Showing papers by "Thomas F. Lüscher published in 2018"

International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology

Abstract: Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management

Abstract: The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis

Abstract: AIMS Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed double-blind randomised controlled trials (RCTs) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose (FCM). This individual patient data meta-analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID. METHODS AND RESULTS Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID. The main outcome measures were recurrent cardiovascular (CV) hospitalisations and CV mortality. Other outcomes included cause-specific hospitalisations and death. The main analyses of recurrent events were backed up by time-to-first-event analyses. In total, 839 patients, of whom 504 were randomised to FCM, were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval (CI) 0.40-0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33-0.86; P = 0.011) and recurrent CV hospitalisations and all-cause mortality (rate ratio 0.60, 95% CI 0.41-0.88; P = 0.009). Time-to-first-event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events. CONCLUSIONS Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID.

2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia

Abstract: A correction has been published: European Heart Journal, Volume 39, Issue 22, 7 June 2018, Pages 2105

Coronary computed tomography angiography for heart team decision-making in multivessel coronary artery disease.

Abstract: Aims Coronary computed tomography angiography (CTA) has emerged as a non-invasive diagnostic method for patients with suspected coronary artery disease, but its usefulness in patients with complex coronary artery disease remains to be investigated. The present study sought to determine the agreement between separate heart teams on treatment decision-making based on either coronary CTA or conventional angiography. Methods and results Separate heart teams composed of an interventional cardiologist, a cardiac surgeon, and a radiologist were randomized to assess the coronary artery disease with either coronary CTA or conventional angiography in patients with de novo left main or three-vessel coronary artery disease. Each heart team, blinded for the other imaging modality, quantified the anatomical complexity using the SYNTAX score and integrated clinical information using the SYNTAX Score II to provide a treatment recommendations based on mortality prediction at 4 years: coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or equipoise between CABG and PCI. The primary endpoint was the agreement between heart teams on the revascularization strategy. The secondary endpoint was the impact of fractional flow reserve derived from coronary CTA (FFRCT) on treatment decision and procedural planning. Overall, 223 patients were included. A treatment recommendation of CABG was made in 28% of the cases with coronary CTA and in 26% with conventional angiography. The agreement concerning treatment decision between coronary CTA and conventional angiography was high (Cohen's kappa 0.82, 95% confidence interval 0.74-0.91). The heart teams agreed on the coronary segments to be revascularized in 80% of the cases. FFRCT was available for 869/1108 lesions (196/223 patients). Fractional flow reserve derived from coronary CTA changed the treatment decision in 7% of the patients. Conclusion In patients with left main or three-vessel coronary artery disease, a heart team treatment decision-making based on coronary CTA showed high agreement with the decision derived from conventional coronary angiography suggesting the potential feasibility of a treatment decision-making and planning based solely on this non-invasive imaging modality and clinical information. Trial registration number NCT02813473.

Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration

Abstract: Division of Translational Research and Clinical Epidemiology, Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, MI, USA; Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; Department of Cardiology, Charite Universit€ats Medizin Berlin, Campus Benjamin Franklin, Berlin, Germany; Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland; Department of Pharmacological and Biomolecular Sciences, MultiMedica Istituto di Ricovero e Cura a Carattere Scientifico, University of Milan, Via Balzaretti, 9, 20133 Milan, Italy; and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College, London, UK

Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk

Abstract: Using an untargeted metabolomics approach in initial (N = 99 subjects) and replication cohorts (N = 1,162), we discovered and structurally identified a plasma metabolite associated with cardiovascular disease (CVD) risks, N6,N6,N6-trimethyl-L-lysine (trimethyllysine, TML). Stable-isotope-dilution tandem mass spectrometry analyses of an independent validation cohort (N = 2,140) confirmed TML levels are independently associated with incident (3-year) major adverse cardiovascular event risks (hazards ratio [HR], 2.4; 95% CI, 1.7-3.4) and incident (5-year) mortality risk (HR, 2.9; 95% CI, 2.0-4.2). Genome-wide association studies identified several suggestive loci for TML levels, but none reached genome-wide significance; and d9(trimethyl)-TML isotope tracer studies confirmed TML can serve as a nutrient precursor for gut microbiota-dependent generation of trimethylamine (TMA) and the atherogenic metabolite trimethylamine N-oxide (TMAO). Although TML was shown to be abundant in both plant- and animal-derived foods, mouse and human fecal cultures (omnivores and vegans) showed slow conversion of TML to TMA. Furthermore, unlike chronic dietary choline, TML supplementation in mice failed to elevate plasma TMAO or heighten thrombosis potential in vivo. Thus, TML is identified as a strong predictor of incident CVD risks in subjects and to serve as a dietary precursor for gut microbiota-dependent generation of TMAO; however, TML does not appear to be a major microbial source for TMAO generation in vivo.

Retinal microvascular dysfunction in heart failure.

Abstract: Aims Retinal vessel analysis (RVA) represents a novel, non-invasive, and reliable method to study the microcirculation in the eye. The goal of this study was to assess the extent of retinal microvascular dysfunction in patients with chronic heart failure (CHF) compared to controls and established measures of vascular function. Methods and results In this prospective, single-centre, observational study, 74 patients with compensated CHF (mean age 63.5 ± 11.2 years, 32% female, mean left-ventricular ejection fraction 37 ± 12.8%), 74 patients with cardiovascular risk factors (CVRF; 64.1 ± 12.7 years, 34% female), and 74 healthy controls (HC; 57.8 ± 14.2 years, 35% female) were included. The primary endpoint, flicker-induced dilatation of retinal arterioles (FIDart), was significantly reduced in patients with CHF compared to CVRF and HC (mean FIDart 0.9 ± 0.2 vs. 2.3 ± 0.3 and vs. 3.6 ± 0.3%, respectively, both P < 0.001 before and after propensity score-weighted analysis). Similar differences were seen for venular FID. FIDart was less impaired in patients with dilated compared to ischaemic cardiomyopathy. No significant differences were observed for arteriovenous ratio and flow-mediated dilatation. Impaired FIDven was associated with echocardiographically estimated systolic pulmonary artery pressure and left atrial volume index. Conclusion Retinal microvascular dilatation in response to flicker light is impaired in CHF. RVA may represent a new and useful method to non-invasively monitor microvascular abnormalities in heart failure in an easy and standardized way without the use of radiation.

Improved risk stratification of patients with acute coronary syndromes using a combination of hsTnT, NT-proBNP and hsCRP with the GRACE score.

Abstract: Background:Clinical scores and biomarkers improve risk stratification of patients with acute coronary syndromes. However, little is known about their value in patients referred for coronary angiogr...

Long-term durability and haemodynamic performance of a self-expanding transcatheter heart valve beyond five years after implantation: a prospective observational study applying the standardised definitions of structural deterioration and valve failure.

Abstract: Aims Long-term results of transcatheter aortic valve implantation (TAVI), in particular the incidence of bioprosthetic valve failure (BVF), are uncertain. This study presents data derived from a long-term, structured follow-up programme of the self-expanding CoreValve device utilising standardised definitions and core lab adjudication of valve performance. Methods and results The study prospectively included all 152 patients who had undergone TAVI with the self-expanding CoreValve up to December 2011 at the Heart Center, Bad Segeberg, Germany. Late BVF (>30 days) was defined as either: 1) severe structural valve deterioration (transprosthetic mean pressure gradient ≥40 mmHg and/or ≥20 mmHg rise from baseline OR severe intraprosthetic aortic regurgitation), OR 2) bioprosthetic valve dysfunction leading to death or reintervention. Echocardiographic follow-up at 6.3±1.0 years (range: 5.0-8.9 years) was 88% complete (60 out of 68 survivors beyond five years) and all echocardiograms were analysed by an independent core laboratory. The all-cause mortality rate at 1, 2, 5, 6, 7 and 8 years was 14%, 20%, 50%, 60%, 65%, and 73%, respectively. Among survivors beyond five years, effective orifice area was 1.60±0.46 cm2, and transvalvular mean pressure gradient was 6.7±3.1 mmHg; no cases showed evidence of structural valve deterioration. Five patients (3.3%) had undergone redo TAVI (n=4) or surgery (n=1) 0.6 to 5.2 years after the index procedure, all due to paravalvular leakage. The estimated rate of BVF at eight years was 7.9% for the actuarial and 4.5% for the actual analysis. Conclusions Long-term follow-up up to 8.9 years after TAVI documents favourable performance of the self-expanding CoreValve with low rates of BVF.

The circadian clock in cardiovascular regulation and disease: Lessons from the Nobel Prize in Physiology or Medicine 2017.

Abstract: Division of Heart and Lungs, Department of Cardiology and Regenerative Medicine Center, University Medical Center, Heideberglaan 100, 3584 CX Utrecht, the Netherlands; Department of Cardiology, Royal Brompton & Harefield Hospitals and Imperial College, Sidney Street, London, SW3 6NP, UK; and Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, 703 19th St. S., ZRB 308, Birmingham, Alabama, 35294 USA

Post-ischaemic administration of the murine Canakinumab-surrogate antibody improves outcome in experimental stroke.

Abstract: Aims The CANTOS trial underscored the efficacy of selective antibody-based interleukin (IL)-1β inhibition with Canakinumab in secondary prevention of cardiovascular events. Despite the success of the trial, incidence of stroke was not reduced likely due to the low number of events and the relatively young age of patients enrolled. Given the established role of IL-1β in stroke, we tested the efficacy of the murine Canakinumab-equivalent antibody in a mouse model of ischaemic stroke. To mimic the clinical scenario of modern stroke management, IL-1β inhibition was performed post-ischaemically upon reperfusion as it would be the case in patients presenting to the emergency room and eligible for thrombolytic therapy. Methods and results Transient middle cerebral artery occlusion (tMCAO) was performed in wild type mice; upon reperfusion, mice were randomly allocated to anti-IL-1β antibody or vehicle treatment. Following tMCAO, cerebral IL-1β levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1β antibody reduced infarct size, cerebral oedema and improved neurological performance as assessed by 2,3,5-triphenyltetrazolium chloride staining, Bederson and RotaRod tests. Antibody-treated animals also exhibited a reduced neutrophil and matrix metalloproteinase (MMP)-2 but not MMP-9, activity in ipsilateral hemispheres as compared to vehicle-treated mice. Noteworthy, tMCAO associated vascular endothelial-cadherin reduction was blunted in IL-1β antibody-treated mice compared to vehicle-treated, likely providing the mechanistic explanation for the improved outcome. Conclusion Our data for the first time demonstrate the efficacy of selective post-ischaemic IL-1β blockade in improving outcome following experimental ischaemia/reperfusion brain injury in the mouse and encourage further focused clinical studies assessing the potential of the approved IL-1β antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic stroke patients.

Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial

Abstract: AIM To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety. METHODS This randomised, double-blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100-200 mg b.d., ibuprofen 600-800 mg t.d.s. or naproxen 375-500 mg b.d. plus esomeprazole, and low-dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE-bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly. RESULTS Mean treatment and follow-up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27-0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32-0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27-0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25-0.62, P < 0.0001) vs naproxen. Even taken with low-dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 [0.29-0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23-0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence. CONCLUSIONS Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co-prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low-dose aspirin or corticosteroids.

Has the time finally come to measure hsCRP universally in primary and secondary cardiovascular prevention

Abstract: Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Deutsches Herzzentrum München, Technische Universität München, DZHK (German Centre for Cardiovascular Research), partner site, Munich Heart Alliance, Munich, Germany; Academic Medical Center of the University of Amsterdam, The Netherlands; Cardiology Department, Geneva University Hospital, Geneva, Switzerland; and Department of Cardiology, University Hospital Zurich, Zurich, Switzerland

Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity

Abstract: BACKGROUND: Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI). Methods and Results: Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3-/- mice (n = 6) was reduced by half compared to Sirt3+/+ wildtype (WT, n = 8, p<0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry (ROTEM) revealed accelerated clot formation and increased clot stability in Sirt3-/- compared to WT blood. ROTEM of cell-depleted plasma showed accelerated clotting initiation in Sirt3-/- mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap (NET) formation was increased in Sirt3-/- bone marrow (BM)-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3-/- mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in BM-derived Sirt3-/- neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, p<0.01). CONCLUSIONS: Sirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of NETs and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.

Approximation of the Incidence of Myocarditis by Systematic Screening With Cardiac Magnetic Resonance Imaging.

Abstract: Objectives This study sought to obtain an approximation of the true incidence of myocarditis by systematic screening of patients at risk using cardiac magnetic resonance imaging (CMR) in a tertiary care center. Background Underdiagnosis of myocarditis and resulting uncertainty about its incidence remain a clinical dilemma. The authors hypothesized that systematic screening of patients presenting with angina-like symptoms, elevated troponin T, and no significant coronary artery disease using cardiac CMR will provide an approximation of the true incidence of myocarditis. Methods The authors performed a retrospective chart review of patients presenting with angina-like symptoms and elevated high-sensitivity troponin T (TnT-hs ≥14 ng/l) in 2015 and 2016. During the year 2015, only patients with elevated TnT-hs, no significant coronary artery disease, and moderate-to-high clinical likelihood of myocarditis underwent CMR. Starting in 2016, CMR was obtained in patients with similar presentation, but independent of clinical likelihood of myocarditis. Results A total of 1,788 patients (74% male, age 69 ± 14 years) qualified for our analysis. In 2015, 521 patients presented with angina-like symptoms and TnT-hs elevation. In 2016, the number increased to 1,267 patients. Although in the year 2015, a total of 4 of 88 (5%) CMRs were positive for myocarditis, the percentage of positive CMRs doubled (26 of 199; 13%; p = 0.03) in 2016. Conclusions A novel diagnostic screening algorithm led to a 6.3-fold increase of the incidence of myocarditis in our hospital. Furthermore, the percentage of CMRs positive for myocarditis doubled, supporting the diagnostic value of this method. Considering the potentially lethal adverse events of myocarditis if left untreated, we recommend a low threshold for the use of CMR in patients with angina-like symptoms and elevated TnT-hs after exclusion of coronary artery disease.

Hybrid SPECT Perfusion Imaging and Coronary CT Angiography: Long-term Prognostic Value for Cardiovascular Outcomes.

Abstract: Purpose To determine the value of cardiac hybrid imaging, performed by combining SPECT myocardial perfusion imaging (MPI) with coronary CT angiography, as a long-term predictor for major adverse cardiac events (MACEs) (death, myocardial infarction [MI], unstable angina requiring hospitalization, coronary revascularization). Materials and Methods For this retrospective single-center study, 428 patients referred between May 2005 and December 2008 were classified according to hybrid imaging findings into the following groups: (a) those with stenosis of 50% or greater (at coronary CT angiography) with ischemia (at SPECT) in subtended territory (matched), (b) those with coronary CT angiography and/or SPECT findings in unrelated territories (unmatched), and (c) those with normal findings at coronary CT angiography and SPECT. End points were all-cause death or MI ("hard events") and a composite of MACEs. The Kaplan-Meier method was used to identify survival free of MACEs, and Cox proportional hazard regression analysis was used to determine independent predictors for MACE. Results During a median follow-up of 6.8 years, a total of 160 MACEs, including 45 deaths, were observed in the final study population (mean age, 62 years ± 11 [standard deviation]; 132 women). The annual hard event rate was more than fivefold higher for patients with matched findings (n = 46 [7.0%]) and was threefold higher for patients with unmatched findings (n = 113 [3.7%]) compared with that for patients with normal findings (1.2%; n = 216 [1.2%]; P < .001). The MACE rates were 21.8%, 9.0%, and 2.4% for matched, unmatched, and normal findings, respectively. A matched finding was an independent predictor for MACE and hard events. Conclusion In patients evaluated for coronary artery disease, cardiac hybrid imaging is an excellent long-term predictor of adverse cardiac events. A matched hybrid finding is associated with a high annual cardiac event rate. © RSNA, 2018.

Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthritis and Patients With Rheumatoid Arthritis: A Randomized Clinical Trial.

Abstract: Objective To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long-term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA). Methods A total of 24,081 patients with OA or RA who had a moderate or high risk for CV disease were enrolled internationally into a double-blind randomized controlled trial. Interventions included celecoxib at a dosage of 100-200 mg twice daily, ibuprofen at a dosage of 600-800 mg 3 times daily, or naproxen at a dosage of 375-500 mg twice daily. The main outcomes were the first occurrence of a major adverse CV event, GI event, or renal event, and mortality. Results In the subgroup of patients with OA, the risk of a major adverse CV event was significantly reduced when celecoxib was compared with ibuprofen (hazard ratio [HR] 0.84, 95% confidence interval [95% CI] 0.72-0.99), but no significant difference was observed when celecoxib was compared with naproxen. In the RA subgroup, comparisons of celecoxib versus ibuprofen and celecoxib versus naproxen for the risk of major adverse CV events revealed HRs of 1.06 (95% CI 0.69-1.63) and 1.22 (95% CI 0.78-1.92), respectively. In the OA subgroup, comparisons of celecoxib versus ibuprofen for the risk of GI events showed an HR of 0.68 (95% CI 0.51-0.91), and a comparison of celecoxib versus naproxen showed an HR of 0.73 (95% CI 0.55-0.98). Duplicate comparisons in patients with RA revealed HRs of 0.48 (95% CI 0.22-1.07) and 0.54 (95% CI 0.24-1.24), respectively. In patients with OA, a comparison of celecoxib versus ibuprofen for the risk of renal events showed an HR of 0.58 (95% CI 0.40-0.82). In patients with RA, celecoxib treatment was associated with significantly lower mortality compared with naproxen treatment (HR 0.47, 95% CI 0.25-0.88). Conclusion Treatment with celecoxib at approved dosages conferred a similar or lower risk of CV, GI, and renal adverse events compared with treatment with ibuprofen or naproxen in patients with OA and patients with RA.

Heart failure subgroups: HFrEF, HFmrEF, and HFpEF with or without mitral regurgitation.

Abstract: Heart failure has recently undergone major changes: while heart failure with reduced ejection fraction or HFrEF is declining due to effective revascularization of patients with acute coronary syndromes, the prevalence and incidence of heart failure with preserved ejection fraction or HFpEF, mainly characterized by diastolic dysfunction, is increasing due to ageing Western societies. In between there is a gap, and this has recently been filled in the most recent ESC Guidelines on Acute and Chronic Heart Failure with the introduction of a novel category, i.e. HFmrEF or heart failure with mid-range ejection fraction. The future will tell if this category can survive the test of time. Of note, the reproducibility and precision of echocardiography, the most frequently used imaging modality in these patients, is not good enough to categorize such patients reliably. Furthermore, a subanalysis of the TOPCAT trial suggests that HFmrEF and HFrEF might be comparable at least in their responsiveness to heart failure drugs such as spironolactone. In a Fast Track paper entitled ‘Betablockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials’, Dipak Kotecha and colleagues from the University of Birmingham College of Medical and Dental Sciences in Birmingham, UK address this issue with an additional heart failure drug in 11 double-blind, randomized, placebocontrolled trials employing an intention-to-treat analysis. In patients in sinus rhythm, beta-blockers reduced all-cause and cardiovascular mortality compared with placebo, an effect that was consistent across left ventricular ejection fraction strata, except for those in the small subgroup with left ventricular ejection fraction >_50% (Figure 1). Left ventricular ejection fraction increased with beta-blockers in all groups in sinus rhythm except in those with a value of >_ 50%. In patients with atrial fibrillation, beta-blockers increased left ventricular ejection fraction when <50% at baseline, but did not improve prognosis. Thus, beta-blockers improve left ventricular ejection fraction and prognosis for patients with heart failure in sinus rhythm with a reduced left ventricular ejection fraction. The data are most robust in HFrEF, but similar benefit was observed in HFmrHF. These relevant findings suggesting that HFrEF and HFmrEF are just the same disease with different severities, are put into context in an Editorial by Douglas Mann from the Washington University School of Medicine in Saint Louis, Missouri, USA. Significant efforts are currently being undertaken to better quantify and eventually reduce functional mitral regurgitation in patients with chronic heart failure in the hope of improving prognosis. In their manuscript entitled ‘Refining the prognostic impact of functional mitral regurgitation in chronic heart failure’, Georg Goliasch and colleagues from the Medical University of Vienna in Austria assessed the impact of functional mitral regurgitation in HFrEF under optimal medical therapy. They prospectively included 576 HFrEF patients in their observational study with a median follow-up of 62 months. Severe functional mitral regurgitation was a significant predictor of mortality with an adjusted hazard ratio of 1.38 independent of clinical and echocardiogrphic confounders. Severe functional mitral regurgitation was associated with poor outcome in an intermediate-failure phenotype of heart failure with reduced ejection fraction, i.e. those with NYHA class II, moderately reduced left ventricular function, and within the second quartile of NT-proBNP. Thus, in a patient cohort under optimal medical therapy, the adverse prognostic impact of functional mitral regurgitation is predominant in those with intermediate heart failure. Maladaptions of the peripheral circulation are importantly involved in the pathophysiology of ageing, hypertension, atherosclerosis, and heart failure. Retinal vessel analysis represents a non-invasive and reliable method to study the microcirculation and endothelial function in the eye. In a further article entitled ‘Retinal microvascular dysfunction in heart failure’, Andreas Flammer and colleagues from the University Hospital Zurich in Switzerland assessed the extent of retinal microvascular dysfunction in patients with chronic heart failure. In 74 patients with compensated chronic heart failure with HFrEF, flicker-induced dilatation of retinal arterioles was assessed. Flicker-induced dilatation was significantly reduced in patients with HFrEF compared with those with risk factors of healthy

Non-invasive screening for coronary artery disease in asymptomatic diabetic patients: a systematic review and meta-analysis of randomised controlled trials.

Abstract: It is unclear whether non-invasive screening of asymptomatic diabetic patients for coronary artery disease (CAD) may improve cardiac outcomes. Thus, we performed a systematic literature review and meta-analysis of randomised controlled trials (RCT's) on this topic. We searched appropriate RCT's in five online databases (PubMed/MEDLINE, Cochrane Library, Embase, Scopus, and Web of Science) from January 2000 to November 2017 and in 41 recent reviews. Two investigators independently extracted and assessed study data using standardised forms. Additional unpublished data were obtained from trial authors. The primary endpoint 'any cardiac event' was a composite of cardiac death, non-fatal myocardial infarction (MI), unstable angina (UA), or heart failure (HF) hospitalisation. We performed a meta-analysis of relative risks (RRs) with 95% confidence intervals (CI) using the Mantel-Haenszel method. We included five RCT's with 3299 patients, of which 189 (5.7%) experienced any cardiac event on follow-up (weighted mean 4.1 years). Non-invasive CAD screening significantly reduced any cardiac event by 27% [RR 0.73 (95% CI 0.55-0.97), P = 0.028, number needed to screen 56]. This result was driven by important, albeit non-significant decreases in non-fatal MI [RR 0.65 (95% CI 0.41-1.02), P = 0.062] and HF hospitalisation [RR 0.61 (95% CI 0.33-1.10), P = 0.100]. Non-invasive CAD screening did not significantly affect cardiac death [RR 0.92 (95% CI 0.53-1.60), P = 0.77] and UA [RR 0.73 (95% CI 0.41-1.31), P = 0.29]. Compared with the standard care, non-invasive CAD screening reduced cardiac events by 27% in asymptomatic diabetic patients, largely through reductions in non-fatal MIs, and HF hospitalisations. The present results justify larger, appropriately powered trials to potentially revisit current recommendations.

Interaction of systolic blood pressure and resting heart rate with clinical outcomes in takotsubo syndrome: insights from the International Takotsubo Registry

Abstract: AIMS: The present study aimed to determine the prognostic impact of resting heart rate (HR) and systolic blood pressure (SBP) in takotsubo syndrome (TTS). METHODS AND RESULTS: Patients from the International Takotsubo Registry with complete data on HR and SBP were enrolled. We analysed all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE) in tertiles of HR ( 94 b.p.m.) and SBP ( 140 mmHg). In addition, linear splines with interactions between HR and SBP were analysed. The risk of all-cause mortality was higher in the second HR tertile (1.89, 1.15-3.10; P = 0.012) and the third HR tertile (3.01, 1.90-4.79; P 70 b.p.m., every 1 b.p.m. increase in HR was associated with a 1.7% increase (P < 0.001), and every 1 mmHg increase in SBP up to 130 mmHg was associated with a 2% risk reduction (P < 0.001). The risk of all-cause mortality thus was particularly elevated when low SBP occurred together with high HR. CONCLUSIONS: High HR and low SBP are associated with an increased risk of all-cause mortality in TTS. HR reduction might be worthy of being investigated as a therapeutic strategy for this condition and high HR and low SBP can be used to evaluate risk in this acute presentation of TTS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01947621.

Prognosis of cardiovascular and non-cardiovascular multimorbidity after acute coronary syndrome.

Abstract: OBJECTIVE To examine the prognosis of patients with cardiovascular and non-cardiovascular multimorbidity after acute coronary syndrome compared to patients without prior multimorbidity. METHODS This multicenter prospective cohort study in Switzerland included 5,635 patients hospitalized with acute coronary syndrome between 2009 and 2014, with a one-year follow-up period. We defined cardiovascular and non-cardiovascular multimorbidity as having at least two prior comorbidities before the index hospitalization. Multivariable adjusted Cox proportional models were built to assess the one-year risk of recurrent cardiovascular events, defined as cardiovascular mortality and non-fatal myocardial infarction or stroke. The final model was adjusted for age, gender, body mass index, tobacco consumption, education, and family history of cardiovascular disease, prescription of high-dose statinsat discharge and use of cardiac rehabilitation after discharge. RESULTS Overall, 3,664 patients (65%) had no multimorbidity, 1,839 (33%) had cardiovascular multimorbidity, 62 (1%) had non-cardiovascular multimorbidity, and 70 (1%) had both cardiovascular and non-cardiovascular multimorbidity. The multivariate risk of recurrent cardiovascular events was increased among patients with cardiovascular multimorbidity (hazard ratio (HR) 2.05, 95% CI: 1.54-2.73, p<0.001) and patients with non-cardiovascular multimorbidity (HR 2.57, 95% CI: 1.04-6.35, p = 0.04) compared to patients without multimorbidity. Patients with cardiovascular and non-cardiovascular multimorbidity had the highest risk of recurrence with a HR of 5.19, 95% CI: 2.79-9.64, p<0.001, compared to patients without multimorbidity. CONCLUSIONS Multimorbidity increased by two-fold the risk of cardiovascular events over the year after an acute coronary syndrome. The magnitude of this increased risk was similar for patients with cardiovascular or non-cardiovascular multimorbidity.