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Background: In patients with HCM at high risk of SCD, an ICD should be considered as a standard of care. Current risk approximation algorithms recommended by ESC 2014 criteria indicate that SCD risk is not stable. The aim of the study was to investigate how the calculated SCD risk in HCM patients with an ICD implanted in the past changed over time. Methods: We analyzed 64 HCM patients with ICD for primary prevention, referred for ICD re-implantation, and 32 HCM patients referred for a first-time ICD placement during the same period. The 5-year-SCD risk was assessed for suitable patients using the recommended ESC calculator. Results: The first-time group had a higher 5-year-SCD risk than those referred for ICD re-implantation: 7.50 (IQR 5.98–10.46) vs. 4.88 (IQR 3.42–7.25), p < 0.05. Out of the patients with an initial calculated risk below 4%, the risk increased in 22% of cases, reaching the 4–6% range. In 78% of patients, the risk remained stable and low. In 31% of patients with an initial calculated SCD risk ≥ 6%, the risk decreased over time to below 6%, and in 14% of the cases, below 4%. Conclusions: SCD risk in HCM patients is usually stable or gets lower. Our data suggest it is important to re-evaluate the risk profile for patients with HCM when ICD re-implantation is considered.

Summary Background Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). Methods In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. Findings Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (p non-inferiority =0·0004; hazard ratio [HR] 0·81 [95% CI 0·62–1·06], p superiority =0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; p non-inferiority =0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59–1·13]; p=0·23). Interpretation Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. Funding Klinikum der Universitat Munchen, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

Object Global cerebral edema is an independent risk factor for early death and poor outcome after subarachnoid hemorrhage (SAH). In the present study, the time course of brain edema formation, neurological deficits, and neuronal cell loss were investigated in the rat filament SAH model. Methods Brain water content and neurological deficits were determined in rats randomized to sham (1-, 24-, or 48-hour survival), SAH by endovascular perforation (1-, 24-, or 48-hour survival), or no surgery (control). The neuronal cell count (CA1–3) was quantified in a separate set of SAH (6-, 24-, 48-, or 72-hour survival) and shamoperated animals. Results Brain water content increased significantly 24 (80.2 ± 0.4% [SAH] vs 79.2 ± 0.1% [sham]) and 48 hours (79.8 ± 0.2% [SAH] vs 79.3 ± 0.1% [sham]) after SAH. The neuroscore was significantly worse after SAH (33 ± 15 [24 hours after SAH] vs 0 ± 0 points [sham]) and correlated with the extent of brain edema formation (r = 0.96, p < 0.001). No hippocampal damage was present up to 72 hours after SAH. Conclusions Brain water content and neurological dysfunction reached a maximum at 24 hours after SAH. This time point, therefore, seems to be optimal to test the effects of therapeutic interventions on brain edema formation. Neuronal cell loss was not present in CA1–3 up to 72 hours of SAH. Therefore, morphological damage needs to be evaluated at later time points.

Lubor Goláň,1 Ozlem Goker-Alpan,2 Myrl Holida,3 Ikka Kantola,4 Mariusz Klopotowski,5 Johanna Kuusisto,6 Aleš Linhart,1 Jacek Musial,7 Kathleen Nicholls,8 Derlis Gonzalez-Rodriguez,9 Reena Sharma,10 Bojan Vujkovac,11 Peter Chang,12 Anna Wijatyk12 1First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic; 2Lysosomal Research and Treatment Unit, Fairfax, VA, USA; 3Stead Family Department of Pediatrics, Division of Medical Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; 4Division of Medicine, Turku University Hospital, Turku, Finland; 5Institute of Cardiology, Warsaw, Poland; 6Department of Medicine, Center for Medicine and Clinical Research, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; 7Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland; 8Department of Nephrology, Royal Melbourne Hospital and the University of Melbourne, VIC, Australia; 9Instituto Privado de Hematologia E Investigacion Clinica (IPHIC), Asuncion, Paraguay; 10Salford Royal NHS Foundation Trust, Salford, UK; 11General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia; 12Shire, Lexington, MA, USA Purpose: Efficacy and safety of agalsidase alfa at 0.2mg/kg weekly were compared with 0.2mg/kg every other week (EOW). Exploratory analyses were performed for 0.4mg/kg weekly.Patients and methods: This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height>50g/m2.7 for males and >47g/m2.7 for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti–agalsidase alfa antibodies.Results: Twenty patients were randomized to 0.2mg/kg EOW (mean age, 50.3years; 70% male), 19 to 0.2mg/kg weekly (51.8years; 53% male), and 5 to 0.4mg/kg weekly (49.4years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2g/m2.7 and 0.5g/m2.7, with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classi­fication. No significant differences were found between 0.2mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (-1.21mL/min/1.73 m2 vs -3.32mL/min/1.73m2) or plasma globotriaosylceramide (-1.05nmol/mL vs -2.13nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti–agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status.Conclusion: No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4mg/kg weekly showed similar results. Keywords: adverse events, exercise tolerance, left ventricular hypertrophy, lysosomal storage disorder, quality of life, renal functionA Letter to the Editor has been received and published for this article.

Hyponatremia is a common electrolyte disorder reported to be a predictor of poor prognosis among hospitalized patients, but individuals with high levels also tend to have less favorable outcomes. This study investigated whether sodium level on admission is predictive of in-hospital outcome in patients with ST-elevation myocardial infarction (STEMI) treated with primary angioplasty.Included were 1858 patients admitted with STEMI for primary angioplasty. Sodium level was measured on admission and analyzed as hypo- versus normonatremia and by grouping patients into sodium quintiles. The relationships between sodium level and in-hospital mortality as well as the composite of death or heart failure were assessed.Ninety-six patients had hyponatremia on admission. The hypo- and normonatremic groups were comparable with respect to baseline characteristics and in-hospital management. Hyponatremics had higher rates of in-hospital mortality (13.5% vs. 3.8%, p0.001) composite of death and heart failure (27.8% vs. 18.4%, p=0.022). After adjustment for covariates, hyponatremia independently correlated with in-hospital mortality (HR: 3.89, 95%CI: 1.59-9.56, p=0.003) and the combined endpoint (HR: 1.73, 95%CI: 1.01-2.99, p=0.047). Patients in the lowest and highest sodium quintiles were 3.27 (95%CI: 1.34-8.02, p=0.009) and 2.65 (95%CI: 1.07-6.60, p=0.036) times more likely to die during hospitalization than those in the 2nd quintile (best survival). In the adjusted model, only patients in the lowest quintile had significantly increased risk of in-hospital death (HR: 6.35, 95%CI: 1.83-21.72, p=0.004).Hyponatremia is a simple laboratory marker independently associated with increased risk of death in STEMI patients treated with primary angioplasty.

Hemoglobin (Hb) levels may interact with inflammatory activation, but it is unknown whether the interaction has any impact on clinical outcomes in acute coronary syndromes. The aim of this study was to assess the relationship between admission Hb levels, leukocytosis and clinical outcomes of ST-elevation myocardial infarction (STEMI) treated with primary angioplasty. Methods and Results The study group comprised 1,904 (1,380 men) patients with STEMI treated with primary percutaneous coronary intervention, enrolled in a prospective registry. The primary endpoint of in-hospital death occurred in 90 (4.7%) patients. According to univariate analysis, extreme values of Hb (for 1(st) and 5(th) vs mid quintiles respectively: hazard ratio (HR) =7.1, P0.001 and HR =3.2, P=0.024) and leukocytosis above median (HR =2.09, P=0.001) significantly correlated with in-hospital death. After dividing patients into high and low white blood cell (WBC) count groups, a U-shaped relationship of Hb levels and mortality was observed for patients with higher leukocytosis (1(st) and 5(th) vs mid quintiles respectively: HR =8.1, P=0.001 and HR =4.4, P=0.022), whereas in patients with lower WBC count higher mortality was related solely to the lowest Hb quintile (HR =6.9, P=0.010 vs mid quintile). Conclusion Higher mortality associated with higher Hb levels in STEMI patients treated with primary angioplasty is limited to patients with increased leukocytosis.

Vasogenic brain edema is one of the major determinants for mortality following subarachnoid hemorrhage (SAH). Although the formation of vasogenic brain edema occurs on the microvascular level by opening of endothelial tight junctions and disruption of the basal lamina, microvascular changes following experimental SAH are poorly characterized. The aim of the present study was therefore to investigate the time course of blood-brain barrier (BBB) dysfunction and basal lamina damage following SAH as a basis for the better understanding of the pathophysiology of SAH. SAH was induced in Sprague-Dawley rats by an endovascular filament. Animals were sacrificed 6, 24, 48, and 72 h thereafter (n=9 per group). Microvascular basal lamina damage was quantified by collagen type IV immunostaining. Western blotting was used to quantify collagen IV protein content and bovine serum albumin (BSA) extravasation as a measure for basal lamina damage and blood-brain barrier disruption, respectively. BSA Western blot revealed significant (p

Mechanisms of early cerebral edema following SAH are poorly understood. Previously, we demonstrated a peak of edema evolution at 24 hours after experimental SAH in rats. Furthermore, brain water content correlated with neurological deficits of animals. In focal cerebral ischemia, alteration of the microvascular basal lamina, a constituent of the blood-brain barrier, and its relevance for development of cerebral edema and hemorrhagic transformation has previously been demonstrated. The present study was designed to demonstrate microvascular basal lamina damage in the context of blood-brain barrier dysfunction as a potential target for therapeutical interventions to reduce vasogenic brain edema following SAH.