One-Year Outcomes after PCI Strategies in Cardiogenic Shock.

BACKGROUND: Among patients with acute myocardial infarction, cardiogenic shock, and multivessel coronary artery disease, the risk of a composite of death from any cause or severe renal failure leading to renal-replacement therapy at 30 days was found to be lower with percutaneous coronary intervention (PCI) of the culprit lesion only than with immediate multivessel PCI. We evaluated clinical outcomes at 1 year. METHODS: We randomly assigned 706 patients to either culprit-lesion-only PCI or immediate multivessel PCI. The results for the primary end point of death or renal-replacement therapy at 30 days have been reported previously. Prespecified secondary end points at 1 year included death from any cause, recurrent myocardial infarction, repeat revascularization, rehospitalization for congestive heart failure, the composite of death or recurrent infarction, and the composite of death, recurrent infarction, or rehospitalization for heart failure. RESULTS: As reported previously, at 30 days, the primary end point had occurred in 45.9% of the patients in the culprit-lesion-only PCI group and in 55.4% in the multivessel PCI group (P=0.01). At 1 year, death had occurred in 172 of 344 patients (50.0%) in the culprit-lesion-only PCI group and in 194 of 341 patients (56.9%) in the multivessel PCI group (relative risk, 0.88; 95% confidence interval [CI], 0.76 to 1.01). The rate of recurrent infarction was 1.7% with culprit-lesion-only PCI and 2.1% with multivessel PCI (relative risk, 0.85; 95% CI, 0.29 to 2.50), and the rate of a composite of death or recurrent infarction was 50.9% and 58.4%, respectively (relative risk, 0.87; 95% CI, 0.76 to 1.00). Repeat revascularization occurred more frequently with culprit-lesion-only PCI than with multivessel PCI (in 32.3% of the patients vs. 9.4%; relative risk, 3.44; 95% CI, 2.39 to 4.95), as did rehospitalization for heart failure (5.2% vs. 1.2%; relative risk, 4.46; 95% CI, 1.53 to 13.04). CONCLUSIONS: Among patients with acute myocardial infarction and cardiogenic shock, the risk of death or renal-replacement therapy at 30 days was lower with culprit-lesion-only PCI than with immediate multivessel PCI, and mortality did not differ significantly between the two groups at 1 year of follow-up. (Funded by the European Union Seventh Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).

Clinical characterization of the first Belgian SCN5A founder mutation cohort.

AIMS: We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected. METHODS AND RESULTS: The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS. CONCLUSION: The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.

PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock.

BACKGROUND: In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial. METHODS: In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke. RESULTS: At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups. CONCLUSIONS: Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI.

BACKGROUND: Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave-free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. METHODS: We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR-guided or FFR-guided coronary revascularization. The primary end point was the 1-year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. RESULTS: At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, -0.2 percentage points; 95% confidence interval [CI], -2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). CONCLUSIONS: Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE-FLAIR ClinicalTrials.gov number, NCT02053038 .).

Abnormal longitudinal peak systolic strain in asymptomatic patients with type I diabetes mellitus.

AIMS: In addition to increased risk of cardiovascular disease, the prevalence of diabetic cardiomyopathy is increasingly recognized in patients with type 1 diabetes mellitus (T1DM). We aimed to identify the occurrence of subclinical markers of cardiovascular risk and cardiac dysfunction and assess their relation to clinical parameters in asymptomatic patients with T1DM. METHODS AND RESULTS: A total of 102 patients (mean age 46 years [20-73], 62% male) with a history of T1DM ranging from 5 to 47 years underwent standard 2D and pulse-wave tissue Doppler echocardiography (Philips iE33) and computerized tomography for assessment of coronary calcium score (CACS) and visceral fat. Global peak longitudinal strain (GPLSS, speckle tracking) was calculated by offline analysis (Qlab 9.0). Whereas systolic function was preserved in all patients (LVEF > 50%), subclinical dysfunction (defined as global longitudinal peak systolic strain [GLPSS] of >-20%) was present in 39% and 66% had diastolic dysfunction. Fifty patients had a CACS above the 50th percentile according to age and gender. These patients were older, more obese, had higher levels of visceral fat, higher SBP and increased levels of LDL cholesterol. Higher CACS meant increased risk of diastolic and subclinical systolic dysfunction. However, decreased GLPSS was also detected in 30% of patients with CACS of <50th percentile. Stepwise linear regression analysis indicated visceral fat as a strong predictor of abnormal GPLSS and CACS. CONCLUSION: Subclinical left ventricular dysfunction and atherosclerosis were highly prevalent in asymptomatic T1DM. Abnormal GPLSS was noted with or without associated increase in CACS. Visceral fat was a strong predictor of increased CACS as well as abnormal GLPSS.

Indications and practical approach to non-invasive ventilation in acute heart failure.

In acute heart failure (AHF) syndromes significant respiratory failure (RF) is essentially seen in patients with acute cardiogenic pulmonary oedema (ACPE) or cardiogenic shock (CS). Non-invasive ventilation (NIV), the application of positive intrathoracic pressure through an interface, has shown to be useful in the treatment of moderate to severe RF in several scenarios. There are two main modalities of NIV: continuous positive airway pressure (CPAP) and pressure support ventilation (NIPSV) with positive end expiratory pressure. Appropriate equipment and experience is needed for NIPSV, whereas CPAP may be administered without a ventilator, not requiring special training. Both modalities have shown to be effective in ACPE, by a reduction of respiratory distress and the endotracheal intubation rate compared to conventional oxygen therapy, but the impact on mortality is less conclusive. Non-invasive ventilation is also indicated in patients with AHF associated to pulmonary disease and may be considered, after haemodynamic stabilization, in some patients with CS. There are no differences in the outcomes in the studies comparing both techniques, but CPAP is a simpler technique that may be preferred in low-equipped areas like the pre-hospital setting, while NIPSV may be preferable in patients with significant hypercapnia. The new modality 'high-flow nasal cannula' seems promising in cases of AHF with less severe RF. The correct selection of patients and interfaces, early application of the technique, the achievement of a good synchrony between patients and the ventilator avoiding excessive leakage, close monitoring, proactive management, and in some cases mild sedation, may warrant the success of the technique.

Cytoprotective effects of transgenic neuroglobin overexpression in an acute and chronic mouse model of ischemic heart disease.

Neuroglobin (NGB) is an oxygen-binding protein that is mainly expressed in nervous tissues where it is considered to be neuroprotective during ischemic brain injury. Interestingly, transgenic mice overexpressing NGB reveal cytoprotective effects on tissues lacking endogenous NGB, which might indicate a therapeutic role for NGB in a broad range of ischemic conditions. In the present study, we investigated the effect of NGB overexpression on survival as well as on the size and occurrence of myocardial infarctions (MI) in a mouse model of acute MI (AMI) and a model of advanced atherosclerosis (ApoE -/- Fbn1 C1039G+/- mice), in which coronary plaques and MI develop in mice being fed a Western-type diet. Overexpression of NGB significantly enhanced post-AMI survival and reduced MI size by 14% 1 week after AMI. Gene expression analysis of the infarction border showed reduction of tissue hypoxia and attenuation of hypoxia-induced inflammatory pathways, which might be responsible for these beneficial effects. In contrast, NGB overexpression did not affect survival or occurrence of MI in the atherosclerotic mice although the incidence of coronary plaques was significantly reduced. In conclusion, NGB proved to act cytoprotectively during MI in the acute setting while this effect was less pronounced in the atherosclerosis model.

A higher volume of fibrotic tissue on virtual histology prior to coronary stent implantation predisposes to more pronounced neointima proliferation.

BACKGROUND: Since neointima smooth muscle cells (SMC) mainly originate from the vessel wall, we investigated whether atherosclerotic plaque composition influences subsequent in-stent neointima proliferation and restenosis. METHODS: We performed intravascular ultrasound (IVUS) with virtual histology in 98 patients prior to elective bare-metal stent (BMS) implantation in de novo coronary artery lesions. Virtual histology variables pre-percutaneous coronary intervention (PCI) were related to in-stent neointima proliferation six months after implantation assessed as late luminal loss of 0.88 mm (interquartile range (IQR) 0.37-1.23 mm) on angiography and as maximal percentage area stenosis of 42% (IQR 33-59%) and percentage volume intima hyperplasia of 27% (IQR 20-36%) on IVUS. A ridge-trace based multiple linear regression model was constructed to account for multicollinearity of the virtual histology variables and was corrected for implanted stent length (18 mm, IQR 15-23 mm), stent diameter (3.0 mm, IQR 2.75-3.5 mm) and lesion volume (146 mm³, IQR 80-201 mm³) prior to PCI. RESULTS: Fibrous tissue volume prior to PCI (49 mm³, IQR 30-77 mm³) was significantly and independently related to late luminal loss (p = .038), maximal percentage area stenosis (p = .041) and percentage volume intima hyperplasia (p = .004). Neither absolute nor relative amounts of fibrofatty, calcified or necrotic core tissue appeared related to any of the restenosis parameters. Subgroup analysis after exclusion of acute coronary syndrome (ACS) patients yielded similar results. CONCLUSION: Lesions with more voluminous fibrotic tissue pre-PCI show more pronounced in-stent neointima proliferation, even after correction for lesion plaque volume.

Comparison of radial access versus femoral access with the use of a vascular closure device for the prevention of vascular complications and mortality after percutaneous coronary intervention.

BACKGROUND: Radial access (RA) and vascular closure devices (VCD) have been shown to be superior to transfemoral access (TFA) with regard to the prevention of vascular complications after percutaneous coronary intervention (PCI). OBJECTIVE: The present study evaluates whether RA is associated with less vascular complications and a lower mortality than VCD. METHODS: A total of 6999 consecutive PCI patients were studied through a single-centre prospective registry from January 2011 to August 2015. RA was applied in 1385 patients (20%), VCDs with Angio-Seal were implanted in 2145 patients (30%) and manual compression of TFA was performed in 3468 patients (50%). RESULTS: RA and VCD patients had comparable baseline risk profiles. The overall vascular complication rate was 2.0% (n = 137) and was composed of false aneurysms (n = 85), clinically relevant haematomas (n = 27), arteriovenous fistulas (n = 12), arterial occlusions (n = 11) and local infections (n = 2). Vascular complications occurred in 0.6% of RA patients, 1.8% of VCD patients and 2.6% of TFA patients (p < .01). In-hospital mortality was 0.8% in RA patients, 0.8% in VCD patients and 3.8% in TFA patients (p < .01). In a multivariate logistic regression model, RA, compared to VCD, was found to be independently associated with a lower rate of vascular complications (OR: 0.34, 95% CI: 0.16-0.75), but not with lower mortality rates (OR: 1.20, 95% CI: 0.51-2.85). CONCLUSION: In this large all-comers PCI population, the radial approach, compared to the femoral approach with VCD use (Angio-Seal), was independently associated with a reduction of vascular complications, but not with lower mortality rates.

Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling.

BACKGROUND: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases. AIMS: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI). METHODS: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls. RESULTS: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (ρ = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA-155 and the amount of monocytes (day 5, ρ = 0.463, p = 0.046). CONCLUSION: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling.

Spontaneous coronary artery dissection.

A new Study Group for this unusual and serious condition was announced at ESC Congress in Rome by the Acute Cardiovascular Care Association (ACCA) of the ESC. Spontaneous Coronary Artery Dissection (SCAD) is an increasingly recognized cause of non-atherosclerotic acute coronary syndromes afflicting predominantly younger women. It is characterized by a separation of the layers of the coronary arterial wall by an accumulation of blood to form a false lumen. A build-up of pressure within the false lumen leads to external compression of the true coronary lumen restricting coronary blood flow and leading to myocardial ischaemia or infarction. SCAD should be distinguished from atherosclerotic dissections arising from plaque rupture events or erosions and from traumatic dissections or iatrogenic dissections arising during coronary procedures. Historically SCAD was primarily considered to be a condition of pregnancy or associated with known connective tissue disorders. However, it is now clear these cases make up a small proportion of the prevalent population and most events occur unheralded in patients with minimal cardiovascular risk factors.1­3 In this conventionally low-risk group, diagnosis is frequently missed or significantly delayed. Furthermore, characteristic angiographic and intracoronary imaging appearances are not widely recognized, partly because of a common misconception that a visible dual lumen or linear dissection 'flap' will usually be present.2,4 Accurate diagnosis of SCAD is important because of key differences in management compared to atherosclerotic coronary disease. Success rates following revascularisation are lower in SCAD and if conservative management is possible (e.g. in haemodynamically stable patients with TIMI 3 flow in the infarct related artery), the dissection usually heals over a few weeks/months.5 Stenting may be essential to restore coronary blood flow but is complicated by the risk of proximal and distal migration of the mural haematoma such that long lengths of stenting may be required to restore coronary integrity and flow. Bypass surgery can be used as a bail out where percutaneous coronary intervention has failed or for high-risk left main stem or proximal dissections but longevity of grafts in the context of SCAD is reduced by healing of the native coronary and subsequent competitive flow leading to high-graft occlusion rates. Management of SCAD-survivors is challenging with considerable uncertainty about the optimal approach. For example, antiplatelet therapy, whilst required in patients following coronary stenting, can precipitate menorrhagia and the indication in conservatively managed patients for a condition whose primary pathophysiological event is an intramural bleed, is less clear, especially after the acute phase. Likewise, the use of statins has been questioned for a condition whose primary pathophysiology appears distinct from atherosclerosis and unrelated to cholesterol. Furthermore, SCAD patients face particular questions unusual in an atherosclerotic population, such as about safe contraception and the risk of pregnancy. Of particular concern is recurrent SCAD which is well recognized and may affect as many as one in four patients over 5 years.4,6 To date research in Europe has been limited to a number of national registries, small clinical studies, and case series. Globally the largest reported series contain just a few hundred cases. As a result, SCAD represents a substantial area of unmet clinical need. There is therefore an urgent necessity to coordinate research internationally to enable larger numbers of patients to be studied. This will advance our knowledge of the epidemiology, pathophysiology, and clinical management of SCAD. With this aim, an inaugural meeting was held to welcome the SCAD Study Group within the Acute Cardiovascular Care Association of the ESC at the recent ESC Congress in Rome. Support from the European Fibromuscular Dysplasia (FMD) Group (a condition which occurs in a significant proportion of SCAD patients1­3) was especially welcome. The aims of the Study Group are: •To establish a collaborative partnership to advance research into SCAD •To maintain a European registry of SCAD patients to advance understanding of epidemiology and variations in patient management and outcomes •To coordinate and support clinical and pre-clinical research into SCAD •To formulate and disseminate a European consensus on the diagnosis and management of SCAD •To improve accurate diagnosis by raising awareness of SCAD •To support patients with this condition The Study Group welcomes any interested clinicians to make contact and hope by working together we can make an important contribution to better understanding SCAD and improving our care and support for SCAD-survivors.

Tumor necrosis factor-α impairs adiponectin signalling, mitochondrial biogenesis, and myogenesis in primary human myotubes cultures.

Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index (r = -0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK (P < 0.01), AMPK activation (P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1ß, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function.

Improving stem cell therapy in cardiovascular diseases: the potential role of microRNA.

The initial promising prospect of autologous bone marrow-derived stem cell therapy in the setting of cardiovascular diseases has been overshadowed by functional shortcomings of the stem cell product. As powerful epigenetic regulators of (stem) cell function, microRNAs are valuable targets for novel therapeutic strategies. Indeed, modulation of specific miRNA expression could contribute to improved therapeutic efficacy of stem cell therapy. First, this review elaborates on the functional relevance of miRNA dysregulation in bone marrow-derived progenitor cells in different cardiovascular diseases. Next, we provide a comprehensive overview of the current evidence on the effect of specific miRNA modulation in several types of progenitor cells on cardiac and/or vascular regeneration. By elaborating on the cardioprotective regulation of progenitor cells on cardiac miRNAs, more insight in the underlying mechanisms of stem cell therapy is provided. Finally, some considerations are made regarding the potential of circulating miRNAs as regulators of the miRNA signature of progenitor cells in cardiovascular diseases.

Multivessel versus culprit lesion only percutaneous revascularization plus potential staged revascularization in patients with acute myocardial infarction complicated by cardiogenic shock: Design and rationale of CULPRIT-SHOCK trial.

BACKGROUND: In acute myocardial infarction complicated by cardiogenic shock (CS), up to 80% of patients present with multivessel coronary artery disease. Currently, the best revascularization strategy is unknown. Therefore, a prospective randomized adequately powered clinical trial is warranted. STUDY DESIGN: The CULPRIT-SHOCK study is a 706-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare culprit lesion only percutaneous coronary intervention (PCI) with possible staged non-culprit lesion revascularization versus immediate multivessel PCI in patients with CS complicating acute myocardial infarction. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of CULPRIT-SHOCK is 30-day mortality and severe renal failure requiring renal replacement therapy. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, an intermediate- and long-term follow-up at 6 and 12 months will be performed. Safety endpoints include the assessment of bleeding and stroke. CONCLUSIONS: The CULPRIT-SHOCK trial will address the question of optimal revascularization strategy in patients with multivessel disease and acute myocardial infarction complicated by CS.

The evolving role of adiponectin as an additive biomarker in HFrEF.

Heart failure (HF) is a growing health problem. Despite improved management and outcome, the number of patients with HF is expected to keep rising in the following years. In recent research, adiponectin was shown to exert beneficial effects in the cardiovascular system, but the protein was also implicated in the development and progression of HF. The objective of this review is to provide an overview of current knowledge on the role of adiponectin in HF with reduced ejection fraction. We discuss the cardioprotective and (anti-) inflammatory actions of adiponectin and its potential use in clinical diagnosis and prognosis.

Childhood obesity-related endothelial dysfunction: an update on pathophysiological mechanisms and diagnostic advancements.

Childhood obesity jeopardizes a healthy future for our society's children as it is associated with increased cardiovascular morbidity and mortality later on in life. Endothelial dysfunction, the first step in the development of atherosclerosis, is already present in obese children and may well represent a targetable risk factor. Technological advancements in recent years have facilitated noninvasive measurements of endothelial homeostasis in children. Thereby this topic ultimately starts to get the attention it deserves. In this paper, we aim to summarize the latest insights on endothelial dysfunction in childhood obesity. We discuss methodological advancements in peripheral endothelial function measurement and newly identified diagnostic markers of vascular homeostasis. Finally, future challenges and perspectives are set forth on how to efficiently tackle the catastrophic rise in cardiovascular morbidity and mortality that will be inflicted on obese children if they are not treated optimally.

Impaired vascular function contributes to exercise intolerance in chronic kidney disease.

BACKGROUND: Exercise intolerance is an important feature in patients with chronic kidney disease (CKD) and is prognostic for both increased morbidity and mortality. Little is known about the underlying mechanisms in predialysis CKD. This study aimed to gain more insight into the role of vascular dysfunction in the exercise intolerance of predialysis CKD. In addition, vascular-related microRNAs (miRNAs)-as epigenetic regulators of exercise capacity-were analysed. METHODS: Sixty-three patients with CKD stages 1-5 and 18 healthy controls were included. Peak oxygen consumption (VO2peak) was determined by cardiopulmonary exercise testing, endothelial function by flow-mediated dilation (FMD) and arterial stiffness by carotid-femoral pulse wave velocity (PWV). Plasma miRNA levels (miR-21, miR-126, miR-146a, miR-150 and miR-210) were quantified by quantitative RT-PCR. RESULTS: VO2peak was already impaired in mild CKD (stages 1-3A) and significantly correlated with estimated glomerular filtration rate (eGFR; r = 0.525, P < 0.001). Likewise, both FMD and PWV were significantly correlated with eGFR (r = 0.319, P = 0.007 and r = -0.365, P = 0.001, respectively). In multiple regression analysis, PWV remained one of the strongest independent determinants of VO2peak (ß = -0.301, P = 0.01). Of the studied miRNA, circulating levels of miR-146a and miR-150 correlated with eGFR, PWV and VO2peak, but the association with the latter was lost when correcting for PWV. CONCLUSIONS: Arterial stiffness contributes to the observed reduced aerobic capacity in predialysis CKD, independent of age, haemoglobin levels and endothelial function and represents a promising therapeutic target for improving exercise capacity in this population. Future work is required to elucidate why higher circulating levels of miR-146a and miR-150 are associated with impaired renal function and increased arterial stiffness.

Primary skeletal muscle myoblasts from chronic heart failure patients exhibit loss of anti-inflammatory and proliferative activity.

BACKGROUND: Peripheral skeletal muscle wasting is a common finding with adverse effects in chronic heart failure (HF). Whereas its clinical relevance is beyond doubt, the underlying pathophysiological mechanisms are not yet fully elucidated. We aimed to introduce and characterize the primary culture of skeletal muscle cells from individual HF patients as a supportive model to study this muscle loss. METHODS AND RESULTS: Primary myoblast and myotubes cultures were successfully propagated from the m. vastus lateralis of 6 HF patients with reduced ejection fraction (HFrEF; LVEF <45 %) and 6 age and gender-matched healthy donors. HFrEF cultures were not different from healthy donors in terms of morphology, such as myoblast size, shape and actin microfilament. Differentiation and fusion indexes were identical between groups. Myoblast proliferation in logarithmic growth phase, however, was attenuated in the HFrEF group (p = 0.032). In addition, HFrEF myoblasts are characterized by a reduced TNFR2 expression and IL-6 secretion (p = 0.017 and p = 0.016; respectively). CONCLUSION: Biopsy derived primary skeletal muscle myoblasts of HFrEF patients produce similar morphological and myogenic differentiation responses as myoblasts of healthy donors, though demonstrate loss of anti-inflammatory and proliferative activity.

Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes.

At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To circumvent these problems, we developed a TAA gene panel for next-generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation-dependent probe amplification identified large deletions in six of the remaining samples, whereas false-negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.