Natural history of cardiac involvement in myotonic dystrophy type 1 - Emphasis on the need for lifelong follow-up.

BACKGROUND: Cardiac involvement represents a major cause of morbidity and mortality in patients with myotonic dystrophy type 1 (DM1) and prevention of sudden cardiac death (SCD) is a central part of patient care. We investigated the natural history of cardiac involvement in patients with DM1 to provide an evidence-based foundation for adjustment of follow-up protocols. METHODS: Patients with genetically confirmed DM1 were identified. Data on patient characteristics, performed investigations (12 lead ECG, Holter monitoring and echocardiography), and clinical outcomes were retrospectively collected from electronic health records. RESULTS: We included 195 patients (52% men) with a mean age at baseline evaluation of 41 years (range 14-79). The overall prevalence of cardiac involvement increased from 42% to 66% after a median follow-up of 10.5 years. There was a male predominance for cardiac involvement at end of follow-up (74 vs. 44%, p < 0.001). The most common types of cardiac involvement were conduction abnormalities (48%), arrhythmias (35%), and left ventricular systolic dysfunction (21%). Only 17% of patients reported cardiac symptoms. The standard 12­lead ECG was the most sensitive diagnostic modality and documented cardiac involvement in 24% at baseline and in 49% at latest follow-up. However, addition of Holter monitoring and echocardiography significantly increased the diagnostic yield with 18 and 13% points at baseline and latest follow-up, respectively. Despite surveillance 35 patients (18%) died during follow-up; seven due to SCD. CONCLUSIONS: In patients with DM1 cardiac involvement was highly prevalent and developed during follow-up. These findings justify lifelong follow-up with ECG, Holter, and echocardiography. CLINICAL PERSPECTIVE: What is new? What are the clinical implications?

OCT or Angiography Guidance for PCI in Complex Bifurcation Lesions.

BACKGROUND: Imaging-guided percutaneous coronary intervention (PCI) is associated with better clinical outcomes than angiography-guided PCI. Whether routine optical coherence tomography (OCT) guidance in PCI of lesions involving coronary-artery branch points (bifurcations) improves clinical outcomes as compared with angiographic guidance is uncertain. METHODS: We conducted a multicenter, randomized, open-label trial at 38 centers in Europe. Patients with a clinical indication for PCI and a complex bifurcation lesion identified by means of coronary angiography were randomly assigned in a 1:1 ratio to OCT-guided PCI or angiography-guided PCI. The primary end point was a composite of major adverse cardiac events (MACE), defined as death from a cardiac cause, target-lesion myocardial infarction, or ischemia-driven target-lesion revascularization at a median follow-up of 2 years. RESULTS: We assigned 1201 patients to OCT-guided PCI (600 patients) or angiography-guided PCI (601 patients). A total of 111 patients (18.5%) in the OCT-guided PCI group and 116 (19.3%) in the angiography-guided PCI group had a bifurcation lesion involving the left main coronary artery. At 2 years, a primary end-point event had occurred in 59 patients (10.1%) in the OCT-guided PCI group and in 83 patients (14.1%) in the angiography-guided PCI group (hazard ratio, 0.70; 95% confidence interval, 0.50 to 0.98; P = 0.035). Procedure-related complications occurred in 41 patients (6.8%) in the OCT-guided PCI group and 34 patients (5.7%) in the angiography-guided PCI group. CONCLUSIONS: Among patients with complex coronary-artery bifurcation lesions, OCT-guided PCI was associated with a lower incidence of MACE at 2 years than angiography-guided PCI. (Funded by Abbott Vascular and others; OCTOBER ClinicalTrials.gov number, NCT03171311.).

Tuning magnetoelectricity in a mixed-anisotropy antiferromagnet.

