Saolta University Health Care Group

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.

This Consensus Document is the first of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The first document appraises the role of intracoronary imaging to guide percutaneous coronary interventions (PCIs) in clinical practice. Current evidence regarding the impact of intracoronary imaging guidance on cardiovascular outcomes is summarized, and patients or lesions most likely to derive clinical benefit from an imaging-guided intervention are identified. The relevance of the use of IVUS or OCT prior to PCI for optimizing stent sizing (stent length and diameter) and planning the procedural strategy is discussed. Regarding post-implantation imaging, the consensus group recommends key parameters that characterize an optimal PCI result and provides cut-offs to guide corrective measures and optimize the stenting result. Moreover, routine performance of intracoronary imaging in patients with stent failure (restenosis or stent thrombosis) is recommended. Finally, strengths and limitations of IVUS and OCT for guiding PCI and assessing stent failures and areas that warrant further research are critically discussed.

Aims: To determine the ranges of pre-test probability (PTP) of coronary artery disease (CAD) in which stress electrocardiogram (ECG), stress echocardiography, coronary computed tomography angiography (CCTA), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and cardiac magnetic resonance (CMR) can reclassify patients into a post-test probability that defines (>85%) or excludes (<15%) anatomically (defined by visual evaluation of invasive coronary angiography [ICA]) and functionally (defined by a fractional flow reserve [FFR] ≤0.8) significant CAD. Methods and results: A broad search in electronic databases until August 2017 was performed. Studies on the aforementioned techniques in >100 patients with stable CAD that utilized either ICA or ICA with FFR measurement as reference, were included. Study-level data was pooled using a hierarchical bivariate random-effects model and likelihood ratios were obtained for each technique. The PTP ranges for each technique to rule-in or rule-out significant CAD were defined. A total of 28 664 patients from 132 studies that used ICA as reference and 4131 from 23 studies using FFR, were analysed. Stress ECG can rule-in and rule-out anatomically significant CAD only when PTP is ≥80% (76-83) and ≤19% (15-25), respectively. Coronary computed tomography angiography is able to rule-in anatomic CAD at a PTP ≥58% (45-70) and rule-out at a PTP ≤80% (65-94). The corresponding PTP values for functionally significant CAD were ≥75% (67-83) and ≤57% (40-72) for CCTA, and ≥71% (59-81) and ≤27 (24-31) for ICA, demonstrating poorer performance of anatomic imaging against FFR. In contrast, functional imaging techniques (PET, stress CMR, and SPECT) are able to rule-in functionally significant CAD when PTP is ≥46-59% and rule-out when PTP is ≤34-57%. Conclusion: The various diagnostic modalities have different optimal performance ranges for the detection of anatomically and functionally significant CAD. Stress ECG appears to have very limited diagnostic power. The selection of a diagnostic technique for any given patient to rule-in or rule-out CAD should be based on the optimal PTP range for each test and on the assumed reference standard.

Importance: The benefit of blood pressure lowering for the prevention of dementia or cognitive impairment is unclear. Objective: To determine the association of blood pressure lowering with dementia or cognitive impairment. Data Sources and Study Selection: Search of PubMed, EMBASE, and CENTRAL for randomized clinical trials published from database inception through December 31, 2019, that evaluated the association of blood pressure lowering on cognitive outcomes. The control groups consisted of either placebo, alternative antihypertensive agents, or higher blood pressure targets. Data Extraction and Synthesis: Data were screened and extracted independently by 2 authors. Random-effects meta-analysis models were used to report pooled treatment effects and CIs. Main Outcomes and Measures: The primary outcome was dementia or cognitive impairment. The secondary outcomes were cognitive decline and changes in cognitive test scores. Results: Fourteen randomized clinical trials were eligible for inclusion (96 158 participants), of which 12 reported the incidence of dementia (or composite of dementia and cognitive impairment [3 trials]) on follow-up and were included in the primary meta-analysis, 8 reported cognitive decline, and 8 reported changes in cognitive test scores. The mean (SD) age of trial participants was 69 (5.4) years and 40 617 (42.2%) were women. The mean systolic baseline blood pressure was 154 (14.9) mm Hg and the mean diastolic blood pressure was 83.3 (9.9) mm Hg. The mean duration of follow-up was 49.2 months. Blood pressure lowering with antihypertensive agents compared with control was significantly associated with a reduced risk of dementia or cognitive impairment (12 trials; 92 135 participants) (7.0% vs 7.5% of patients over a mean trial follow-up of 4.1 years; odds ratio [OR], 0.93 [95% CI, 0.88-0.98]; absolute risk reduction, 0.39% [95% CI, 0.09%-0.68%]; I2 = 0.0%) and cognitive decline (8 trials) (20.2% vs 21.1% of participants over a mean trial follow-up of 4.1 years; OR, 0.93 [95% CI, 0.88-0.99]; absolute risk reduction, 0.71% [95% CI, 0.19%-1.2%]; I2 = 36.1%). Blood pressure lowering was not significantly associated with a change in cognitive test scores. Conclusions and Relevance: In this meta-analysis of randomized clinical trials, blood pressure lowering with antihypertensive agents compared with control was significantly associated with a lower risk of incident dementia or cognitive impairment.

