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Journal articleChow A, Stuckey DJ, Kidher E, et al., 2017,
Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Encapsulating Bioactive Hydrogels Improve Rat Heart Function Post Myocardial Infarction.
, Stem Cell Reports, Vol: 9, Pages: 1415-1422, ISSN: 2213-6711Tissue engineering offers an exciting possibility for cardiac repair post myocardial infarction. We assessed the effects of combined polyethylene glycol hydrogel (PEG), human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM), and erythropoietin (EPO) therapy in a rat model of myocardial infarction. PEG with/out iPSC-CMs and EPO; iPSC-CMs in saline; or saline alone was injected into infarcted hearts shortly after infarction. Injection of almost any combination of the therapeutics limited acute elevations in chamber volumes. After 10 weeks, attenuation of ventricular remodeling was identified in all groups that received PEG injections, while ejection fractions were significantly increased in the gel-EPO, cell, and gel-cell-EPO groups. In all treatment groups, infarct thickness was increased and regions of muscle were identified within the scar. However, no grafted cells were detected. Hence, iPSC-CM-encapsulating bioactive hydrogel therapy can improve cardiac function post myocardial infarction and increase infarct thickness and muscle content despite a lack of sustained donor-cell engraftment.
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Journal articleCalkins H, Hindricks G, Cappato R, et al., 2017,
2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation
, EP-Europace, Vol: 20, Pages: E1-E160, ISSN: 1099-5129 -
Journal articleLeong KMW, Ng FS, Patil S, et al., 2017,
An electrocardiogram opinion from an National Health Service walk-in centre
, Emergency Medicine Journal, Vol: 34, Pages: 631-632, ISSN: 1472-0205 -
Journal articleSikkel MB, Francis DP, Howard J, et al., 2017,
Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies
, Cardiovascular Research, Vol: 113, Pages: 1743-1752, ISSN: 1755-3245AimsIt is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests).Methods and resultsCa2+ transients were recorded in cells loaded with Fura-2AM and sparks were recorded in cells loaded with Fluo-4AM. Data were analysed twice, once with the common statistical approach (assumption of independence) and once with hierarchical statistical methodologies designed to allow for any clustering. The statistical tests found that there was significant hierarchical clustering. This caused the common statistical approach to underestimate the standard error and report artificially small P values. For example, this would have led to the erroneous conclusion that time to 50% peak transient amplitude was significantly prolonged in HF.Spark analysis showed clustering, both within each cell and also within each rat, for morphological variables. This means that a three-level hierarchical model is sometimes required for such measures. Standard statistical methodologies, if used instead, erroneously suggest that spark amplitude is significantly greater in HF and spark duration is reduced in HF.ConclusionCa2+ fluxes in isolated cardiomyocytes show so much clustering that the common statistical approach that assumes independence of each data point will frequently give the false appearance of statistically significant changes. Hierarchical statistical methodologies need a little more effort, but are necessary for relia
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Journal articleSau A, Sikkel MB, Luther V, et al., 2017,
The sawtooth EKG pattern of typical atrial flutter is not related to slow conduction velocity at the cavotricuspid isthmus.
, Journal of Cardiovascular Electrophysiology, Vol: 28, Pages: 1445-1453, ISSN: 1045-3873INTRODUCTION: We hypothesized that very high density mapping of typical atrial flutter (AFL) would facilitate a more complete understanding of its circuit. Such very high density mapping was performed with the Rhythmia mapping system using its 64 electrode basket catheter. METHODS AND RESULTS: Data were acquired from 13 patients in AFL. Functional anatomy of the right atrium (RA) was readily identified during mapping including the Crista Terminalis and Eustachian ridge. The leading edge of the activation wavefront was identified without interruption and its conduction velocity (CV) calculated. CV was not different at the cavotricuspid isthmus (CTI) compared to the remainder of the RA (1.02 vs. 1.03 m/s, p = 0.93). The sawtooth pattern of the surface EKG flutter waves were compared to the position of the dominant wavefront. The downslope of the surface EKG flutter waves represented on average, 73% ± 9% of the total flutter cycle length. During the downslope the activation wavefront travelled significantly further than during the upslope (182 ± 21 ms vs. 68 ± 29 ms, p < 0.0001) with no change in conduction velocity between the two phases (0.88 vs. 0.91 m/s, p = 0.79). CONCLUSION: CV at the CTI is not slower than other RA regions during typical AFL. The gradual downslope of the sawtooth EKG is not due to slow conduction at the CTI suggesting that success of ablation at this site relates to anatomical properties rather than presence of a "slow isthmus". This article is protected by copyright. All rights reserved.
