Debate: Do all patients with heart failure require automatic implantable defibrillators for the prevention of sudden death?

Surrogate outcomes are frequently used in cardiovascular disease research. A concern is that changes in surrogate markers may not reflect changes in disease outcomes. Two recent clinical trials (Heart and Estrogen/Progestin Replacement Study [HERS], and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]) underscore this problem since their results contradicted what was expected based on the surrogate outcomes. The current regulatory policy to allow new therapies to be introduced onto the market based solely on surrogate outcomes may need to be reviewed.     

Risk stratification for sudden cardiac death in patients with non-ischemic dilated cardiomyopathy

Non ischemic dilated cardiomyopathy (NIDCM) is a disorder of myocardium. It has varying etiologies. Albeit the varying etiologies of this heart muscle disorder, it presents with symptoms of heart failure, and rarely as sudden cardiac death (SCD). Manifestations of this disorder are in many ways similar to its counterpart, ischemic dilated cardiomyopathy (IDCM). A proportion of patients with NIDCM carries a grave prognosis and is prone to sudden cardiac death from sustained ventricular arrhythmias. Identification of this subgroup of patients who carry the risk of sudden cardiac death despite adequate medical management is a challenge. Yet another method is a blanket treatment of patients with this disorder with anti arrhythmic medications or anti tachyarrhythmia devices like implantable cardioverter defibrillators (ICD). However this modality of treatment could be a costly exercise even for affluent economies. In this review we try to analyze the existing data of risk stratification of NIDCM and its clinical implications in practice.     

Ventricular tachycardia as the presenting feature in two patients with cardiac lipoma and cardiac fibroma

We hereby present two patients with benign cardiac tumours presenting as ventricular tachycardia (VT). Most such tumours have a favorable prognosis, unless complicated by arrhythmias. Intracavitary tumours are easily diagnosed by echocardiography. Intramural tumours as in our patients may be missed at times by echocardiography. Multimodality imaging helped confirm the diagnosis and etiology, since biopsy was not safe. Surgical removal was not feasible due to extensive infiltration. The patients are so far doing well on medical therapy.     

Mesoporous silica templated-albumin nanoparticles with high doxorubicin payload for drug delivery assessed with a 3-D tumor cell model

Human serum albumin (HSA) nanoparticles emerge as promising carriers for drug delivery. Among challenges, one important issue is the design of HSA nanoparticles with a low mean size of ca. 50?nm and having a high drug payload. The original strategy developed here is to use sacrificial mesoporous nanosilica templates having a diameter close to 30?nm to drive the protein nanocapsule formation. This new approach ensures first an efficient high drug loading (ca. 30%) of Doxorubicin (DOX) in the porous silica by functionalizing silica with an aminosiloxane layer and then allows the one-step adsorption and the physical cross-linking of HSA by modifying the silica surface with isobutyramide (IBAM) groups. After silica template removal, homogenous DOX-loaded HSA nanocapsules (30–60?nm size) with high drug loading capacity (ca. 88%) are thus formed. Such nanocapsules are shown efficient in multicellular tumor spheroid models (MCTS) of human hepatocarcinoma cells by their significant growth inhibition with respect to controls. Such a new synthesis approach paves the way toward new protein based nanocarriers for drug delivery.     

Dynamic and Irregular Distribution of RyR2 Clusters in the Periphery of Live Ventricular Myocytes