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application. Optical coherence tomography (OCT) has been widely adopted in research on coronary atherosclerosis and adopted clinically to optimize percutaneous coronary intervention. In this Review, Jang and colleagues summarize this rapidly progressing field, with the aim of standardizing the use of OCT in coronary atherosclerosis.

This consensus document is the second of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near infrared spectroscopy (NIRS)-IVUS. Beyond guidance of stent selection and optimization of deployment, invasive imaging facilitates angiographic interpretation and may guide treatment in acute coronary syndrome. Intravascular imaging can provide additional important diagnostic information when confronted with angiographically ambiguous lesions and allows assessment of plaque morphology enabling identification of vulnerability characteristics. This second document focuses on useful imaging features to identify culprit and vulnerable coronary plaque, which offers the interventional cardiologist guidance on when to adopt an intracoronary imaging-guided approach to the treatment of coronary artery disease and provides an appraisal of intravascular imaging-derived metrics to define the haemodynamic significance of coronary lesions.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.

AIMS: To provide a pooled estimation of contemporary pre-test probabilities (PTPs) of significant coronary artery disease (CAD) across clinical patient categories, re-evaluate the utility of the application of diagnostic techniques according to such estimates, and propose a comprehensive diagnostic technique selection tool for suspected CAD. METHODS AND RESULTS: Estimates of significant CAD prevalence across sex, age, and type of chest pain categories from three large-scale studies were pooled (n = 15 815). The updated PTPs and diagnostic performance profiles of exercise electrocardiogram, invasive coronary angiography, coronary computed tomography angiography (CCTA), positron emission tomography (PET), stress cardiac magnetic resonance (CMR), and SPECT were integrated to define the PTP ranges in which ruling-out CAD is possible with a post-test probability of <10% and <5%. These ranges were then integrated in a new colour-coded tabular diagnostic technique selection tool. The Bayesian relationship between PTP and the rate of diagnostic false positives was explored to complement the characterization of their utility. Pooled CAD prevalence was 14.9% (range = 1-52), clearly lower than that used in current clinical guidelines. Ruling-out capabilities of non-invasive imaging were good overall. The greatest ruling-out capacity (i.e. post-test probability <5%) was documented by CCTA, PET, and stress CMR. With decreasing PTP, the fraction of false positive findings rapidly increased, although a lower CAD prevalence partially cancels out such effect. CONCLUSION: The contemporary PTP of significant CAD across symptomatic patient categories is substantially lower than currently assumed. With a low prevalence of the disease, non-invasive testing can rarely rule-in the disease and focus should shift to ruling-out obstructive CAD. The large proportion of false positive findings must be taken into account when patients with low PTP are investigated.

AIMS: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. METHODS AND RESULTS: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. CONCLUSION: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

BACKGROUND AND OBJECTIVES: The detection of a simple and reliable prognostic biomarker for colorectal cancer (CRC) outcomes remains a significant challenge. The use of neutrophil-to-lymphocyte ratio (NLR), has been reported to predict surgical and survival outcomes. The aim of our review was to assess the predictive value of pre-operative NLR in predicting post-operative outcomes in CRC. METHODS: A systematic review of the available studies on NLR in CRC was performed. Primarily, we assessed its ability to predict survival outcomes, and highlight values that would help adjuvant therapy choices. RESULTS: 19 studies comprising 10 259 patients were included. Eleven and eight studies reported on patients with localized CRC and colorectal liver metastasis, respectively. Five-year survival for those with localized CRC was 77.2% in patients with a "low" pre-operative NLR versus 50.8% in those with a "high" pre-operative NLR value. Alternatively, for patients with colorectal liver metastasis, patients with a "high" pre-operative NLR value had a 5-year survival of 27%. CONCLUSION: Elevated pre-operative NLR>5 is associated with poorer long-term survival in both patients with localized CRC and those with liver metastasis. NLR is a useful biomarker in delineating those patients with poorer prognosis and whom may benefit from adjuvant therapies.

