Implantable defibrillator therapy and mortality in patients with non-ischaemic dilated cardiomyopathy : An updated meta-analysis and effect on Dutch clinical practice by the Task Force of the Dutch Society of Cardiology.

BACKGROUND: Primary prophylactic implantable cardioverter-defibrillators (ICDs) in patients with non-ischaemic cardiomyopathy (NICMP) remains controversial. This study sought to assess the benefit of ICD therapy with or without cardiac resynchronisation therapy (CRT) in patients with NICMP. In addition, data were compared with real-world clinical data to perform a risk/benefit analysis. METHODS: Relevant randomised clinical trials (RCTs) published in meta-analyses since DANISH, and in PubMed, EMBASE and Cochrane databases from 2016 to 2020 were identified. The benefit of ICD therapy stratified by CRT use was assessed using random effects meta-analysis techniques. RESULTS: Six RCTs were included in the meta-analysis. Among patients without CRT, ICD use was associated with a 24% reduction in mortality (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.62-0.93; P = 0.008). In contrast, among patients with CRT, a CRT-defibrillator was not associated with reduced mortality (HR: 0.74, 95% CI 0.47-1.16; P = 0.19). For ICD therapy without CRT, absolute risk reduction at 3­years follow-up was 3.7% yielding a number needed to treat of 27. CONCLUSION: ICD use significantly improved survival among patients with NICMP who are not eligible for CRT. Considering CRT, the addition of defibrillator therapy was not significantly associated with mortality benefit compared with CRT pacemaker.

Downgrade of cardiac defibrillator devices to pacemakers in elderly heart failure patients: clinical considerations and the importance of shared decision-making.

Implantable cardioverter defibrillators are implanted on a large scale in patients with heart failure (HF) for the prevention of sudden cardiac death. There are different scenarios in which defibrillator therapy is no longer desired or indicated, and this is occurring increasingly in elderly patients. Usually device therapy is continued until the device has reached battery depletion. At that time, the decision needs to be made to either replace it or to downgrade to a pacing-only device. This decision is dependent on many factors, including the vitality of the patient and his/her preferences, but may also be influenced by changes in recommendations in guidelines. In the last few years, there has been an increased awareness that discussions around these decisions are important and useful. Advanced care planning and shared decision-making have become important and are increasingly recognised as such. In this short review we describe six elderly patients with HF, in whose cases we discussed these issues, and we aim to provide some scientific and ethical rationale for clinical decision-making in this context. Current guidelines advocate the discussion of end-of-life options at the time of device implantation, and physicians should realise that their choices influence patients' options in this critical phase of their illness.

Large variability in clinical judgement and definitions of left bundle branch block to identify candidates for cardiac resynchronisation therapy.

BACKGROUND: Left bundle branch block (LBBB) morphology is associated with improved outcome of cardiac resynchronisation therapy (CRT) and is an important criterion for patient selection. There are, however, multiple definitions for LBBB. Moreover, applying these definitions seems subjective. We investigated the inter- and intraobserver agreement in the determination of LBBB using available definitions, and clinicians' judgement of LBBB. METHODS: Observers were provided with 12­lead ECGs of 100 randomly selected CRT patients. Four observers judged the ECGs based on different LBBB-definitions (ESC, AHA/ACC/HRS, MADIT, and Strauss). Additionally, four implanting cardiologists scored the same 100 ECGs based on their clinical judgement. Observer agreement was summarized through the proportion of agreement (P) and kappa coefficient (k). RESULTS: Relative intra-observer agreement using different LBBB definitions, and within clinical judgement was moderate (range k 0.47-0.74 and k = 0.76 (0.14), respectively). The inter-observer agreement between observers using LBBB definitions as well as between clinical observers was minimal to weak (range k 0.19-0.44 and k = 0.35 (0.20), respectively). The probability of classifying an ECG as LBBB by available definitions varied considerably (range 0.20-0.76). The agreement between different definitions of LBBB ranged from good (P = 0.95 (0.07)) to weak (P = 0.40 (0.22)). Furthermore, correlation between the different LBBB definitions and clinical judgement was poor (range phi 0.30-0.55). CONCLUSION: Significant variation in the probability of classifying LBBB is present in using different definitions and clinical judgement. Considerable intra- and inter-observer variability adds to this variation. Interdefinition agreement varies significantly and correlation of clinical judgement with LBBB classification by definitions is modest at best.