Cardiac ryanodine receptors (RyR2s) are Ca²⁺ release channels clustering in the sarcoplasmic reticulum membrane. These clusters are believed to be the elementary units of Ca²⁺ release. The distribution of these Ca²⁺ release units plays a critical role in determining the spatio-temporal profile and stability of sarcoplasmic reticulum Ca²⁺ release. RyR2 clusters located in the interior of cardiomyocytes are arranged in highly ordered arrays. However, little is known about the distribution and function of RyR2 clusters in the periphery of cardiomyocytes. Here, we used a knock-in mouse model expressing a green fluorescence protein (GFP)-tagged RyR2 to localize RyR2 clusters in live ventricular myocytes by virtue of their GFP fluorescence. Confocal imaging and total internal reflection fluorescence microscopy was employed to determine and compare the distribution of GFP-RyR2 in the interior and periphery of isolated live ventricular myocytes and in intact hearts. We found tightly ordered arrays of GFP-RyR2 clusters in the interior, as previously described. In contrast, irregular distribution of GFP-RyR2 clusters was observed in the periphery. Time-lapse total internal reflection fluorescence imaging revealed dynamic movements of GFP-RyR2 clusters in the periphery, which were affected by external Ca²⁺ and RyR2 activator (caffeine) and inhibitor (tetracaine), but little detectable movement of GFP-RyR2 clusters in the interior. Furthermore, simultaneous Ca²⁺- and GFP-imaging demonstrated that peripheral RyR2 clusters with an irregular distribution pattern are functional with a Ca²⁺ release profile similar to that in the interior. These results indicate that the distribution of RyR2 clusters in the periphery of live ventricular myocytes is irregular and dynamic, which is different from that of RyR2 clusters in the interior.     

Ultrasound Molecular Imaging with Targeted Microbubbles for Cancer Diagnostics: From Bench to Bedside

Background

Ultrasound plays an important role in cancer diagnosis. B-mode imaging and contrast-enhanced ultrasound are routinely used to detect cancerous lesions in breast and liver. The use of ultrasound contrast agents (UCAs) such as microbubbles (MBs), which can be functionalized with targeting ligands, has further enabled ultrasound molecular imaging (USMI) of specific molecular markers in pre-clinical and the first clinical studies. As targeted MBs have a diameter of 1–4 μm, they are limited to the blood vasculature upon intravenous injection, and can bind to markers of the vascular endothelium. USMI with targeted MBs was applied for imaging of markers of inflammation, angiogenesis, and the tumor endothelium.

Quality and concordance of genotyping array data of 12,064 samples from 5840 cancer patients

Genotyping arrays characterize genome-wide SNPs for a study cohort and were the primary technology behind genome wide association studies over the last decade. The Cancer Genome Atlas (TCGA) is one of the largest cancer consortium studies, and it collected genotyping data for all of its participants. Using TCGA SNP data genotyped using the Affymetrix 6.0 SNP array from 12,064 samples, we conducted a comprehensive comparisons across DNA sources (tumor tissue, normal tissue, and blood) and sample storage protocols (formalin-fixed paraffin-embedded (FFPE) vs. freshly frozen (FF)), examining genotypes, transition/transversion ratios, and mutation catalogues. During the analysis, we made important observations in relevance to the data quality issues. SNP concordance was excellent between blood and normal tissues, and slightly lower between blood and tumor tissue due to potential somatic mutations in the tumors. The observed poor SNP concordance between FFPE and FF samples suggested a batch effect. The transition/transversion ratio, a metric commonly used for quality control purpose in exome sequencing projects, appeared less applicable for genotyping array data due to the whole-genome coverage built into the array design. Moreover, there were substantially more loss of heterozygosity events than gain of heterozygosity when comparing tumors relative to normal tissues and blood. This might be a consequence of extensive copy number deletions in tumors. In summary, our thorough evaluation calls for more adequate quality control practices and provides guidelines for improved application of TCGA genotyping data.     

Omega-3 consumption and sudden cardiac death in schizophrenia

People with schizophrenia show a two- to three-fold increased risk to die prematurely. Mortality is accounted for by a combination of factors (patients’ life style, suicide, premature cardiovascular disease, metabolic syndromes and, not so often mentioned, sudden death). The cause of sudden death in schizophrenia is unknown, but cardiac arrhythmia plays a potential role. Patients with schizophrenia are at high risk for cardiovascular disease, and some antipsychotics may be associated with cardiovascular adverse events (e.g., electrocardiograph QT interval prolongation), suggesting that this could lead to sudden cardiac death. Animal and clinical studies have shown that omega-3 fatty acids could be useful in the prevention and treatment of schizophrenia. As omega-3 fatty acids have been considered a cardioprotector agent, reducing cardiac arrhythmias and hence sudden cardiac deaths and given their relative safety and general health benefits, our update article summarizes the knowledge by the possible positive effects of omega-3 supplementation and fish consumption against sudden cardiac death in patients with schizophrenia. However, fish species should be selected with caution due to contamination with toxic methylmercury.     