Background: Recent American College of Cardiology/American Heart Association Primary Prevention Guidelines recommended considering low-dose aspirin therapy only among adults 40 to 70 years of age who are at higher atherosclerotic cardiovascular disease (ASCVD) risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified. The present study aimed to assess the value of coronary artery calcium (CAC) for guiding aspirin allocation for primary prevention by using 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk. Methods: The study included 6470 participants from the MESA Study (Multi-Ethnic Study of Atherosclerosis). ASCVD risk was estimated using the pooled cohort equations, and 3 strata were defined: <5%, 5% to 20%, and >20%. All participants underwent CAC scoring at baseline, and CAC scores were stratified as =0, 1 to 99, ≥100, and ≥400. A 12% relative risk reduction in cardiovascular disease events was used for the 5-year number needed to treat (NNT 5 ) calculations, and a 42% relative risk increase in major bleeding events was used for the 5-year number needed to harm (NNH 5 ) estimations. Results: Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the American College of Cardiology/American Heart Association guidelines and using >20% estimated ASCVD risk to define higher risk. Benefit/harm calculations were restricted to aspirin-naive participants <70 years of age not at high risk of bleeding (n=3540). The overall NNT 5 with aspirin to prevent 1 cardiovascular disease event was 476 and the NNH 5 was 355. The NNT 5 was also greater than or similar to the NNH 5 among estimated ASCVD risk strata. Conversely, CAC≥100 and CAC≥400 identified subgroups in which NNT 5 was lower than NNH 5 . This was true both overall (for CAC≥100, NNT 5 =140 versus NNH 5 =518) and within ASCVD risk strata. Also, CAC=0 identified subgroups in which the NNT 5 was much higher than the NNH 5 (overall, NNT 5 =1190 versus NNH 5 =567). Conclusions: CAC may be superior to the pooled cohort equations to inform the allocation of aspirin in primary prevention. Implementation of current 2019 American College of Cardiology/American Heart Association guideline recommendations together with the use of CAC for further risk assessment may result in a more personalized, safer allocation of aspirin in primary prevention. Confirmation of these findings in experimental settings is needed.

Despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide. Progress has been challenging as half of the individuals who suffer sudden cardiac death do not experience premonitory symptoms. Furthermore, it is well-recognized that also a plaque that does not cause a haemodynamically significant stenosis can trigger a sudden cardiac event, yet the majority of ruptured or eroded plaques remain clinically silent. In the past 30 years since the term 'vulnerable plaque' was introduced, there have been major advances in the understanding of plaque pathogenesis and pathophysiology, shifting from pursuing features of 'vulnerability' of a specific lesion to the more comprehensive goal of identifying patient 'cardiovascular vulnerability'. It has been also recognized that aside a thin-capped, lipid-rich plaque associated with plaque rupture, acute coronary syndromes (ACS) are also caused by plaque erosion underlying between 25% and 60% of ACS nowadays, by calcified nodule or by functional coronary alterations. While there have been advances in preventive strategies and in pharmacotherapy, with improved agents to reduce cholesterol, thrombosis, and inflammation, events continue to occur in patients receiving optimal medical treatment. Although at present the positive predictive value of imaging precursors of the culprit plaques remains too low for clinical relevance, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and could facilitate optimal allocation of novel, more aggressive, and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and 'local' diagnostics and therapies. The present state-of-the-art document aims to present and critically appraise the latest evidence, developments, and future perspectives in detection, prevention, and treatment of 'high-risk' plaques occurring in 'vulnerable' patients.

