patients, markedly down-regulated leucocyte CETP mRNA expression was observed after coronary artery ligation in CETP transgenic mice, which also correlated with increased serum amyloid A levels. CONCLUSIONS: We are the first to report that episodes of UAP in humans and myocardial infarction in CETP transgenic mice are associated with reduced leucocyte CETP expression. We propose that the impairment in leucocyte CETP production is associated with an enhanced inflammatory status, which could be clinically relevant for the pathogenesis of ACS.

Monocyte gene expression in childhood obesity is associated with obesity and complexity of atherosclerosis in adults.

Childhood obesity coincides with increased numbers of circulating classical CD14++CD16- and intermediate CD14++CD16+ monocytes. Monocytes are key players in the development and exacerbation of atherosclerosis, which prompts the question as to whether the monocytosis in childhood obesity contributes to atherogenesis over the years. Here, we dissected the monocyte gene expression profile in childhood obesity using an Illumina microarray platform on sorted monocytes of 35 obese children and 16 lean controls. Obese children displayed a distinctive monocyte gene expression profile compared to lean controls. Upon validation with quantitative PCR, we studied the association of the top 5 differentially regulated monocyte genes in childhood obesity with obesity and complexity of coronary atherosclerosis (SYNTAX score) in a cohort of 351 adults at risk for ischemic cardiovascular disease. The downregulation of monocyte IMPDH2 and TMEM134 in childhood obesity was also observed in obese adults. Moreover, downregulation of monocyte TMEM134 was associated with a higher SYNTAX atherosclerosis score in adults. In conclusion, childhood obesity entails monocyte gene expression alterations associated with obesity and enhanced complexity of coronary atherosclerosis in adults.

Chemokines and atherosclerotic plaque progression: towards therapeutic targeting?

Atherosclerosis is currently viewed as an inflammatory disease in which the initiation and progression of the atherosclerotic plaque towards a rupture prone, unstable plaque is driven by leukocyte recruitment mediated by various inflammatory mediators. Recently, interest in chemotactic cytokines or chemokines with regard to atherosclerosis has been growing as chemokines mediate the influx of leukocytes that is typical of atherothrombosis. The activity of the majority of chemokines is overlapping and chemokines are not only produced by the various cellular constituents of the atherosclerotic plaque but also by activated platelets. Consequently, the direct influence of individual chemokines on plaque destabilisation and rupture is widespread and rather unclear. Experimental research has already established the role of a number of chemokines in advanced atherosclerosis. Nevertheless, given the complexity and size of the chemokine family, further screening of cardiovascular disease for chemokine level and genetic polymorphisms for chemokines will be warranted as the search for viable biomarkers of plaque destabilization as well as novel therapeutic targets for specific atheroregressive therapeutic compounds is ongoing. With regard to the latter, clinical trials with specific chemokine inhibitory strategies, like chemokine receptor antagonists, are already underway in other inflammatory disorders. Summarizing, chemokine inhibition likely constitutes an important therapeutic option next to already established drugs in the management of cardiovascular disease.