Towards a better risk stratification for sudden cardiac death in patients with structural heart disease

With the introduction of the implantable cardioverter defibrillator (ICD), patients can be protected against sudden cardiac death (SCD) due to ventricular arrhythmia (VA). Guidelines have been drawn up for selecting patients for primary and secondary prophylaxis. However, most ICD recipients today who receive an ICD for primary prevention will not experience a life-threatening VA requiring antitachypacing or shock therapy. Better risk stratification is desirable with efficacy, costs and complication rate in mind. An overview is presented of widely accepted and potentially valuable risk markers and the role they may play in better identifying candidates for ICD therapy. (Neth Heart J 2009;17:101–6.)     

Three new records of powdery mildews found in Mexico with one genus and one new species proposed

Cystotheca lanestris on the new host Quercus canbyi, Microidium bauhiniicola on the new host Bauhinia macranthera and an undescribed species of Phyllactinia on Mimosa aculeaticarpa have recently been collected in Mexico. Analyses of morphological traits and molecular sequence data led to identifications of the causal agents of the powdery mildew diseases involved. Microidium bauhiniicola, hitherto only known from Argentina and Brazil, is new to Mexico. The phylogenetic analysis revealed an isolated position distant from Microidium indicating an undescribed genus, which is introduced as Bulbomicroidium gen. nov. Sequences derived from a Mexican specimen of C. lanestris on Quercus canbyi agree completely with other North American sequences, but differ from sequences retrieved from Asian collections, suggesting that C. lanestris in Asia is not conspecific with C. lanestris s. str. in North America. A new species of Phyllactinia on Mimosa malacophylla is morphologically similar to P. dalbergiae but readily distinguishable by differences in the asexual morph. Based on morphological peculiarities and results of molecular sequence analyses, this species is described as Phyllactinia mimosae sp. nov.     

Thiazole- and selenazole-comprising high-affinity inhibitors possess bright microsecond-scale photoluminescence in complex with protein kinase CK2

A previously disclosed protein kinase (PK) CK2-selective inhibitor 4-(2-amino-1,3-thiazol-5-yl)benzoic acid (ATB) and its selenium-containing counterpart (ASB) revealed remarkable room temperature phosphorescence when bound to the ATP pocket of the protein kinase CK2. Conjugation of these fragments with a mimic of CK2 substrate peptide resulted in bisubstrate inhibitors with increased affinity towards the kinase. Attachment of the fluorescent acceptor dye 5-TAMRA to the conjugates led to significant enhancement of intensity of long-lifetime (microsecond-scale) photoluminescence of both sulfur- and selenium-containing compounds. The developed photoluminescent probes make possible selective determination of the concentration of CK2 in cell lysates and characterization of CK2 inhibitors by means of time-gated measurement of photoluminescence.     

FABMS/derivatisation strategies for the analysis of heparin-derived oligosaccharides

Derivatisation/FABMS strategies applicable to the structure analysis of low microgramme quantities of heparin-derived oligosaccharides are described. Negative and positive FAB data from permethyl derivatives and positive FAB data from the products of subsequent methanolysis are reported for sulfated tetrasaccharides prepared by nitropus acid degradation of heparin. The preparation and FAB behaviour of acetylated derivatives of sulfated oligosaccharides are described for the first time, and the stability of the sulfate groups to base-catalysed acetylation is demonstrated. The acetylation/FABMS methodology, which yields high quality data, shows promise for the characterisation of a wide range of sulfated glycoconjugates.     

Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics

Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, I_Kur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current I_Ks, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for I_Kur over I_Ks (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.