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Aims: Pressure-wire assessment of coronary stenosis is considered the invasive reference standard for detection of ischaemia-generating lesions. Recently, methods to estimate the fractional flow reserve (FFR) from conventional angiography without the use of a pressure wire have been developed, and were shown to have an excellent diagnostic accuracy. The present systematic review and meta-analysis aimed at determining the diagnostic performance of angiography-derived FFR for the diagnosis of haemodynamically significant coronary artery disease. Methods and results: A systematic review and meta-analysis of studies assessing the diagnostic performance of angiography-derived FFR systems were performed. The primary outcome of interest was pooled sensitivity and specificity. Thirteen studies comprising 1842 vessels were included in the final analysis. A Bayesian bivariate meta-analysis yielded a pooled sensitivity of 89% (95% credible interval 83-94%), specificity of 90% (95% credible interval 88-92%), positive likelihood ratio (+LR) of 9.3 (95% credible interval 7.3-11.7) and negative likelihood ratio (-LR) of 0.13 (95% credible interval 0.07-0.2). The summary area under the receiver-operating curve was 0.84 (95% credible interval 0.66-0.94). Meta-regression analysis did not find differences between the methods for pressure-drop calculation (computational fluid dynamics vs. mathematical formula), type of analysis (on-line vs. off-line) or software packages. Conclusion: The accuracy of angiography-derived FFR was good to detect haemodynamically significant lesions with pressure-wire measured FFR as a reference. Computational approaches and software packages did not influence the diagnostic accuracy of angiography-derived FFR. A diagnostic strategy trial with angiography-derived FFR evaluating clinical endpoints is warranted.

AIMS: The value of elective coronary revascularisation plus medical therapy over medical therapy alone in managing stable patients with coronary artery disease is debated. We reviewed all trials comparing the two strategies in this population. METHODS AND RESULTS: From inception through November 2020, MEDLINE, EMBASE, Google Scholar, and other databases were searched for randomised trials comparing revascularisation against medical therapy alone in clinically stable coronary artery disease patients. Treatment effects were measured by rate ratios (RRs) with 95% confidence intervals, using random-effects models. Cardiac mortality was the pre-specified primary endpoint. Spontaneous myocardial infarction (MI) and its association with cardiac mortality were secondary endpoints. Further endpoints included all-cause mortality, any MI, and stroke. Longest follow-up data were abstracted. The study is registered with PROSPERO (CRD42021225598). Twenty-five trials involving 19 806 patients (10 023 randomised to revascularisation plus medical therapy and 9783 to medical therapy alone) were included. Compared with medical therapy alone, revascularisation yielded a lower risk of cardiac death [RR 0.79 (0.67-0.93), P < 0.01] and spontaneous MI [RR 0.74 (0.64-0.86), P < 0.01]. By meta-regression, the cardiac death risk reduction after revascularisation, compared with medical therapy alone, was linearly associated with follow-up duration [RR per 4-year follow-up: 0.81 (0.69-0.96), P = 0.008], spontaneous MI absolute difference (P = 0.01) and percentage of multivessel disease at baseline (P = 0.004). Trial sequential and sensitivity analyses confirmed the reliability of the cardiac mortality findings. All-cause mortality [0.94 (0.87-1.01), P = 0.11], any MI (P = 0.14), and stroke risk (P = 0.30) did not differ significantly between strategies. CONCLUSION: In stable coronary artery disease patients, randomisation to elective coronary revascularisation plus medical therapy led to reduced cardiac mortality compared with medical therapy alone. The cardiac survival benefit after revascularisation improved with longer follow-up times and was associated with fewer spontaneous MIs.

AIMS: This study evaluated the views of the cardiology community on the clinical use of coronary intravascular imaging (IVI). METHODS AND RESULTS: A web-based survey was distributed to 31,893 individuals, with 1,105 responses received (3.5% response rate); 1,010 of 1,097 respondents (92.1%) self-reported as interventional cardiologists, 754 (68.7%) with >10 years experience. Overall, 96.1% had personal experience with IVI (95.5% with intravascular ultrasound [IVUS], 69.8% with optical coherence tomography [OCT], and 7.9% with near-infrared spectroscopy); 34.7% of respondents were from Europe and 52.0% were from Asia (45.4% from Japan). The most commonly reported indications for IVI were optimization of stenting (88.5%), procedural/strategy guidance (79.6%), and guidance of left main interventions (77.0%). Most respondents reported perceived equipoise regarding choice between IVUS and OCT for guidance of coronary intervention. High cost (65.9%) and prolongation of the procedure (35.0%) were the most commonly reported factors limiting use. IVI was used more frequently (>15% of cases guided by IVI) in Japan than Europe (96.6% vs. 10.4%, respectively; P<0.001) and by operators with longer interventional experience. CONCLUSIONS: In a sample of predominantly experienced interventional cardiologists, there was a high rate of personal experience with IVI in clinical practice. The most commonly identified indications for IVI were optimization of stenting, procedural/strategy guidance, and guidance of left main interventions. Variability in practice patterns is substantial according to geographic region and interventional experience.

