Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) have been widely proposed as in vitro models of myocardial physiology and disease. A significant obstacle, however, is their immature phenotype. We hypothesised that Ca2+ cycling of iPSC-CM is influenced by culture conditions and can be manipulated to obtain a more mature cellular behaviour. To test this hypothesis we seeded iPSC-CM onto fibronectin coated microgrooved polydimethylsiloxane (PDMS) scaffolds fabricated using photolithography, or onto unstructured PDMS membrane. After two weeks in culture, the structure and function of iPSC-CM were studied. PDMS microgrooved culture substrates brought about cellular alignment (p < 0.0001) and more organised sarcomere. The Ca2+ cycling properties of iPSC-CM cultured on these substrates were significantly altered with a shorter time to peak amplitude (p = 0.0002 at 1 Hz), and more organised sarcoplasmic reticulum (SR) Ca2+ release in response to caffeine (p < 0.0001), suggesting improved SR Ca2+ cycling. These changes were not associated with modifications in gene expression. Whilst structured tissue culture may make iPSC-CM more representative of adult myocardium, further construct development and characterisation is required to optimise iPSC-CM as a model of adult myocardium.
Systolic anterior motion (SAM) of the mitral valve (MV) can be a life-threatening condition. The SAM can result in severe left ventricular outflow tract obstruction and/or mitral regurgitation and is associated with an up to 20% risk of sudden death (which is substantially lower in hypertrophic cardiomyopathy (HCM)). The mechanisms of SAM are complex and depend on the functional status of the ventricle. The SAM can occur in the normal population, but is typically observed in patients with HCM or following MV repair. Echocardiography (2D, 3D and stress) has a central diagnostic role as the application of echocardiographic SAM predictors allows the incorporation of prevention techniques during surgery and post-operative SAM assessment. Cardiac magnetic resonance imaging has a special role in understanding the dynamic nature of SAM, especially in anatomically atypical hearts (including HCM). This article describes what the clinician needs to know about SAM ranging from pathophysiological mechanisms and imaging modalities to conservative (medical) and surgical approaches and their respective outcomes. A stepwise approach is advocated consisting of medical therapy, followed by aggressive volume loading and beta-adrenoceptor blockade. Surgery is the final option. The correct choice of surgical technique requires an understanding of the anatomical substrate of SAM.
OPCAB may be associated with lower incidence of death, stroke and AF in the elderly, which may result in shorter length of hospital stay. A large randomised trial would confirm whether the elderly would benefit more from OPCAB surgery.
The internal thoracic artery is the most effective conduit for coronary artery bypass surgery; however, most patients have multivessel disease and require additional saphenous vein or radial artery grafts. In this systematic review of the literature and meta-analysis, we aim to compare reported patency rates for these conduits and explore if differences are homogeneous across follow-up intervals. A literature search was performed using Embase, Medline, Cochrane Library, Google Scholar and randomised controlled trial databases to identify studies published between 1965 and October 2009. All studies reporting angiographic comparison of saphenous vein and radial artery conduit patency were included, irrespective of language. The end point was angiographic graft patency stratified over different follow-up intervals. Meta-analysis was performed according to recommendations from the Cochrane Collaboration and Meta-analysis Of Observational Studies in Epidemiology guidelines. We used a random-effect model and the odds ratio as the summary statistic. A total of 35 studies were identified. They reported early patency (≤ 1 year, 6795 grafts), medium-term patency (1-5 years, 3232 grafts) and long-term patency (>5 years, 1157 grafts). Significant variation of comparative patency existed across different follow-up intervals. Early saphenous vein patency was similar to radial artery patency with odds ratio of 1.04 (95% confidence interval 0.68-1.61). Medium-term saphenous vein patency, however, deteriorated significantly (odds ratio 2.06, 95% confidence interval 1.29-3.29). Similarly, long-term patency was better for radial artery conduits (odds ratio 2.28, 95% confidence interval 1.32-3.94). Heterogeneity was due to angiographic patency characteristics and related to risk of bias. In conclusion, the findings of this systematic review of the published literature and meta-analysis support the use of radial artery in preference to saphenous vein conduits for coronary artery bypass surgery.
Ca2+‐induced Ca2+ release (CICR) is critical for contraction in cardiomyocytes. The transverse (t)‐tubule system guarantees the proximity of the triggers for Ca2+ release [L‐type Ca2+ channel, dihydropyridine receptors (DHPRs)] and the sarcoplasmic reticulum Ca2+ release channels [ryanodine receptors (RyRs)]. Transverse tubule disruption occurs early in heart failure (HF). Clinical studies of left ventricular assist devices in HF indicate that mechanical unloading induces reverse remodelling. We hypothesize that unloading of failing hearts normalizes t‐tubule structure and improves CICR.
Methods and results
Heart failure was induced in Lewis rats by left coronary artery ligation for 12 weeks; sham‐operated animals were used as controls. Failing hearts were mechanically unloaded for 4 weeks by heterotopic abdominal heart transplantation (HF‐UN). HF reduced the t‐tubule density measured by di‐8‐ANEPPS staining in isolated left ventricular myocytes, and this was reversed by unloading. The deterioration in the regularity of the t‐tubule system in HF was also reversed in HF‐UN. Scanning ion conductance microscopy showed the reappearance of normal surface striations in HF‐UN. Electron microscopy revealed recovery of normal t‐tubule microarchitecture in HF‐UN. L‐type Ca2+ current density, measured using whole‐cell patch clamping, was reduced in HF but unaffected by unloading. The variance of the time‐to‐peak of the Ca2+ transient, an index of CICR dyssynchrony, was increased in HF and normalized by unloading. The increased Ca2+ spark frequency observed in HF was reduced in HF‐UN. These results could be explained by the recoupling of orphaned RyRs in HF, as indicated by immunofluorescence.
Our data show that mechanical unloading of the failing heart reverses the pathological remodelling of the t‐tubule system and improves CICR.
Sub-valvular apparatus preservation after mitral valve replacement is not a new concept, yet to date there has been no quantification of its clinical effectiveness as a procedure and no consensus as to which surgical preservation technique should be adopted to achieve the best immediate and midterm clinical outcomes. This systematic review of current available literature aims to use an evidence synthesis and meta-analytic approach to compare outcomes following replacement of the mitral valve with (MVR-P) or without preservation (MVR-NP) of its apparatus. It considers all the relevant anatomical, experimental, echocardiographic, and clinical studies published in the literature and appraises all reported mitral valve sub-valvular apparatus preservation techniques. The results of this review strongly suggest that MVR-P is superior to MVR-NP with regards to the incidence of early postoperative low-cardiac output requiring inotropic support, and early or mid-term survival. They also suggest that the operative decision should be individualised based on patient's anatomy, pathology and ventricular function and therefore surgeons should be familiar with more than one surgical preservation technique. Finally, this paper highlights the need for further high quality research focusing particularly on the long-term assessment of quality of life and health utility following MVR-P.
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