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Journal articlePerbellini F, Watson SA, Scigliano M, et al., 2017,
Investigation of cardiac fibroblasts using myocardial slices
, Cardiovascular Research, Vol: 114, Pages: 77-89, ISSN: 1755-3245AimsCardiac fibroblasts (CFs) are considered the principal regulators of cardiac fibrosis. Factors that influence CF activity are difficult to determine. When isolated and cultured in vitro, CFs undergo rapid phenotypic changes including increased expression of α-SMA. Here we describe a new model to study CFs and their response to pharmacological and mechanical stimuli using in vitro cultured mouse, dog and human myocardial slices.Methods and resultsUnloading of myocardial slices induced CF proliferation without α-SMA expression up to 7 days in culture. CFs migrating onto the culture plastic support or cultured on glass expressed αSMA within 3 days. The cells on the slice remained αSMA(−) despite transforming growth factor-β (20 ng/ml) or angiotensin II (200 µM) stimulation. When diastolic load was applied to myocardial slices using A-shaped stretchers, CF proliferation was significantly prevented at Days 3 and 7 (P < 0.001).ConclusionsMyocardial slices allow the study of CFs in a multicellular environment and may be used to effectively study mechanisms of cardiac fibrosis and potential targets.
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Journal articleMasoud S, Lim PB, Kitas GD, et al., 2017,
Sudden cardiac death in patients with rheumatoid arthritis
, WORLD JOURNAL OF CARDIOLOGY, Vol: 9, Pages: 562-573, ISSN: 1949-8462- Author Web Link
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Journal articleYang C, Xu Y, Yu M, et al., 2017,
Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.
, Human Molecular Genetics, Vol: 26, Pages: 3031-3045, ISSN: 0964-6906Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.
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Conference paperMirza K, Zuliani C, Hou B, et al., 2017,
An Individually Addressable Microneedle Device for Real-Time Wireless pH Monitoring
, 39th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC'17)This paper describes the development of an array of individually addressable pH sensitive microneedles using injection moulding and their integration within a portable device for real-time wireless recording of pH distributions in biological samples. The fabricated microneedles are subjected to gold pat- terning followed by electrodeposition of iridium oxide to sensitize them to 0.07 units of pH change. Miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data are embodied within the device, enabling it to measure real-time pH of soft biological samples such as muscles. In this paper, real-time recording of the cardiac pH distribution, during ischemia followed by reperfusion cycles in cardiac muscles of male Wistar rats has been demonstrated by using the microneedle array.
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Conference paperMirza K, Zuliani C, Hou B, et al., 2017,
An Individually Addressable Microneedle Device for Real-Time Wireless pH Monitoring
, 9th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC'17)This paper describes the development of an array of individually addressable pH sensitive microneedles using injection moulding and their integration within a portable device for real-time wireless recording of pH distributions in biological samples. The fabricated microneedles are subjected to gold pat- terning followed by electrodeposition of iridium oxide to sensitize them to 0.07 units of pH change. Miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data are embodied within the device, enabling it to measure real-time pH of soft biological samples such as muscles. In this paper, real-time recording of the cardiac pH distribution, during ischemia followed by reperfusion cycles in cardiac muscles of male Wistar rats has been demonstrated by using the microneedle array.
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