The role of cardiac implantable electronic device (CIED)-related tricuspid regurgitation (TR) is increasingly recognized as an independent clinical entity. Hence, interventional TR treatment options continuously evolve, surgical risk assessment and peri-operative care improve the management of CIED-related TR, and the role of lead extraction is of high interest. Furthermore, novel surgical and interventional tricuspid valve treatment options are increasingly applied to patients suffering from TR associated with or related to CIEDs. This multidisciplinary review article developed with electrophysiologists, interventional cardiologists, imaging specialists, and cardiac surgeons aims to give an overview of the mechanisms of disease, diagnostics, and proposes treatment algorithms of patients suffering from TR associated with CIED lead(s) or leadless pacemakers.

Monocytes are a highly plastic innate immune cell population that displays significant heterogeneity within the circulation. Distinct patterns of surface marker expression have become accepted as a basis for distinguishing three monocyte subsets in humans. These phenotypic subsets, termed classical, intermediate and nonclassical, have also been demonstrated to differ in regard to their functional properties and disease associations when studied in vitro and in vivo. Nonetheless, for the intermediate monocyte subset in particular, functional experiments have yielded conflicting results and some studies point to further levels of heterogeneity. Developments in genetic sequencing technology have provided opportunities to more comprehensively explore the phenotypic and functional differences among conventionally-recognized immune cell subtypes as well as the potential to identify novel subpopulations. In this review, we summarize the transcriptomic evidence in support of the existence of three separate monocyte subsets. We also critically evaluate the insights into subset functional distinctions that have been garnered from monocyte gene expression analysis and the potential utility of such studies to unravel subset-specific functional changes which arise in disease states.

