Short and medium chain acylcarnitines as markers of outcome in diabetic and non-diabetic subjects with acute coronary syndromes.

BACKGROUND: Carnitine metabolism produces numerous molecular species of short-, medium-, and long-chain acylcarnitines, which play important roles in energy homeostasis and fatty acid transport in the myocardium. Given that disturbances in the carnitine metabolism are linked to cardiometabolic disease, we studied the relationship of circulating acylcarnitines with outcomes in patients with acute coronary syndromes (ACS) and evaluated differences in circulating levels of these metabolites between diabetic and non-diabetic patients. METHODS: Harnessing a prospective multicentre cohort study (SPUM-ACS; NCT01000701), we measured plasma levels of acylcarnitines, carnitine, and carnitine metabolites to assess their relationship with adjudicated major adverse cardiac events (MACE), defined as composite of myocardial infarction, stroke, clinically indicated revascularization, or death of any cause. The SPUM-ACS study enrolled patients presenting with ACS to Swiss University Hospitals between 2009 and 2012. Acetylcarnitine, octanoylcarnitine, proprionylcarnitine, butyrylcarnitine, pentanoylcarnitine, hexanoylcarnitine, carnitine, γ-butyrobetaine, and trimethylamine N-oxide were measured in plasma using stable isotope dilution high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. RESULTS: A total of 1683 patients with ACS were included in the study. All measured metabolites except γ-butyrobetaine and carnitine were higher in diabetic subject (n = 294) than in non-diabetic subjects (n = 1389). On univariate analysis, all metabolites, apart from octenoylcarnitine, were significantly associated with MACE at 1 year. After multivariable adjustment for established risk factors, acetylcarnitine remained an independent predictor of MACE at 1-year (quartile 4 vs. quartile 1, adjusted hazard ratio 2.06; 95% confidence interval 1.12-3.80, P = 0.020). CONCLUSION: Circulating levels of acetylcarnitine independently predict residual cardiovascular risk in patients with ACS.

Occlusion of the infarct-related coronary artery presenting as acute coronary syndrome with and without ST-elevation: impact of inflammation and outcomes in a real-world prospective cohort.

BACKGROUND: Patients with ST-segment elevation typically feature total coronary occlusion (TCO) of the infarct-related artery (IRA) on angiography, which may result in worse outcomes. Yet, relying solely on electrocardiogram (ECG) findings may be misleading and those presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) may have TCO as well. Herein, we aimed to delineate clinical characteristics and outcomes of patients with ACS stratified by IRA location. METHODS: A total of 4787 ACS patients were prospectively recruited between 2009 and 2017 in SPUM-ACS (ClinicalTrials.gov Identifier: NCT01000701). The primary endpoint was major adverse cardiovascular events (MACEs), a composite of all-cause death, non-fatal myocardial infarction and non-fatal stroke at 1 year. Multivariable-adjusted survival models were fitted using backward selection. RESULTS: A total of 4412 ACS patients were included in this analysis, 56.0% (n = 2469) ST-elevation myocardial infarction (STEMI) and 44.0% (n = 1943) NSTE-ACS. The IRA was the right coronary artery (RCA) in 33.9% (n = 1494), the left-anterior descending coronary artery (LAD) in 45.6% (n = 2013), and the left circumflex (LCx) in 20.5% (n = 905) patients. In STEMI patients, TCO (defined as TIMI 0 flow at angiography) was observed in 55% of cases with LAD, in 63% with RCA, and in 55% with LCx. In those presenting with NSTE-ACS, TCO was more frequent in those with LCx and RCA as compared to the LAD (27 and 24%, respectively, vs. 9%, P < 0.001). Among patients with NSTE-ACS, occlusion of the LCx was associated with an increased risk of MACE during 1 year after the index ACS (fully adjusted hazard ratio 1.68, 95% confidence interval 1.10-2.59, P = 0.02; reference: RCA and LAD). Features of patients with NSTE-ACS associated with TCO of the IRA included elevated lymphocyte and neutrophil counts, higher levels of high-sensitivity C reactive protein (hs-CRP) and high-sensitivity cardiac troponin T, lower eGFR, and notably a negative history of MI. CONCLUSION: In NSTE-ACS, both LCx and RCA involvement was associated with TCO at angiography despite the absence of ST-segment elevation. Involvement of the LCx, but not the LAD or RCA, as the IRA represented an independent predictor of MACE during 1-year follow-up. Hs-CRP, lymphocyte, and neutrophil counts were independent predictors of total IRA occlusion, suggesting a possible role of systemic inflammation in the detection of TCO irrespective of ECG presentation.