Control of magnetization and electric polarization is attractive in relation to tailoring materials for data storage and devices such as sensors or antennae. In magnetoelectric materials, these degrees of freedom are closely coupled, allowing polarization to be controlled by a magnetic field, and magnetization by an electric field, but the magnitude of the effect remains a challenge in the case of single-phase magnetoelectrics for applications. We demonstrate that the magnetoelectric properties of the mixed-anisotropy antiferromagnet LiNi1-xFexPO4 are profoundly affected by partial substitution of Ni2+ ions with Fe2+ on the transition metal site. This introduces random site-dependent single-ion anisotropy energies and causes a lowering of the magnetic symmetry of the system. In turn, magnetoelectric couplings that are symmetry-forbidden in the parent compounds, LiNiPO4 and LiFePO4, are unlocked and the dominant coupling is enhanced by almost two orders of magnitude. Our results demonstrate the potential of mixed-anisotropy magnets for tuning magnetoelectric properties.

Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

The Barriers to Rapid Reperfusion in Acute ST-Elevation Myocardial Infarction.

INTRODUCTION: This study aimed to quantify the contribution of various obstacles to timely reperfusion therapy in acute ST-elevation myocardial infarction (STEMI) and to improve performance in a mixed remote rural/urban region. METHODS: From November 1, 2020 to April 23, 2021, patients with acute STEMI were prospectively monitored with the critical time intervals, treatment modalities, and outcomes registered. Selected clinical decision-makers in 11 hospitals were appointed as improvement agents and systematically provided with weekly updated information about absolute and relative performance. Suggestions for improvements were invited and shared. RESULTS: Only 29% of the 146 patients received reperfusion therapy within recommended time limits [prehospital thrombolysis, 2/48; in-hospital thrombolysis, 0/20; primary percutaneous coronary intervention (pPCI), 37/68, with median intervals from the first medical contact of 44, 49, and 133 min, respectively]. Efficiency varied considerably between health trusts: median time from the first medical contact to prehospital thrombolysis ranged from 29 to 54 min (hazard ratio 4.89). The predominant, remediable causes for delays were erroneous tactical choices and protracted electrocardiographic diagnostication, decision-making, and administration of fibrinolytic medication. During the trial, the time to pPCI was non-significantly reduced. CONCLUSION: We found several targets for system improvements in order to mitigate reperfusion delays along the entire chain of care, regardless of reperfusion modality chosen. More patients should receive prehospital thrombolysis. The most important measures will be training to ensure a more efficient on-site workflow, improved protocols and infrastructure facilitating the communication between first responders and in-hospital clinicians, and education emphasizing prehospital transport times. CLINICAL TRIALS IDENTIFIER: NCT04614805.

Outcomes after coronary angiography for unstable angina compared to stable angina, myocardial infarction and an asymptomatic general population.

Background: The outcomes of real-world unstable angina (UA) in the high-sensitivity troponin era are unclear. We aimed to investigate the outcomes of UA referred to coronary angiography compared to stable angina (SA), non-ST-segment elevation myocardial infarction (NSTEMI), STEMI and a general population. Methods: We included the 9,694 patients with no prior coronary artery disease (CAD) referred to invasive or CT coronary angiography from 2013 to 2018 in Northern Norway (51% SA, 12% UA, 23% NSTEMI and 14% STEMI), and 11,959 asymptomatic individuals recruited from the Tromsø Study. We used Cox models to estimate the hazard ratios (HR) for all-cause mortality and major adverse cardiovascular events (MACE), defined as cardiovascular death, MI or obstructive CAD. Results: The median follow-up time was 2.8 years. The incidence rate of death was 8.5 per 1000 person-years (95 % confidence interval [CI] 8.0-9.0) in the general population, 9.7 (95 % CI 8.3-11.5) in SA, 14.9 (95 % CI 11.4-19.6) in UA, 29.7 (95 % CI 25.6-34.3) in NSTEMI and 36.5 (95 % CI 30.9-43.2) in STEMI. In multivariable adjusted analyses, compared with UA, SA had a 38 % lower risk of death and a non-significant lower risk of MACE (HR 0.62, 95 % CI 0.44-0.89; HR 0.86, 95 % CI 0.66-1.11). NSTEMI had a 2.4-fold higher risk of death (HR 2.39, 95 % CI 1.38-4.14) and a 1.6-fold higher risk of MACE (HR 1.62, 95 % CI 1.11-2.38) compared tox UA during the first year after coronary angiography, but a similar risk thereafter. There was no difference in the risk of death for UA with non-obstructive CAD and obstructive CAD (HR 0.78, 95 % CI 0.39-1.57). Conclusion: UA had a higher risk of death but a similar risk of MACE compared to SA and a lower 1-year risk of death and MACE compared to NSTEMI.

Left atrial appendage occlusion in haemophilia patients with atrial fibrillation.

PURPOSE: Advanced targeted therapy has resulted in increasing life expectancy and incidence of age-related cardiovascular diseases like atrial fibrillation in patients with haemophilia. Oral anticoagulation constitutes a significant dilemma in this patient category as the risks of stroke and bleeding are difficult to balance. We sought to demonstrate the feasibility of left atrial appendage occlusion (LAAO) in patients with haemophilia and atrial fibrillation. METHODS: All patients with haemophilia treated with LAAO at Aarhus University Hospital, Denmark, were identified from a local prospective database comprising all consecutive LAAO procedures from 2010 up to November 2020. Based on review of the medical records, a retrospective descriptive analysis was performed. RESULTS: Seven patients with haemophilia A and atrial fibrillation underwent LAAO after multidisciplinary conference. Peri-procedural coagulation management was guided by factor VIII activity and treated with repeated bolus administrations of recombinant factor VIII targeting an activity of 100%. The implantation was successful in all patients with only minor bleeding complications post-procedurally. Based on these experiences, a suggested regime has been formulated. CONCLUSIONS: LAAO is feasible in haemophilia patients with concurrent atrial fibrillation. However, special care including intravenous substitution with coagulation factors must be given in the periprocedural management.

Percutaneous coronary intervention in calcified stenoses: a protocol for a systematic review with meta-analysis, trial sequential analysis and network meta-analysis.

INTRODUCTION: Severely calcified coronary stenoses are difficult to treat with percutaneous coronary interventions. The presence of severe calcifications complicates lesion preparation, advancement of stents and achievement of full stent expansion. Intervention in these lesions is associated with an increased risk of complications and procedural failure compared with treatment of less calcified lesions. Due to the high burden of comorbidity, patients with severely calcified lesions are often excluded from interventional trials, and there is little evidence on how to treat these patients. METHODS AND ANALYSIS: We will conduct a systematic review of randomised trials enrolling patients with calcified coronary artery disease undergoing percutaneous coronary intervention. We will investigate any percutaneous treatment option including any lesion preparation, stenting or postdilatation technique. We will search The Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, and Excerpta Medica database for studies from inception to 31 October 2022. The coprimary outcome is all-cause mortality and serious adverse events. If appropriate, we will conduct meta-analysis, trial sequential analysis and network meta-analysis. ETHICS AND DISSEMINATION: No ethics approval is required for this study. The results will be published in a peer-reviewed journal in this field. PROSPERO REGISTRATION NUMBER: CRD42021226034.

Low Pain Tolerance Is Associated With Coronary Angiography, Coronary Artery Disease, and Mortality: The Tromsø Study.

Background The initial presentation to coronary angiography and extent of coronary artery disease (CAD) vary greatly among patients, from ischemia with no obstructive CAD to myocardial infarction with 3-vessel disease. Pain tolerance has been suggested as a potential mechanism for the variation in presentation of CAD. We aimed to investigate the association between pain tolerance, coronary angiography, CAD, and death. Methods and Results We identified 9576 participants in the Tromsø Study (2007-2008) who completed the cold-pressor pain test, and had no prior history of CAD. The median follow-up time was 10.4 years. We applied Cox-regression models with age as time-scale to calculate hazard ratios (HR). More women than men aborted the cold pressor test (39% versus 23%). Participants with low pain tolerance had 19% increased risk of coronary angiography (HR, 1.19 [95% CI, 1.03-1.38]) and 22% increased risk of obstructive CAD (HR, 1.22 [95% CI, 1.01-1.47]) adjusted by age as time-scale and sex. Among women who underwent coronary angiography, low pain tolerance was associated with 54% increased risk of obstructive CAD (HR, 1.54 [95% CI, 1.09-2.18]) compared with high pain tolerance. There was no association between pain tolerance and nonobstructive CAD or clinical presentation to coronary angiography (ie, stable angina, unstable angina, and myocardial infarction). Participants with low pain tolerance had increased risk of mortality after adjustment for CAD and cardiovascular risk factors (HR, 1.40 [95% CI, 1.19-1.64]). Conclusions Low cold pressor pain tolerance is associated with a higher risk of coronary angiography and death.

Incidence and risk factors for major bleeding among patients undergoing percutaneous coronary intervention: Findings from the Norwegian Coronary Stent Trial (NORSTENT).

INTRODUCTION: Bleeding is a concern after percutaneous coronary intervention (PCI) and subsequent dual antiplatelet therapy (DAPT). We herein report the incidence and risk factors for major bleeding in the Norwegian Coronary Stent Trial (NORSTENT). MATERIALS AND METHODS: NORSTENT was a randomized, double blind, pragmatic trial among patients with acute coronary syndrome or stable coronary disease undergoing PCI during 2008-11. The patients (N = 9,013) were randomized to receive either a drug-eluting stent or a bare-metal stent, and were treated with at least nine months of DAPT. The patients were followed for a median of five years, with Bleeding Academic Research Consortium (BARC) 3-5 major bleeding as one of the safety endpoints. We estimated cumulative incidence of major bleeding by a competing risks model and risk factors through cause-specific Cox models. RESULTS: The 12-month cumulative incidence of major bleeding was 2.3%. Independent risk factors for major bleeding were chronic kidney disease, low bodyweight (< 60 kilograms), diabetes mellitus, and advanced age (> 80 years). A myocardial infarction (MI) or PCI during follow-up increased the risk of major bleeding (HR = 1.67, 95% CI 1-29-2.15). CONCLUSIONS: The 12-month cumulative incidence of major bleeding in NORSTENT was higher than reported in previous, explanatory trials. This analysis strengthens the role of chronic kidney disease, advanced age, and low bodyweight as risk factors for major bleeding among patients receiving DAPT after PCI. The presence of diabetes mellitus or recurrent MI among patients is furthermore a signal of increased bleeding risk. CLINICAL TRIAL REGISTRATION: Unique identifier NCT00811772; http://www.clinicaltrial.gov.

Pre-test characteristics of unstable angina patients with obstructive coronary artery disease confirmed by coronary angiography.

Objective: Patients referred for acute coronary angiography (CAG) with unstable angina (UA) have low mortality and low rate of obstructive coronary artery disease (CAD). Better pre-test selection criteria are warranted. We aimed to assess the current guidelines against other clinical variables as predictors of obstructive CAD in patients with UA referred for acute CAG. Methods: From 2005 to 2012, all CAGs performed at the University Hospital of North Norway, the sole provider of CAG in the region, were recorded in a registry. We included 979 admissions of UA and retrospectively collected data regarding presenting clinical parameters from patient hospital records. Obstructive CAD was defined as ≥50% stenosis and considered prognostically significant if found in the left main stem, proximal LAD or all three main coronary arteries. Characteristics were analysed by logistic regression analysis. A score was developed using ORs from significant factors in a multivariable model. Results: The overall rate of obstructive CAD was 45%, and the rate of prognostically significant CAD was 11%. The risk criteria recommended in American College of Cardiology/American Heart Association and European Society of Cardiology guidelines had an area under the curve (AUC) of 0.58. Adding clinical information increased the AUC to 0.77 (95% CI 0.74 to 0.80). Applying the derived score, we found that 56% (n=546) of patients had a score of <13, which was associated with a negative predictive value of 95% for prognostic significant CAD. Conclusions: The current results suggest that CAG may be postponed or cancelled in more than half of patients with UA by improving pre-test selection criteria with the addition of clinical parameters to current guidelines.