High blood pressure (BP) is associated with adverse cardiovascular outcomes.1 A number of highly effective pharmacological therapies are available to treat hypertension but a substantial proportion of affected subjects remain inadequately controlled world-wide.2 There are many reasons for this situation, such as lack of access to treatments, physician inertia, inadequate dosing or combinations of treatments, suboptimal patient adherence to treatment, the use of interfering drugs or substance of abuse, the presence of undiagnosed secondary hypertension or of treatment-resistant hypertension. A large number of patients with hypertension are reluctant to take or adhere to pharmacotherapeutic regimens, because of interference with their daily lives, fear/experience of side effects, preferences for alternative medications, or other reasons.3 Treatment-resistant hypertension is commonly defined as BP level above target [office systolic BP (SBP) ≥140 mmHg or diastolic BP ≥90 mmHg] despite treatment with at least 3 antihypertensive medications in adequate doses, one of which should be a diuretic.4 The difficulty of treating hypertension, its high prevalence and severe consequences, and the absence of novel antihypertensive drugs on the horizon and the limitations of purely pharmacologic approaches have prompted the development of interventional approaches to provide complementary treatments. Several device-based approaches have been invented and subsequently tested; one which has received much positive as well as skeptical attention is catheter-based renal denervation (RDN).5 , 6 The method uses radiofrequency energy, alternatively ultrasound or chemical ablation, to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys.7 Historical observations showed that surgical sympathectomy can reduce BP as well as morbidity and mortality in patients with uncontrolled hypertension.8 Even though based on strong pathophysiological rationale,8 catheter-based RDN has not conclusively demonstrated its value for the treatment of resistant hypertension and its place in the therapeutic armamentarium remains uncertain.9–12 Other device-based approaches under investigation include the creation of a central iliac arteriovenous (AV)–anastomosis with a coupler, the stimulation of the carotid sinus, the ablation of the carotid body, and stent-based expansion of the carotid bulb.13 , 14 The multidisciplinary European Expert Group has previously published proceedings from their 2014 clinical consensus conference aiming at exploring the gaps in our knowledge about RDN and making recommendations of future randomized controlled trial design.6 A follow-up conference was convened in October 2016 to evaluate the position of device therapies for hypertension in the light of the latest clinical developments. This article presents the main conclusions from this event. We first present a survey of the changing clinical environment surrounding hypertension and its implications for clinical trials in the field. This is followed by an update on currently on-going clinical trials of device-based hypertension therapy and design considerations for further trials. Finally, needs and recommendations on the standardised assessment of emerging device therapies are discussed. Since the last consensus conference in 2014, several clinical trials have been published, which may influence how device-based therapies are viewed and investigated. The results raise questions around treatment regimens, BP targets, and the most appropriate way to measure BP. In patients with resistant hypertension, the option of adding a fourth antihypertensive drug has been investigated. The crossover trial PATHWAY-2 recently showed spironolactone to be superior to placebo as an add-on in patients with resistant hypertension who had been identified by renin profiling as potential responders to the therapy.15 Despite the positive results from PATHWAY-2, the Expert Group has discussed whether these results should prompt adding spironolactone as a fourth line treatment in the management of resistant hypertension to define a trial population for device-based proof of concept studies. In the PATHWAY-2 trial, patients were on a low-dose of bendroflumethiazide, a drug less effective than chlorthalidone or indapamide, which may have favoured the BP response to spironolactone; BP response was not analysed per aldosterone levels, body mass index or BP at baseline; the short time (6 weeks) of exposure to the maximum dose of spironolactone (50 mg/d) was insufficient for an accurate assessment of the long-term tolerability of this drug; and there are no data on efficacy and safety in patients with eGFR <45 mL/min/1.73 m2 since they were excluded from the trial. Moreover, in clinical practise spironolactone has a challenging tolerability profile with higher rates of intolerance than in PATHWAY-2, including gynecomastia and erectile dysfunction, which may cause treatment interruption or termination at the request of the healthcare provider or patient.16 Indeed, an unexpectedly low rate of side effects occurred in the PATHWAY-2 study, possibly because of the relatively short treatment duration. Based on these reservations, the European Expert Group felt that there is no need to mandate failure to control BP on spironolactone as an inclusion criteria for resistant hypertension patients in a proof-of-concept trial of device-based hypertension therapies. The results from Systolic Blood Pressure Intervention Trial (SPRINT) have generated a vivid discussion around treatment targets and the most appropriate way to measure office BP. SPRINT reported a significantly lower risk for cardiovascular disease outcomes and all-cause mortality by targeting SBP <120 mmHg compared with <140 mmHg in a population of hypertensive persons with ≥1 additional cardiovascular risk factor.17 The SPRINT results have been interpreted as supporting a lower recommended target SBP than the currently widely accepted 140 mmHg. An expedited review of the SPRINT study was undertaken by the Canadian Hypertension Education Programme, which led to the recommendation that in selected high-risk patients, intensive BP reduction to target SBP ≤120 mmHg should be considered to lower the risk of cardiovascular events.18 From a safety standpoint, it is generally accepted that there is very low risk for harm from further SBP reductions below 140 mmHg.19 , 20 However, several design idiosyncrasies in the SPRINT study are relevant to the discussion on the most appropriate method to measure BP in clinical trials. SPRINT is the only outcomes trial