Initial systolic blood pressure associates with systemic inflammation, myocardial injury, and outcomes in patients with acute coronary syndromes.

AIMS: Outcomes after acute coronary syndromes (ACS) are determined by baseline risk profiles, including initial systolic blood pressure (sBP) levels. Herein, we aimed to characterize ACS patients stratified by initial sBP levels and study their relation to inflammation, myocardial injury and post-ACS outcomes. METHODS AND RESULTS: We analysed 4724 prospectively recruited ACS patients according to invasively assessed sBP (<100, 100-139, and ≥140 mmHg) at admission. Biomarkers of systemic inflammation [high-sensitivity C-reactive protein (hs-CRP)] and myocardial injury [high-sensitivity cardiac troponin T (hs-cTnT)] were measured centrally. Major adverse cardiovascular events (MACE; composite measure of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) were externally adjudicated. Leukocyte counts, hs-CRP, hs-cTnT, and creatine kinase (CK) levels decreased from low to high sBP strata (ptrend < 0.001). Patients with sBP < 100 mmHg developed more often cardiogenic shock (CS; P < 0.001), and had a 1.7-fold increased multivariable-adjusted MACE risk at 30 days (HR 1.68, 95% CI 1.05-2.69, P = 0.031) which did not persist at one year (HR 1.38, 95% CI 0.92-2.05, P = 0.117). Those with sBP < 100 mmHg and CS showed a higher leukocyte count (P < 0.001), an increased neutrophil-to-lymphocyte-ratio (P = 0.031), and higher hs-cTnT and CK levels relative to those without CS (P < 0.001 and P = 0.002, respectively), whereas hs-CRP levels did not differ. Patients who developed CS had a 3.6- and 2.9-fold increased MACE risk at 30 days (HR 3.58, 95% CI 1.77-7.24, P < 0.001) and at one year (HR 2.94 95% CI, 1.57-5.53, P < 0.001), which was intriguingely attenuated after controlling for distinct inflammatory profiles. CONCLUSION: In patients with ACS, proxies of systemic inflammation and myocardial injury are inversely associated with initial sBP levels, with highest biomarker levels observed in those <100 mmHg. If linked to high levels of cellular inflammation, these patients are prone to develop CS and are at high MACE and mortality risk.

History of peripheral artery disease and cardiovascular risk of real-world patients with acute coronary syndrome: Role of inflammation and comorbidities.

BACKGROUND: Patients with acute coronary syndromes (ACS) remain at risk of cardiovascular disease (CVD) recurrences. Peripheral artery disease (PAD) may identify a very high risk (VHR) group who may derive greater benefit from intensified secondary prevention. METHODS: Among ACS-patients enrolled in the prospective multi-center Special Program University Medicine (SPUM), we assessed the impact of PAD on major cardiovascular events (MACE: composite of myocardial infarction, stroke and all-cause death) and major bleeding. Multivariate analysis tested the relation of each significant variable with MACE, as well as biomarkers of inflammation and novel markers of atherogenesis. RESULTS: Out of 4787 ACS patients, 6.0% (n = 285) had PAD. PAD-patients were older (p < 0.001), with established CVD and signs of increased persistent inflammation (hs-CRP; 23.6 ± 46.5 vs 10.4 ± 27.2 mg/l, p < 0.001 and sFlt-1; 1399.5 ± 1501.3 vs 1047.2 ± 1378.6 ng/l, p = 0.018). In-hospital-death (3.2% vs 1.4%, p = 0.022) and -MACE (5.6% vs 3.0%, p = 0.017) were higher in PAD-patients. MACE at 1 year (18.6% vs 7.9%,p < 0.001) remained increased even after adjustment for confounders (Adj. HR 1.53, 95% CI: 1.14-2.08, p = 0.005). Major bleeding did not differ between groups (Adj. HR 1.18; 95% CI 0.71-1.97, p = 0.512). Although PAD predicted MACE, PAD-patients were prescribed less frequently for secondary prevention at discharge. CONCLUSIONS: In this real-world ACS patient cohort, concomitant PAD is a marker of VHR and is associated with increased and persistent inflammation, higher risk for MACE without an increased risk of major bleeding. Therefore, a history of PAD may be useful to identify those ACS patients at VHR who require more aggressive secondary prevention.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes.