Magnetic resonance imaging in patients with cardiac implantable electronic devices.

In recent years the prevalence of implantation of a cardiac implantable electronic device (CIED) has increased due to expanding implantation indications and prolonged life expectancy. Diagnostic strategies increasingly employ magnetic resonance imaging (MRI) to aid therapeutic strategies. In earlier guidelines, MRI was contra-indicated in patients with CIEDs, mainly due to previous reports of severe complications. With the development of MRI-conditional CIEDs and recent evidence concerning non-MRI-conditional CIEDs, MRIs in CIED patients can be safely performed in many hospitals.However, there are several questions that need to be addressed. Which patients can we scan? How can the scans be performed safely? And last but not least, can cardiac MRI provide diagnostic yield in patients with CIEDs?Current European guidelines are rather outdated and vague about patient selection and practical issues. There are national guidelines on this topic but several issues need extra attention and those are addressed in this point of view. It is important to create an environment with proper patient selection without unnecessary MRI scans in CIED patients, but also without unnecessary fear of complications, preventing access to MRI in patients who can benefit from this powerful diagnostic tool.

Rasagiline improves polysomnographic sleep parameters in patients with Parkinson's disease: a double-blind, baseline-controlled trial.

BACKGROUND AND PURPOSE: The aim was to study the effects of rasagiline on sleep quality in patients with Parkinson's disease (PD) with sleep disturbances. Sleep disorders are common in PD. Rasagiline is widely used in patients with PD, but double-blind polysomnographic trials on its effects on sleep disturbances are missing. METHODS: This was a single-center, double-blind, baseline-controlled investigator-initiated clinical trial of rasagiline (1 mg/day) over 8 weeks in patients with PD with sleep disturbances. Blinding was achieved by running a strategic matched placebo parallel group. Co-primary outcome measures were the changes between baseline and end of the treatment period in sleep maintenance/efficiency as assessed by polysomnography and the Parkinson's Disease Sleep Scale Version 2 (PDSS-2) score. RESULTS: A total of 20 of 30 patients were randomized to rasagiline (mean ± SD age, 69.9 ± 6.9 years; 10 male; Hoehn-Yahr stage, 1.9 ± 0.8). Compared with baseline, sleep maintenance was significantly increased at the end of the treatment period (relative change normalized to baseline, +16.3 ± 27.9%; P = 0.024, paired two-sided t-test) and a positive trend for sleep efficiency was detected (+12.1 ± 28.6%; P = 0.097). Treatment with rasagiline led to significantly decreased wake time after sleep onset, number of arousals, percentage of light sleep and improved daytime sleepiness as measured by the Epworth Sleepiness Scale. We did not observe changes in the co-primary endpoint PDSS-2 score, and no correlations of polysomnographic sleep parameters or PDSS-2 score with motor function (Unified Parkinson's Disease Rating Scale motor score). Rasagiline was well tolerated with no unexpected adverse events. CONCLUSIONS: In patients with PD with sleep disturbances, rasagiline showed beneficial effects on sleep quality as measured by polysomnography. These effects were probably not related to motor improvement or translated into improved overall sleep quality perception by patients.

A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI.

Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19-32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 × 0.44 mm2) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases.

[Cardiac resynchronization therapy: who is a candidate and who is not?] / Cardiale-resynchronisatietherapie.

- Cardiac resynchronisation therapy (CRT) is a treatment for patients with impaired cardiac pump function (left ventricular ejection fraction ≤ 35%) and a wide QRS complex who, despite maximum tolerated medical therapy, remain symptomatic.- In addition to reducing symptoms, CRT can reduce hospital admissions and improve survival.- Selection of patients for CRT remains difficult. Despite the fact that predicting and influencing success of CRT has improved, ~30% of patients do not respond to the therapy.- Optimizing therapy and follow-up of patients after implantation requires a multidisciplinary approach tailored to the individual patient.- Cardiac rehabilitation with life style advices and structured exercise training maximizes patient benefit from CRT.

Genomewide single nucleotide polymorphism discovery in Atlantic salmon (Salmo salar): validation in wild and farmed American and European populations.

A considerable number of single nucleotide polymorphisms (SNPs) are required to elucidate genotype-phenotype associations and determine the molecular basis of important traits. In this work, we carried out de novo SNP discovery accounting for both genome duplication and genetic variation from American and European salmon populations. A total of 9 736 473 nonredundant SNPs were identified across a set of 20 fish by whole-genome sequencing. After applying six bioinformatic filtering steps, 200 K SNPs were selected to develop an Affymetrix Axiom(®) myDesign Custom Array. This array was used to genotype 480 fish representing wild and farmed salmon from Europe, North America and Chile. A total of 159 099 (79.6%) SNPs were validated as high quality based on clustering properties. A total of 151 509 validated SNPs showed a unique position in the genome. When comparing these SNPs against 238 572 markers currently available in two other Atlantic salmon arrays, only 4.6% of the SNP overlapped with the panel developed in this study. This novel high-density SNP panel will be very useful for the dissection of economically and ecologically relevant traits, enhancing breeding programmes through genomic selection as well as supporting genetic studies in both wild and farmed populations of Atlantic salmon using high-resolution genomewide information.

Vascular hippocampal plasticity after aerobic exercise in older adults.

Aerobic exercise in young adults can induce vascular plasticity in the hippocampus, a critical region for recall and recognition memory. In a mechanistic proof-of-concept intervention over 3 months, we investigated whether healthy older adults (60-77 years) also show such plasticity. Regional cerebral blood flow (rCBF) and volume (rCBV) were measured with gadolinium-based perfusion imaging (3 Tesla magnetic resonance image (MRI)). Hippocampal volumes were assessed by high-resolution 7 Tesla MRI. Fitness improvement correlated with changes in hippocampal perfusion and hippocampal head volume. Perfusion tended to increase in younger, but to decrease in older individuals. The changes in fitness, hippocampal perfusion and volume were positively related to changes in recognition memory and early recall for complex spatial objects. Path analyses indicated that fitness-related changes in complex object recognition were modulated by hippocampal perfusion. These findings indicate a preserved capacity of the aging human hippocampus for functionally relevant vascular plasticity, which decreases with progressing age.

Contemporary use of devices in heart failure.

Devices have become a cornerstone of heart failure (HF) therapy. Implantable cardioverter-defibrillators (ICDs) decrease mortality, and cardiac resynchronization therapy (CRT) improves symptoms and mortality. Most data have been collected in patients with systolic dysfunction. Data in patients with preserved systolic function are scarce, but interesting therapeutic concepts are evolving. Besides therapeutic functions, devices can have add-on diagnostic features such as early detection of fluid overload. In addition, stand-alone diagnostic devices are now also being developed for HF.

Cardiac gene expression profiling - the quest for an atrium-specific biomarker.