to date to have used automated, unattended BP measurements with a dedicated device. This was done to reduce the influence of the presence of physicians or other healthcare professionals, or ‘white coat hypertension’. Though two other major blood pressure trials, Secondary Prevention of Small Subcortical Strokes (SPS3)21 and Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus (ACCORD),22 also used automated BP devices but with less standardized unattended BP measurement than in SPRINT. It has been noted that unobserved measures of SBP may be 5–15 mmHg lower than BP measured manually, or when patients are being observed.23 Previous studies in treated hypertensive subjects have shown that automatic unattended office BP measurements may be even lower than daytime ambulatory SBP, and up to 20 mmHg lower than conventional attended auscultatory office SBP.24 Finally, a recent meta-analysis of intervention trials on the effects of more or less intense BP lowering on outcome, which included SPRINT data, has provided evidence that a significant reduction in the absolute risk of events occurred whenever systolic BP was reduced below 150, 140, or even 130 mmHg, although the absolute reduction in risk of events was smaller when aiming at a systolic BP reduction <130 mmHg.25 In parallel, however, another recent meta-analysis of intervention trials by the same group has clearly shown that the lower the systolic BP achieved by treatment, the higher the number of patients who discontinued their drug therapy because of treatment-related side effects, which indicates a failure in achieving patients’ protection through pharmacological hypertension management.26 As target BP in a clinical trial of device-based therapy in hypertension, the European Expert Group recommended an attended target seated office BP < 140 mmHg using the conventional method and a validated device. Whichever method is used, it is critical that consistency is maintained in all centres and at all visits. The recommended target is closely related to clinical practice, in line with current guidelines as well as with our previous It is also the target used in many currently on-going clinical trials, although their efficacy is the ambulatory BP The European Expert Group further that targets may cause trials to as even they substantial and significant BP The alternative of using BP measurements at was also discussed. to BP may BP control and patient adherence to treatment and is included in the most recent guidelines from the European for A number of and are emerging to the for patients and its by the less well of compared with the European Expert Group not using BP measurement as a in clinical trials, there is large that it can be used as a secondary in device trials BP may influence adherence the trial hypertensive to the therapy as a A related to the and of clinical trials is of BP reduction associated with a recent a reduction of and mmHg in office BP as , have been used in the for clinical studies and is to can be achieved with one antihypertensive are for A but relevant reduction in BP a proof of concept in a controlled study of device therapies. It is also highly to reduce BP trial the of in hypertension device trials the European Expert Group considered a mmHg reduction in office SBP to be a This to mmHg in all BP targets the method of measurement should be The group that should be the efficacy in device trials of hypertension. the of the results with RDN in the randomized trial in there was a in clinical trials of have from the trials and the has up in recent a number of randomized trials are RDN in patients with resistant hypertension as well as in hypertensive patients Since is a there is no need for a trial with RDN a as as the is in lowering BP in a randomized controlled trial with a safety trials for device-based therapies in patients with hypertension to < mmHg to < mmHg and and to < mmHg to < mmHg and and to < to < mmHg at Secondary and mmHg SBP to < mmHg no drugs 3 drugs drugs daytime at secondary outcomes mmHg SBP mmHg at 6 Secondary at 6 mmHg, mmHg, ≥140 mmHg at 6 at BP ≥140 to mmHg to mmHg design ≥140 mmHg mmHg at 3 at to < mmHg to < mmHg and and to < mmHg to < mmHg and and to < to < mmHg at Secondary and mmHg SBP to < mmHg no drugs 3 drugs drugs daytime at secondary outcomes mmHg SBP mmHg at 6 Secondary at 6 mmHg, mmHg, ≥140 mmHg at 6 at BP ≥140 to mmHg to mmHg design ≥140 mmHg mmHg at 3 at office systolic ambulatory systolic major adverse cardiovascular renal of device trials for device-based therapies in patients with hypertension to < mmHg to < mmHg and and to < mmHg to < mmHg and and to < to < mmHg at Secondary and mmHg SBP to < mmHg no drugs 3 drugs drugs daytime at secondary outcomes mmHg SBP mmHg at 6 Secondary at 6 mmHg, mmHg, ≥140 mmHg at 6 at BP ≥140 to mmHg to mmHg design ≥140 mmHg mmHg at 3 at to < mmHg to < mmHg and and to < mmHg to < mmHg and and to < to < mmHg at Secondary and mmHg SBP to < mmHg no drugs 3 drugs drugs daytime at secondary outcomes mmHg SBP mmHg at 6 Secondary at 6 mmHg, mmHg, ≥140 mmHg at 6 at BP ≥140 to mmHg to mmHg design ≥140 mmHg mmHg at 3 at office systolic ambulatory systolic major adverse cardiovascular renal of device a first and latest clinical trial a first and latest clinical trial The RDN is in patients with uncontrolled hypertension in the absence and presence of antihypertensive medications trials have a efficacy of in SBP from to The control treatment with renal the ultrasound to a with the in daytime ambulatory SBP from to 2 in two and of patients with uncontrolled hypertension. 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The of the trials above include a There was an around the need for a group in trials the BP lowering efficacy of device-based for hypertension, but at this However, the use of a is associated with of including the of a an risk of adverse in trials patients with to hypertension who are at low cardiovascular and A index should be used to the efficacy of in clinical device The index can be used for not only study subjects and An assessment of appropriate is in randomized controlled device trials can be highly A with BP and should be in clinical device trials in hypertension to reduce by to the trials of treatment resistant therapeutic should be the The need for consistency of pharmacotherapeutic was in the consensus trials in a used in trials with antihypertensive The or the is a highly design to reduce and that all patients appropriate cardiovascular and validated to BP an dose or drug has been Several trials currently patients with or 2 hypertension but not