Gas-phase diffusivity and tortuosity of structured soils.

Modeling gas-phase diffusion of volatile contaminants in the unsaturated zone relies on soil-gas diffusivity models often developed for repacked and structureless soil columns. These suffer from the flaw of not reflecting preferential diffusion through voids and fractures in the soil, thus possibly causing an underestimation of vapor migration towards building foundations and vapor intrusion to indoor environments. We measured the ratio of the gas diffusion coefficient in soil and in free air (D(p)/D(0)) for 42 variously structured, intact, and unsaturated soil cores taken from 6 Danish sites. Whilst the results from structureless fine sand were adequately described using previously proposed models, results that were obtained from glacial clay till and limestone exhibited a dual-porosity behavior. Instead, these data were successfully described using a dual-porosity model for gas-phase diffusivity, considering a presence of drained fractures surrounded by a lower diffusivity matrix. Based on individual model fits, the tortuosity of fractures in till and limestone was found to be highest in samples with a total porosity <40%, suggesting soil compaction to affect the geometry of the fractures. In summary, this study highlights a potential order of magnitude underestimation associated in the use of classical models for prediction of subsurface gas-phase diffusion coefficients in heterogeneous and fractured soils.

Variability of soil potential for biodegradation of petroleum hydrocarbons in a heterogeneous subsurface.

Quantifying the spatial variability of factors affecting natural attenuation of hydrocarbons in the unsaturated zone is important to (i) performing a reliable risk assessment and (ii) evaluating the possibility for bioremediation of petroleum-polluted sites. Most studies to date have focused on the shallow unsaturated zone. Based on a data set comprising analysis of about 100 soil samples taken in a 16 m-deep unsaturated zone polluted with volatile petroleum compounds, we statistically and geostatistically analysed values of essential soil properties. The subsurface of the site was highly layered, resulting in an accumulation of pollution within coarse sandy lenses. Air-filled porosity, readily available phosphorous, and the first-order rate constant (k(1)) of benzene obtained from slurry biodegradation experiments were found to depend on geologic sample characterization (P<0.05), while inorganic nitrogen was homogenously distributed across the soil stratigraphy. Semivariogram analysis showed a spatial continuity of 4-8.6 m in the vertical direction, while it was 2-5 times greater in the horizontal direction. Values of k(1) displayed strong spatial autocorrelation. Even so, the soil potential for biodegradation was highly variable, which from autoregressive state-space modeling was partly explained by changes in soil air-filled porosity and gravimetric water content. The results suggest considering biological heterogeneity when evaluating the fate of contaminants in the subsurface.

Soil Physical Constraints on Intrinsic Biodegradation of Petroleum Vapors in a Layered Subsurface.

Naturally occurring biodegradation of petroleum hydrocarbons in the vadose zone depends on the physical soil environment influencing field-scale gas exchange and pore-scale microbial metabolism. In this study, we evaluated the effect of soil physical heterogeneity on biodegradation of petroleum vapors in a 16-m-deep, layered vadose zone. Soil slurry experiments (soil/water ratio 10:30 w/w, 25°C) on benzene biodegradation under aerobic and well-mixed conditions indicated that the biodegradation potential in different textured soil samples was related to soil type rather than depth, in the order: sandy loam > fine sand > limestone. Similarly, O(2) consumption rates during in situ respiration tests performed at the site were higher in the sandy loam than in the fine sand, although the difference was less significant than in the slurries. Laboratory and field data generally agreed well and suggested a significant potential for aerobic biodegradation, even with nutrient-poor and deep subsurface conditions. In slurries of the sandy loam, the biodegradation potential declined with increasing in situ water saturation (i.e., decreasing air-filled porosity in the field). This showed a relation between antecedent undisturbed field conditions and the slurry biodegradation potential, and suggested airfilled porosity to be a key factor for the intrinsic biodegradation potential in the field.