AIMS: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031). CONCLUSION: Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD. CLINICAL TRIAL REGISTRATION: NCT01000701.

Cardiorenal risk of celecoxib compared with naproxen or ibuprofen in arthritis patients: insights from the PRECISION trial.

AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, both prescribed and over the counter. The long-term cardiovascular safety of NSAIDs in patients with arthritis has engendered controversy. Concerns remain regarding the relative incidence and severity of adverse cardiorenal effects, particularly in arthritis patients with established cardiovascular (CV) disease or risk factors for disease as illustrated by the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen) trial participants (NCT00346216).We further investigated whether the selective COX-2 Inhibitor celecoxib has a superior cardiorenal safety profile compared with ibuprofen or naproxen in the PRECISION population. METHODS AND RESULTS: Twenty-four thousand eighty-one patients who required NSAIDs for osteoarthritis or rheumatoid arthritis (RA) and had increased CV risk randomly received celecoxib, ibuprofen, or naproxen. The current pre-specified secondary analysis assessed the incidence, severity, and NSAID-related risk of the pre-specified composite cardiorenal outcome (adjudicated renal event, hospitalization for congestive heart failure, or hospitalization for hypertension) in the intention-to-treat (ITT) population. An on-treatment analysis assessed safety in those taking the study medication. Following a mean treatment duration of 20.3 ± 16.0 months and a mean follow-up of 34.1 ± 13.4 months, the primary cardiorenal composite outcome occurred in 423 patients (1.76%) in the ITT population. Of these 423 patients, 118 (28%) were in the celecoxib, 166 (39%) in the ibuprofen, and 139 (33%) in the naproxen group. In a multivariable Cox regression model adjusted for independent clinical variables, celecoxib showed a significantly lower risk compared with ibuprofen [hazard ratio (HR) 0.67, confidence interval (CI) 0.53-0.85, P = 0.001) and a trend to lower risk compared with naproxen (HR 0.79, CI 0.61-1.00, P = 0.058). In the ITT analysis, clinically significant renal events occurred in 220 patients with events rates of 0.71%, 1.14%, and 0.89% for celecoxib, ibuprofen, and naproxen, respectively (P = 0.052), while in the on-treatment analysis the rates were 0.52%, 0.91%, and 0.78% (P &lt; 0.001). CONCLUSION: In the current era, long-term NSAID use was associated with few cardiorenal events in arthritis patients. At the doses studied, celecoxib displayed fewer renal events and hence more favourable cardiovascular safety compared with ibuprofen or naproxen. These results have considerable clinical implications for practitioners managing individuals with chronic arthritis pain and high risk of impaired renal function and/or heart failure.Clinical Trial Registration: NCT00346216.

Prognostic value of inflammatory biomarkers and GRACE score for cardiac death and acute kidney injury after acute coronary syndromes.

AIMS: The aim of this study was to analyse the role of inflammation and established clinical scores in predicting acute kidney injury (AKI) after acute coronary syndromes (ACS). METHODS AND RESULTS: In a prospective multicentre cohort including 2034 patients with ACS undergoing percutaneous coronary intervention, high-sensitivity C-reactive protein (hsCRP), neutrophil count, neutrophil-to-lymphocyte ratio (NL-ratio), and creatinine were measured at the index procedure. AKI (n = 39, defined according to RIFLE criteria) and major cardiovascular and cerebrovascular events were adjudicated after 1 year. Associations between inflammation, AKI, and cardiac death (CD) were assessed by C-statistics and Cox proportional hazard models with log-rank test to compare survival. Patients with ACS with elevated neutrophil count >7.8 × 109/L, NL-ratio >5, combined neutrophil-count/creatinine, or NL-ratio/creatinine at baseline showed a higher incidence of AKI (all P < 0.05) and CD (all P < 0.001). The risk of AKI, CD, and their combination was increased in patients with higher neutrophil count/creatinine (heart rate (HR) = 3.7, 95% cardiac index (CI) 1.9-7.1; HR = 2.7, 95% CI 1.6-4.6; HR = 3.2, 95% CI 2.1-4.9); NL-ratio/creatinine (HR = 2.1, 95% CI 1.6-4.1; HR = 2.2, 95% CI 1.3-3.8; HR = 2.3, 95% CI 1.5-3.5); and hsCRP (HR = 1.8, 95% CI 0.9-3.5; HR = 2.2, 95% CI 1.3-3.6; HR = 1.9, 95% CI 1.2-2.8) after adjustment for age, diabetes, hypertension, previous heart failure, kidney function, haemodynamic instability at admission, statin, and renin-angiotensin-aldosterone antagonists use. Subjects with higher GRACE score 1.0/NL-ratio had higher rate of AKI, CD, and both (HR = 1.4, 95% CI 0.5-4.2; HR = 2.7, 95% CI 1.3-5.9; HR = 2.1, 95% CI 1-4.3). CONCLUSIONS: Inflammation markers may predict AKI after correction for renal function at the index procedure. hsCRP performed better than the NL-ratio. However, the integration of inflammation markers to traditional risk factors or scores does not add prognostic information. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01000701.

Impact of malignancy on clinical outcomes in patients with acute coronary syndromes.

BACKGROUND: The impact of cancer on survival in patients with coronary artery disease has not been well defined. We designed the present study to explore the prevalence and prognostic influence of cancer in patients with acute coronary syndrome (ACS). METHODS: 2'132 patients with ACS were enrolled in the prospective, multicenter Special Program University Medicine ACS (SPUM-ACS) cohort. The primary endpoints of major cardiovascular and cerebrovascular events (MACCE) and death were independently adjudicated at 30-day and at one-year follow-up. RESULTS: Of the 2'132 ACS patients 7.74% (n = 165) had cancer. At 30-day, except for net adverse clinical events (NACE defined as MACCE plus major bleeding), outcomes did not differ significantly between the two groups. At one year, MACCE rate was higher in cancer than in non-cancer patients (21.8 vs. 12.2%, p < 0.001). Even after adjusting for covariates, one-year all-cause mortality was higher in cancer patients than in those without (30.3% vs. 11.9%; p < 0.0001) as was cardiovascular mortality (15.7% vs. 5.9%; p < 0.001) and revascularization (12.7% vs. 5.5%, p < 0.001). Net adverse clinical events were also higher in patients with cancer at one-year follow-up (33.9% vs. 19.8%, p < 0.001). A sub-analysis revealed that those with solid tumors, but not hematological malignancies were more likely to experience MACCE (p = 0.001) as well as a higher cardiovascular and all cause mortality (both p = 0.001) at one-year follow-up. CONCLUSIONS: ACS patients with cancer, specifically those with solid tumors, have a higher MACCE as well as cardiovascular and total mortality rate than non-cancer patients independent of cardiovascular risk factors. Thus, cancer is an independent risk factor for a poor outcome in ACS patients.

Prognostic role of plasma galectin-3 levels in acute coronary syndrome.

AIM: Cystatin C, neutrophil gelatinase-associated lipocalin and galectin-3 have emerged as biomarker candidates to predict cardiovascular outcomes and mortality in the general population as well as in patients with coronary artery or renal disease. However, their predictive role and clinical utility in patients with acute coronary syndromes alone or in combination beyond currently used risk scores remains to be determined. METHODS AND RESULTS: Cystatin C, neutrophil gelatinase-associated lipocalin, and galectin-3 were measured in plasmas of 1832 patients at the time of presentation with acute coronary syndromes requiring percutaneous coronary intervention or coronary artery bypass grafting. The primary outcomes were major adverse cardiac and cerebrovascular events (defined as the composite of all-cause mortality, cerebrovascular events, any repeat revascularization or myocardial infarction) and all-cause mortality after 1 year and occurred in 192 (10.5%) and 78 (4.3%) of patients, respectively. All three biomarkers were increased in those with major adverse cardiac and cerebrovascular events compared with those without (p<0.001). However, only galectin-3 (all-cause mortality: hazard ratio=1.027 (95% confidence interval (1.011-1.043); p=0.001), major adverse cardiac and cerebrovascular events: hazard ratio=1.025 (95% confidence interval (1.012-1.037); p<0.001)) but not cystatin C nor neutrophil gelatinase-associated lipocalin emerged as independent predictors of both major adverse cardiac and cerebrovascular events and death. The risks were particularly high in the highest quartile of galectin-3. The integration of galectin-3 into the global registry of acute coronary events (GRACE) score improved the prediction of major adverse cardiac and cerebrovascular events and all-cause mortality significantly. The areas under the receiver operator characteristics curves increased from 0.6701 to 0.6932 for major adverse cardiac and cerebrovascular events (p=0.0474) and from 0.804 to 0.8199 for all-cause mortality (p=0.0197). Finally, we applied net reclassification improvement index using different cut-offs for major adverse cardiac and cerebrovascular events which showed negative results (for the cut-offs of 5% and 15%, net reclassification improvement index 0.028, p=0.586, for the cut-offs of 10% and 20%, net reclassification improvement index 0.072, p=0.1132 and for the cut-offs of 10% and 30% the net reclassification improvement index is 0.0843, p=0.077). CONCLUSION: In acute coronary syndromes patients, galectin-3 has moderate prognostic accuracy, provides statistically significant incremental value in some, but not all models, and that the magnitude of any improvement would seem of questionable clinical value.

Plugs for left atrial appendage occlusion: an overview of available devices.

INTRODUCTION: Approximately one-third of all ischemic strokes and the ensuing health and economic burden can be attributed to the presence of atrial fibrillation (AF). The global prevalence of AF continues to rise, thus making it by far the most common diagnosed cardiac arrhythmia. Percutaneous left atrial appendage (LAA) occlusion or obliteration has been developed to protect from the occurrence of stroke in patients with nonvalvular AF. AREAS COVERED: We address the characteristics and techniques for implantation as well as some clinical registries and randomized trials of the various catheter-based devices for the occlusion of the LAA that are either currently available or in the clinical evaluation stage. EXPERT OPINION: Over less than 2 decades, LAA occlusion progressed from being a concept applied in a few specialized centers to a globally recognized procedure implemented in numerous hospitals as part of daily interventional practice. The respective devices are to date safer and easier to deploy than initially. Periprocedural and postprocedural complications will continue to decrease as already evident from prospective randomized trials and registries. Although current indications focus on patients with nonvalvular AF and contraindications for oral anticoagulation, it is all but certain that the future will bring a widening in the spectrum of indications, applicability, and usage of these devices.

Clinical benefits and safety of renal denervation in severe arterial hypertension: A long-term follow-up study.

The clinical benefits of renal denervation are still under discussion, since randomized controlled clinical studies have provided inconsistent results. The present retrospective study examined the clinical effects of renal denervation with focus on office blood pressure, heart rate, and changes in renal function. Patients with treatment-resistant hypertension (blood pressure ≥ 140/90 mm Hg in spite of 3 antihypertensive drugs including a diuretic) underwent renal denervation at the University Hospital of Zurich, Switzerland and were followed up until 36 months. Renal denervation was performed using 3 different renal denervation systems. The primary outcome consisted of change in office blood pressure, heart rate, and plasma creatinine at 1, 6, 12, 24, and 36 months after renal denervation. 58 patients underwent renal denervation between August 2010 and December 2017. After exclusion, 50 patients were included in the analyses. At 36 months, the mean office systolic and diastolic blood pressure change was -26.4/-8.8 mm Hg (95% CI: -34.6 to -18.2/-13.5 to -4.2 mm Hg; P < .001 for both). Office heart rate showed no significant change during follow-up (P = .361). Plasma creatinine increased from 90.6 µmol/L (95% CI: 82.1 to 99.0 µmol/L) at baseline to 102.1 µmol/L (95% CI: 95.8 to 108.3 µmol/L) at 36 months (P = .007). No major adverse events occurred. Renal denervation is a safe and effective procedure for patients with treatment-resistant hypertension with a clinically significant antihypertensive effect. Further randomized trials are needed to determine the specific context within which renal denervation should be considered a therapeutic option in antihypertensive care.

Diabetes and baseline glucose are associated with inflammation, left ventricular function and short- and long-term outcome in acute coronary syndromes: role of the novel biomarker Cyr 61.

BACKGROUND: Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes. METHODS: The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; < 6, 6-11.1 and > 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA). RESULTS: Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL < 6.0 mmol/L or 6.0-11.1 mmol/L (HR-ratio 4.78 and 6.6; p < 0.001). The novel biomarker Cyr61 strongly associated with high BSL and STEMI and was independently associated with 1 year outcomes (HR 2.22; 95% CI 1.33-3.72; Tertile 3 vs. Tertile 1). CONCLUSIONS AND RELEVANCE: In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial Registration Number: NCT01000701. Registered October 23, 2009.

Baseline Predictors of Renal Failure in Transcatheter Aortic Valve Implantation.

BACKGROUND: Acute kidney injury (AKI) post transcatheter aortic valve implantation (TAVI) is associated with worsened short- and long-term outcomes. We sought to identify significant baseline predictors of AKI and establish a high-risk group within patients enrolled in the multicenter SWISS-TAVI cohort. METHODS AND RESULTS: A total of 526 patients who underwent TAVI were included in our analysis. Patients on hemodialysis were excluded. Within the first week after valve implantation, fifty patients (9.5%) developed AKI. There was a significantly higher prevalence of diabetes mellitus in the AKI group (45% vs 28%; P=.02). The odds ratio (OR) for patients suffering from diabetes mellitus who developed AKI was 1.9 after multivariable binary regression analysis (95% confidence interval, 1.018-3.553; P=.04). Chronic kidney disease (CKD) stage ≥4 was more prevalent in the AKI group (26% vs 14%; P=.04). Every 1 mg/dL creatinine above normal level at baseline increased AKI risk by a factor of 1.6 (OR, 1.605; 95% CI, 1.111-2.319; P=.01). Age, gender, body mass index, history of dyslipidemia, and history of hypertension were similar between the groups. In the diabetic population of 155 patients (29.5%), AKI developed in 22 patients (14.2%), compared with the non-diabetic population of 370 patients (70.5%), where AKI developed in 27 patients (7.3%). In the diabetic population, an elevation by 1 mg/dL in baseline creatinine was an independent predictor of developing kidney injury (OR, 2.061; 95% CI, 1.154-3.683; P=.02, while in non-diabetic patients, neither baseline glomerular filtration rate, CKD grade, STS score, EuroScore II, ACEF score, nor procedural contrast usage were predictors of AKI. CONCLUSION: Diabetics with CKD stage ≥4 (as defined by the Kidney Disease: Improving Global Outcomes criteria) constitute a high-risk group for developing AKI after TAVI. In this high-risk subgroup, baseline creatinine in combination with amount of contrast agent used were strong risk factors for developing AKI. AKI in non-diabetics was less predictable by baseline characteristics.

Atrial Fibrillation: A New Indicator for Advanced Colorectal Neoplasia in Screening Colonoscopy.

BACKGROUND: Colorectal cancer (CRC) is a common and potentially preventable malignancy. Evidence has emerged that coronary artery disease patients are at increased risk for developing CRC by shared risk factors. Here we investigated an association between CRC and atrial fibrillation (AF), a surrogate marker of cardiovascular risk, in the setting of routine screening colonoscopy. METHODS: We investigated 1949 asymptomatic participants (median age 61 [54-67] years, 49% females) undergoing screening colonoscopy within the SAKKOPI registry (Salzburg Colon Cancer Prevention Initiative). Forty-six participants with AF (2.4%) were identified, and colonoscopy findings were compared to non-AF participants. Propensity Score Matching (PSM) was used to create 1:1 and 3:1 age- and gender-matched couples. RESULTS: Abnormal findings on screening colonoscopy (any form of adenoma or carcinoma) were more common in AF participants with an odds ratios (OR) of 2.4 [1.3-4.3] in the unmatched analysis, and 2.6 [1.1-6.3] and 2.0 [1.1-4.0] in the 1:1 and 3:1 matched groups, respectively. Correspondingly, the odds of finding advanced adenomas or carcinomas was elevated about three-fold across the different matched and unmatched analyses (OR 3.3 [1.1-10.8] for 3:1 matched participants). At the same time, the prevalence and number of colonic lesions were significantly higher in AF participants (63.0% vs. 33.4% for 3:1 matched participants, p < 0.001). Non-CRC related findings on colonoscopy, like diverticulosis, were non-different between groups. CONCLUSION: Participants with AF had a higher burden of advanced premalignant adenomas and CRC in routine colonoscopy screening. Our data suggest that practitioners should monitor the CRC screening status, especially in AF patients.

Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes.

AIMS: Trimethyllysine (TML) serves as a nutrient precursor of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) and is associated with incident cardiovascular (CV) events in stable subjects. We examined the relationship between plasma TML levels and incident CV events in patients presenting with acute coronary syndromes (ACS). METHODS AND RESULTS: Plasma levels of TML were quantified in two independent cohorts using mass spectrometry, and its relationship with CV events was investigated. In a Cleveland Cohort (N = 530), comprised of patients presenting to the emergency department with chest pain and suspected ACS, TML was associated with major adverse cardiac events (MACE, myocardial infarction, stroke, need for revascularization, or all-cause mortality) over both 30 days [3rd tertile (T3), adjusted odds ratio (OR) 1.77, 95% confidence interval (CI) 1.04-3.01; P < 0.05] and 6 months (T3, adjusted OR 1.95, 95% CI 1.15-3.32; P < 0.05) of follow-up independent of traditional CV risk factors and indices of renal function. Elevated TML levels were also associated with incident long-term (7-year) all-cause mortality [T3, adjusted hazard ratio (HR) 2.52, 95% CI 1.50-4.24; P < 0.001], and MACE even amongst patients persistently negative for cardiac Troponin T at presentation (e.g. 30-day MACE, T3, adjusted OR 4.49, 95% CI 2.06-9.79; P < 0.001). Trimethyllysine in combination with TMAO showed additive significance for near- and long-term CV events, including patients with 'negative' high-sensitivity Troponin T levels. In a multicentre Swiss Cohort (N = 1683) comprised of ACS patients, similar associations between TML and incident 1-year adverse cardiac risks were observed (e.g. mortality, adjusted T3 HR 2.74, 95% CI 1.28-5.85; P < 0.05; and MACE, adjusted T3 HR 1.55, 95% CI 1.04-2.31; P < 0.05). CONCLUSION: Plasma TML levels, alone and together with TMAO, are associated with both near- and long-term CV events in patients with chest pain and ACS.

Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.

AIMS: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). METHODS AND RESULTS: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. CONCLUSIONS: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.

Right coronary artery motion analysis: a novel method to measure right ventricular systolic function by selective coronary angiography.

Right ventricular systolic dysfunction is prognostic in various cardiovascular diseases. Right ventricular systolic function is not commonly assessed in the catheterization laboratory. Therefore, we developed a novel, reproducible method to measure right ventricular systolic function during selective coronary angiography. We analyzed the angiographic systolic translational motion and maximum speed of the right coronary artery (RCA) in 97 consecutive patients and compared it to the tricuspid annular plane systolic excursion (TAPSE) as measured by echocardiography. All measurements were performed by two independent operators on two occasions. Inter-observer variability and intra-observer variability were excellent for RCA motion distance and for RCA maximum speed. There was a significant correlation of the RCA motion distance and RCA maximum speed with the TAPSE measured by echocardiography (Pearson's correlation for RCA distance: r = 0.59, p < 0.001, r2 = 0.35; for RCA speed: r = 0.40, p < 0.001, r2 = 0.16). The area under the receiver operating curve for the RCA motion distance was 0.88 (95% CI 0.80-0.96) for discrimination of normal and abnormal right ventricular systolic function. A cut-off value less than 22.3 mm systolic RCA motion had a specificity of 93.3% and a sensitivity of 75.6% for identifying an abnormal right ventricular systolic function. Analysis of the RCA motion is a reproducible and reliable method to measure right ventricular systolic function during selective coronary angiography. It is a simple and useful tool to assess right ventricular function in the catheterization laboratory and may serve for risk assessment for right ventricular failure. CLINICAL TRIAL REGISTRATION: Data for this study was collected retrospectively from Swiss Transcatheter Aortic Valve Implantation Registry (NCT01368250). https://clinicaltrials.gov/show/NCT01368250 .

A novel score in the prediction of rhythm outcome after ablation of atrial fibrillation: The SUCCESS score.

OBJECTIVE: The aim of the present study was to assess the predictive value of the CHADS2, CHA2DS2-VASc, R2CHADS2, and APPLE scores for rhythm outcome in patients with atrial fibrillation (AF) after catheter ablation. METHODS: The cohort of the present study consisted of 192 patients with AF who underwent a total of 265 ablations. Rhythm outcome was documented between 3 and 24 month after ablation. The mentioned scores were calculated for every patient. RESULTS: Of the patients, 139 (72%) were successfully treated having freedom of any atrial tachyarrhythmia, whereas 21 (11%) had partial success, and 32 (17%) had failure. For univariate analysis, the APPLE score was the only significant predictor of outcome after ablation with an odds ratio (OR) of 1.485 [95% confidence interval (CI) 1.075-2.052, p-value 0.017]. A multivariate binary regression corrected for possible confounders showed that the APPLE score (OR 1.527, 95% CI 1.082-2.153, p-value 0.016) along with the number of previous ablations (OR 5.831, 95% CI 1.356-25.066, p-value 0.018) is a significant predictor of outcome. A novel score (SUCCESS) was created by adding one point to the APPLE score for each previously performed ablation. This novel score demonstrated an improvement in receiver operating characteristic curve analysis (area under the curve 0.657 vs. 0.620). However, these findings were not significant in our study (p-value 0.219). CONCLUSION: Both the APPLE and the novel SUCCESS scores are superior to the CHADS2, CHA2DS2-VASc, and R2CHADS2 scores in predicting AF recurrence after catheter ablation. The SUCCESS score appears to have a higher predictive value than the APPLE score and might be a valuable tool to estimate the risk of AF recurrence in patients eligible for catheter ablation.

Pre-existing treatment with aspirin or statins influences clinical presentation, infarct size and inflammation in patients with de novo acute coronary syndromes.

BACKGROUND: Influence of pre-existing treatment with aspirin and/or statins prior to a first acute coronary syndrome (ACS) on clinical presentation, infarct size and inflammation markers. We analyzed patients from the Swiss Program University Medicine ACS-cohort (SPUM-ACS; ClinicalTrials.govnumber:NCT01075867). METHODS: 1639 patients were categorized into 4 groups: (1) patients without either drug (n = 1181); (2) patients only on aspirin (n = 157); (3) patients only on statins (n = 133) and (4) patients on both drugs (n = 168). Clinical features, electrocardiogram (ECG), creatinine kinase (CK, U/l), high-sensitivity troponin T (hsTNT, µg/l), N-terminal brain natriuretic peptide (NT-proBNP, ng/l), leucocytes (Lc, G/l), neutrophils (Nc, G/l), C-reactive protein (CRP, mg/l) and angiographic features were documented at baseline. RESULTS: Incidences of ST-elevation myocardial infarction (STEMI) were 64% in group 1, 45% in group 2, 52% in group 3 and 40% in group 4 (p < 0.0001). Those with both drugs had significantly lower CK (median 145 U/l, interquartile range (IQR) 89-297), hsTNT (median 0.13 µg/l, IQR 0.03-0.52) and higher left ventricular ejection fraction values (LVEF) (mean 55 ±â€¯12%) compared to untreated patients (median CK 273 U/l, IQR 128-638; median hsTNT 0.26 µg/l, IQR 0.08-0.85; mean LVEF 51 ±â€¯11%) (p < 0.0001, p = 0.001, p = 0.028, respectively). Co-medicated groups matched for high risk factors presented less frequently as STEMIs (p < 0.0001), had significantly smaller infarcts determined by CK and hsTNT (both p < 0.0001) and lower CRP levels (p = 0.01) compared to patients without pre-existing treatment with either drug. CONCLUSION: Pre-existing treatment with aspirin and/or statins and particularly with their combination changes the clinical presentation, infarct size, inflammation markers and LVEF in patients suffering their first ACS.