treated with This may be a more population than treated resistant patients to proof of concept for It also whether device-based can reduce or the need for antihypertensive drugs in achieving BP control and whether it may the efficacy of However, these trials may potential as the patients treatment with and treatment not be in with the recommendations of The European Expert group this in the consensus However, studies in hypertensive patients can be to A follow-up of 3 reduce the risk to patients from uncontrolled hypertension and may be to efficacy in a proof of concept trial. the results are further studies be in to clinical to the of the An study design is to patients the efficacy is and to a antihypertensive drug in a design provide the therapy to all patients as well as provide data on whether the intervention the response to patients’ in the study it may be to patients who are a based In the of the group a number of hypertensive of are reluctant to on a In such be less of an to as as patients provide to including the of a It has to be considered that device-based therapies may lower BP more in the presence of antihypertensive drugs in patients with resistant hypertension, which the need for clinical studies with standardized drug It be to adherence to antihypertensive treatment and measures as much as such as mass have it to measure drug adherence in and the have been used to adherence as a in resistant hypertension and , The method to be for use in trials as an alternative to of However, adherence should not be the main of a trial of device therapies as the needs more the European Expert Group considered that is and be in all trials of device therapies for hypertension. include and The European Expert Group further that the large number of on-going studies in the a to and not only on the therapies but also on the effects of Since current trials have inclusion and a patient based meta-analysis the to which patient group most from The group the of an which should be access to all data from all to a meta-analysis based on using data on the use of healthcare and for should be to the results should be analysed to adherence to for trial of renal denervation in hypertensive patients RDN should be in the of hypertension of the antihypertensive pharmacological The clinical of patients that had the BP response to RDN and further study RDN in these including and ablation the of RDN on long-term cardiovascular and renal risk in hypertension, and failure for RDN such as trials may be considered to of radiofrequency RDN chemical ultrasound there are higher with effects on BP in patients with or antihypertensive drug therapy and further study RDN in these the appropriate clinical hypertension resistant hypertension, higher with long-term the appropriate clinical hypertension intolerance to effects by drug long-term RDN should be in the of hypertension of the antihypertensive pharmacological The clinical of patients that had the BP response to RDN and further study RDN in these including and ablation the of RDN on long-term cardiovascular and renal risk in hypertension, and failure for RDN such as trials may be considered to of radiofrequency RDN chemical ultrasound there are higher with effects on BP in patients with or antihypertensive drug therapy and further study RDN in these the appropriate clinical hypertension resistant hypertension, higher with long-term the appropriate clinical hypertension intolerance to effects by drug long-term RDN should be in the of hypertension of the antihypertensive pharmacological The clinical of patients that had the BP response to RDN and further study RDN in these including and ablation the of RDN on long-term cardiovascular and renal risk in hypertension, and failure for RDN such as trials may be considered to of radiofrequency RDN chemical ultrasound there are higher with effects on BP in patients with or antihypertensive drug therapy and further study RDN in these the appropriate clinical hypertension resistant hypertension, higher with long-term the appropriate clinical hypertension intolerance to effects by drug long-term RDN should be in the of hypertension of the antihypertensive pharmacological The clinical of patients that had the BP response to RDN and further study RDN in these including and ablation the of RDN on long-term cardiovascular and renal risk in hypertension, and failure for RDN such as trials may be considered to of radiofrequency RDN chemical ultrasound there are higher with effects on BP in patients with or antihypertensive drug therapy and further study RDN in these the appropriate clinical hypertension resistant hypertension, higher with long-term the appropriate clinical hypertension intolerance to effects by drug long-term The with and appropriate patients need to be to large trials within a time trials of device therapies in hypertension are by In one by no the trial patients a to patients who were in the trials in treatment resistant patients, the need to 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In our first consensus in the European Expert Group to the major need of of trial design and the large number of currently in the this need has even through and to for patient and assessment of outcomes it be to whether device therapies for hypertension are effective and are patient the proof of concept is further studies with a design relevant to clinical be to the place of devices in the treatment The clinical and has a large to or the value of in to that antihypertensive devices provide future patients with the and the We for with this The European Expert was by an from of has received for from has received from was as in and is as in the and has received a from has received for and is a in the European study by is of a that has a for renal In the for has in or has received or study from the has received from and and from and from has received for and from and has received from has received for from is by the and the for and has received and from and within the 3 is by the and has received and from and has received from is by and and has received and from and has received received for from has received for from has received has received from and and is of has received for and from has received and study from and from has received from and or from of and and has received for has received and from and has received from The is from

AIMS: Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. METHODS AND RESULTS: Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20). CONCLUSION: In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling.