Left atrial appendage strain predicts subclinical atrial fibrillation in embolic strokes of undetermined source.

Aims: Left atrial (LA) strain is promising in prediction of clinical atrial fibrillation (AF) in stroke patients. However, prediction of subclinical AF is critical in patients with embolic strokes of undetermined source (ESUS). The aim of this prospective study was to investigate novel LA and left atrial appendage (LAA) strain markers in prediction of subclinical AF in ESUS patients. Methods and results: A total of 185 patients with ESUS, mean age 68 ± 13years, 33% female, without diagnosed AF, were included. LAA and LA function by conventional echocardiographic parameters and reservoir strain (Sr), conduit strain (Scd), contraction strain (Sct), and mechanical dispersion (MD) of Sr were assessed with transoesophageal and transthoracic echocardiography. Subclinical AF was detected by insertable cardiac monitors during follow-up. LAA strain was impaired in 60 (32%) patients with subclinical AF compared to those with sinus rhythm: LAA-Sr, 19.2 ± 4.5% vs. 25.6 ± 6.5% (P < 0.001); LAA-Scd, -11.0 ± 3.1% vs. -14.4 ± 4.5% (P < 0.001); and LAA-Sct, -7.9 ± 4.0% vs. -11.2 ± 4% (P < 0.001), respectively, while LAA-MD was increased, 34 ± 24 ms vs. 26 ± 20 ms (P = 0.02). However, there was no significant difference in phasic LA strain or LA-MD. By ROC analyses, LAA-Sr was highly significant in prediction of subclinical AF and showed the best AUC of 0.80 (95% CI 0.73-0.87) with a sensitivity of 80% and a specificity of 73% (P < 0.001). LAA-Sr and LAA-MD were both independent and incremental markers of subclinical AF in ESUS patients. Conclusion: LAA function by strain and mechanical dispersion predicted subclinical AF in ESUS patients. These novel echocardiographic markers may improve risk stratification in ESUS patients.

QRS fragmentation is associated with increased risk of ventricular arrhythmias in high-risk patients; Data from the SMASH 1 Study.

INTRODUCTION: QRS fragmentation (fQRS), defined as the presence of additional spikes within the QRS complex, has been associated with myocardial conduction abnormalities and arrhythmogenicity. OBJECTIVE: We aimed to assess whether fQRS is associated with incident ventricular arrhythmias (VA) in high-risk patients treated with implantable cardioverter-defibrillator (ICD) for primary and secondary prevention. METHODS: In a prospective observational multicenter study, we included 495 patients treated with ICD. fQRS was analyzed according to previously validated criteria, by two physicians blinded for outcome data. Incident VA were obtained from ICD recordings. RESULTS: ECG recordings interpretable for fQRS were available in 459 patients (93%), aged 66 ± 12 years with left ventricular ejection fraction 40% ± 13%. fQRS was present in 52 patients (11%) with comparable baseline characteristics to patients without fQRS, except higher age, higher prevalence of coronary artery disease (CAD), lower prevalence of cardiomyopathy, and more frequently a secondary prevention ICD indication. Among patients with native QRS, those with fQRS had similar QRS duration and axis to those without fQRS. During 3.1 ± 0.7 years follow-up, 126 patients (28%) had ≥1 VA . fQRS was associated with increased risk of VA (HR 3.41 [95% CI 2.27-5.13], p < .001), which persisted after adjusting for age, gender, sex, BMI, CAD, heart failure, renal function, ICD indication, QRS duration, QRS axis, Q waves, and bundle branch block. fQRS was more strongly associated with VA in patients with a primary (HR 6.05 [95% CI 3.16-11.60]) versus secondary (HR 2.39 [95% CI 1.41-4.04]) ICD indication (p-for-interaction = .047). CONCLUSIONS: fQRS is associated with threefold increased risk of VA in high-risk patients, independent of established risk factors.

Prediction of occult atrial fibrillation in patients after cryptogenic stroke and transient ischaemic attack: PROACTIA.

AIMS: Studies with implantable cardiac monitors (ICMs) show that one-third of patients with cryptogenic stroke/transient ischaemic attack (TIA) have episodes of subclinical atrial fibrillation (SCAF) and benefit switching from antiplatelet- to anticoagulant therapy. However, ICMs are costly and resource demanding. We aimed to build a score based on participant's baseline characteristics that could assess individual risk of SCAF. METHODS AND RESULTS: In a prospective study, 236 eligible patients with a final diagnosis of cryptogenic stroke/TIA had an ICM implantated during the index hospitalization. Pre-specified evaluated variables were: CHA2DS2-VASc, P-wave duration, P-wave morphology, premature atrial beats (PAC)/24 h, supraventricular tachycardia/24 h, left atrial end-systolic volume index (LAVI), Troponin-T, NT-proBNP, and D-dimer. SCAF was detected in 84 patients (36%). All pre-specified variables were significantly associated with SCAF detection in univariate analysis. P-wave duration, followed by PAC/24 h, NT-proBNP, and LAVI, had the largest ratio of SCAF prevalence between its upper and lower quartiles (3.3, vs. 3.2, vs. 3.1 vs. 2.8, respectively). However, in a multivariate analysis, only PAC/24t, P-wave duration, P-wave morphology, and LAVIs remained significant predictors and were included in the PROACTIA score. Subclinical atrial fibrillation prevalence was 75% in the highest vs. 10% in the lowest quartile of the PROACTIA score with a 10-fold higher number of patients with an atrial fibrillation burden >6 h in the highest vs. the lowest quartile. CONCLUSION: The PROACTIA score can identify patients with cryptogenic stroke/TIA at risk of subsequent SCAF detection. The large difference in SCAF prevalence between groups may provide a basis for future tailored therapy. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: ClinicalTrials.gov; NCT02725944.

Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza.

AIM: Explore the role of viral factors and immune response in patients with severe pandemic pdmH1N1 illness without significant co-morbidity. MATERIALS: Seven patients with pdmH1N1 influenza, bilateral chest X-rays infiltrates, requiring mechanical ventilator support were consecutively recruited. Seven age- and gender-matched healthy individuals served as controls. RESULTS: Four patients were viremic, two with the mutant D222G/N pdmH1N1.Microarray analyses of peripheral blood leukocytes suggested a marked granulocytes activation, but no up-regulation of inflammatory cytokine mRNA. Patients with severe pdmH1NI had a marked systemic complement activation, and in contrast to the lack of cytokine mRNA up-regulation in blood leukocytes, plasma levels of a broad range of inflammatory mediators, including IP-10, and mediators involved in pulmonary remodelling were markedly elevated. Patients with mutant virus had particularly high IP-10 levels, and the most pronounced complement activation. CONCLUSIONS: In severe pdmH1N1, viremia was common and the D222G/N mutant was found in half of the viremic patients. Host immune response was characterized by strong activation of the innate immune system, including complement and granulocytes activation, increased serum levels of inflammation and pulmonary remodelling markers, possibly contributing to the observed tissue damage. However, few patients were included and further studies are needed to characterize the immune response in severe pdmH1N1 infection.

Hospitalised patients with suspected 2009 H1N1 influenza A in a hospital in Norway, July - December 2009.

BACKGROUND: The main objective of this study was to describe the patients who were hospitalised at Oslo University Hospital Aker during the first wave of pandemic Influenza A (H1N1) in Norway. METHODS: Clinical data on all patients hospitalised with influenza-like illness from July to the end of November 2009 were collected prospectively. Patients with confirmed H1N1 Influenza A were compared to patients with negative H1N1 tests. RESULTS: 182 patients were hospitalised with suspected H1N1 Influenza A and 64 (35%) tested positive. Seventeen patients with positive tests (27%) were admitted to an intensive care unit and four patients died (6%). The H1N1 positive patients were younger, consisted of a higher proportion of non-ethnic Norwegians, had a higher heart rate on admission, and fewer had pre-existing hypertension, compared to the H1N1 negative patients. However, hypertension was the only medical condition that was significantly associated with a more serious outcome defined as ICU admission or death, with a univariate odds ratio of the composite endpoint in H1N1 positive and negative patients of 6.1 (95% CI 1.3-29.3) and 3.2 (95% CI 1.2-8.7), respectively. Chest radiography revealed pneumonia in 24/59 H1N1 positive patients. 63 of 64 H1N1 positive patients received oseltamivir. CONCLUSIONS: The extra burden of hospitalisations was relatively small and we managed to admit all the patients with suspected H1N1 influenza without opening new pandemic isolation wards. The morbidity and mortality were similar to reports from comparable countries. Established hypertension was associated with more severe morbidity and patients with hypertension should be considered candidates for vaccination programs in future pandemics.

Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein.

The interleukin-6 cytokines, acting via gp130 receptor pathways, play a pivotal role in the reduction of cardiac injury induced by mechanical stress or ischemia and in promoting subsequent adaptive remodeling of the heart. We have now identified the small proline-rich repeat proteins (SPRR) 1A and 2A as downstream targets of gp130 signaling that are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress. Upregulation of SPRR1A and 2A was markedly reduced in the gp130 cardiomyocyte-restricted knockout mice. In cardiomyocytes, MEK1/2 inhibitors prevented SPRR1A upregulation by gp130 cytokines. Furthermore, binding of NF-IL6 (C/EBPbeta) and c-Jun to the SPRR1A promoter was observed after CT-1 stimulation. Histological analysis revealed that SPRR1A induction after mechanical stress of pressure overload was restricted to myocytes surrounding piecemeal necrotic lesions. A similar expression pattern was found in postinfarcted rat hearts. Both in vitro and in vivo ectopic overexpression of SPRR1A protected cardiomyocytes against ischemic injury. Thus, this study identifies SPRR1A as a novel stress-inducible downstream mediator of gp130 cytokines in cardiomyocytes and documents its cardioprotective effect against ischemic stress.

Mechanisms of elevated plasma endothelin-1 in CHF: congestion increases pulmonary synthesis and secretion of endothelin-1.

OBJECTIVE: The pulmonary circulation may contribute to elevated plasma levels of endothelin-1 (ET-1) in congestive heart failure (CHF). The aims of the present study were to determine the mechanisms of increased secretion of ET-1 from the pulmonary circulation in CHF. METHODS: Juvenile pigs were subjected to sham operation (n=9) or rapid cardiac pacing-induced CHF (215-240 bpm, n=15). RESULTS: Three weeks of rapid pacing led to significant left ventricular dilatation, increased cardiac filling pressures, and reduced contractility (CHF pigs). Arterial plasma ET-1 levels in the CHF pigs were increased 4-fold compared to sham pigs (P<0.001). Single-bolus multiple indicator-dilution experiments revealed that pulmonary synthesis and release of ET-1 was increased in CHF, while pulmonary clearance of plasma ET-1 remained unaltered despite significant reduction of pulmonary fractional extraction of plasma ET-1. Pulmonary ECE-1 isozyme activity (pmol.min-1.mg protein-1) was selectively increased in lower lobe segments of CHF pigs (2.0+/-0.3) compared to lower lobe segments of controls (1.1+/-0.1, P<0.02), and to upper lobe segments of CHF pigs (1.1+/-0.1, P<0.005), and correlated significantly with the wet/dry weight ratios of the pulmonary tissue samples (R=0.75, P<0.001), i.e. a marker of pulmonary congestion. Furthermore, alveolar macrophages in congested lobe segments were identified as likely sites of increased synthesis and release of ET-1. CONCLUSIONS: In rapid pacing-induced CHF, a complex cardiopulmonary interaction revealed by pulmonary congestion causes increased pulmonary production and secretion of ET-1 due to enhanced pulmonary ECE-1 activities. Pulmonary secretion of ET-1 during evolving CHF is an important contributor to elevated plasma ET-1 levels in the systemic circulation.