Biomarkers are gaining increasing interest to predict risk but also to aid in diagnostics. Tissue-specific biomarkers are of utmost importance to detect diseases of respective organs. As of yet there are no atrium-specific biomarkers for risk stratification of atrial disease, such as atrial fibrillation. Bioinformatics such as mRNA microarrays can help to detect tissue-enriched and possibly tissue-specific expressed genes that can be targets for biomarkers. We describe an approach to identify genes preferably expressed in atrial cardiomyocytes compared with ventricular cardiomyocytes by RNA microarray and confirmed by quantitative real-time polymerase chain reaction. By this approach we identified several atrium-enriched genes but also ventricle-enriched genes. As expected atrial natriuretic peptide (ANP) mRNA showed higher expression in atrial cardiomyocytes while with adrenergic stimulation expression was almost as high in ventricular as in atrial cells. Brain-type natriuretic peptide (BNP), however, was not different between atrial and ventricular cells giving a possible explanation for increased levels of NT-proBNP in atrial fibrillation patients. Interesting identified candidates are serpine1 and ltbp2 as atrium-enriched genes whereas alpha-adrenergic receptor subtype 1b and S100A1 expression was significantly higher in ventricular cells. The identified genes need to be confirmed in human tissue and might ultimately be tested as potential biomarkers for atrial stress. (Neth Heart J 2010;18:610-4.).

Augmentation of venous, arterial and microvascular blood supply in the leg by isometric neuromuscular stimulation via the peroneal nerve.

BACKGROUND: Deep vein thrombosis (DVT) is the formation of a blood clot within the deep veins. During periods of sitting, blood flow is decreased and this contributes to an increased risk of DVT. Trials have shown that 5% to 10% of passengers undertaking long-haul flights develop asymptomatic calf DVT. AIM: To investigate the safety and efficacy of a novel neuromuscular device that augments peripheral blood flow. METHODS: Thirty healthy volunteers were assessed while seated. Each subject had one leg connected to the stimulator and the other leg immobile acting as control. Fifteen sequential electrical stimulations were applied for 5 min each followed by a 10 min recovery phase. The following noninvasive measurements were performed before, during and after the stimulation programs: photoplethysmography, strain gauge plethysmography, laser Doppler fluxmetry, transcutaneous oxygen tension, pulse oximetry, superficial femoral vein blood flow and vessel diameter (ultrasound); discomfort questionnaires were also administered. RESULTS: During neuromuscular stimulation, significant increases in blood volume flow and velocity and skin capillary blood flow were found; transdermal skin oxygen levels were maintained. No changes were observed in heart rate, blood pressure, oxygen saturation or femoral vein vessel diameter. CONCLUSIONS: Using a newly developed device, electrical nerve stimulation of the lower leg significantly increased blood flow; the device in the present study is, therefore, a promising tool for the development of a novel DVT prevention device. Because this method of electrical nerve stimulation is virtually pain free, the present study has significant implications for the prevention of DVT in hospitals, outpatient settings and community care settings, as well as in preventing travel-related thrombosis.

Cardiac resynchronisation therapy and the role of optimal device utilisation.

Despite established selection criteria, 30 to 40% of patients do not respond to cardiac resynchronisation therapy. By optimising programming of the device response to cardiac resynchronisation, therapy can be improved. (Neth Heart J 2009;17:354-7.).

Evolution of probability measures by cellular automata on algebraic topological Markov chains

In this paper we review some recent results on the evolution of probability measures under cellular automata acting on a fullshift. In particular we discuss the crucial role of the attractiveness of maximal measures. We enlarge the context of the results of a previous study of topological Markov chains that are Abelian groups; the shift map is an automorphism of this group. This is carried out by studying the dynamics of Markov measures by a particular additive cellular automata. Many of these topics were within the focus of Francisco Varela's mathematical interests.

Hydroxyl radical-induced acute diastolic dysfunction is due to calcium overload via reverse-mode Na(+)-Ca(2+) exchange.

Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca(2+) levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (F(dia)) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca(2+) (EC(50): 3.27+/-0.24 x 10(-6) versus 2.69+/-0.15 x 10(-6) mol/L; P<0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca(2+) sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540+/-93%) and pharmacologically blocked sarcoplasmic reticulum (539+/-77%), and was also similar in presence of the L-type Ca(2+)-channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca(2+) sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca(2+) influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.