BackgroundSevere coronary artery calcification is associated with poor procedural and clinical outcomes in patients undergoing percutaneous coronary intervention. Rotational atherectomy (RA) and... Show moreBackgroundSevere coronary artery calcification is associated with poor procedural and clinical outcomes in patients undergoing percutaneous coronary intervention. Rotational atherectomy (RA) and intravascular lithotripsy (IVL) are techniques used to optimize lesion preparation and facilitate stent implantation in this anatomical scenario. However, their comparative efficacy and safety remain unknown.MethodsWe retrospectively analyzed 101 patients who underwent PCI utilizing RA or IVL for lesion preparation in heavily calcified balloon-crossable coronary stenosis. The primary endpoint was procedural success. In addition, the occurrence of major adverse cardiovascular events (MACE, defined as the composite of all-cause mortality, target lesion revascularization(TLR), stroke and stent thrombosis (ST)) at 6-months was analyzed.ResultsHigh rates of procedural success were achieved in both RA and IVL (82 % vs. 92 %; p = 0.25), with a low in hospital complication rate (8 % vs. 4 %; p = 0.678). No significant differences were found in overall MACE at 6-months (12 % vs 6 %; P = 0.487), death (8 % vs. 2 %; p = 0.362), TLR (2 % vs. 2 %; p = 1.000), stroke (2 % vs. 2 %; P = 1.000) or ST (2 % vs. 0 %; P = 1.000). Moreover, IVL is associated with a significantly shorter fluoroscopy time (32 [22–45] vs 26 [16–37]; P = 0.041).ConclusionsBoth IVL and RA are safe and effective methods for treatment of heavily calcified coronary lesions with similar outcomes at short term follow up. Show less
Bingen, B.O.; Amri, I. al; Montero Cabezas, J.M.; Kley, F. van der 2022
Coronary access difficulty and stent compression by the juxtaposed aortic valve leaflet hamper percutaneous management of delayed coronary artery obstruction (CAO) after valve-in-valve (Edwards... Show moreCoronary access difficulty and stent compression by the juxtaposed aortic valve leaflet hamper percutaneous management of delayed coronary artery obstruction (CAO) after valve-in-valve (Edwards Sapien 3 in St. Jude Trifecta) transcatheter aortic valve replacement (TAVR). Here, we present a case of delayed post-TAVR CAO treated with intravascular lithotripsy and multistenting to overcome stent compression by the adjacent calcified leaflet. Show less
Stent underexpansion is a common problemin heavily calcified coronary lesions treated with percutaneous coronary intervention, and has been associated with in-stent restenosis, stent thrombosis and... Show moreStent underexpansion is a common problemin heavily calcified coronary lesions treated with percutaneous coronary intervention, and has been associated with in-stent restenosis, stent thrombosis and, subsequently, poor clinical outcomes. Adequate preparation of heavily calcified coronary lesions (e.g. using non-compliant balloons, cutting/scoring balloons, rotational/orbital atherectomy or intravascular lithotripsy) prior to stent implantation is essential in preventing stent underexpansion. However, in certain cases the deployed stent may remain underexpanded despite extensive lesion preparation. To date, no consensus exists on how to treat stent underexpansion in this scenario. We present a cases series in which post-stenting intravascular lithotripsy was performed to treat acute stent underexpansion in heavily calcified lesions, describing the technical aspects, angiographic results as well as clinical outcomes at mid-term follow-up. (c) 2021 Published by Elsevier Inc. Show less
Cabezas, J.M.M.; Bingen, B.O.; Amri, I. al; Scherptong, R.W.C. 2022
Cardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the... Show moreCardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the treatment options available for these arrhythmias rely on sole alleviation of symptoms or prevention of complications secondary to the arrhythmia, or are associated with non-trivial adverse effects. An increased understanding of the mechanisms underlying cardiac tachyarrhythmias as well as the means to reverse them is a critical prerequisite if we are to shift towards more specific, more effective and less harmful arrhythmia treatment. Therefore, the research described in this thesis investigates the molecular and cellular determinants of cardiac tachyarrhythmias in ex vivo and in vitro models of cardiac hypertropfy/fibrosis, ventricular fibrillation and atrial fibrillation using state of the art electrophysiological and genetic tools. Show less
AIMS Sustained ventricular fibrillation (VF) is maintained by multiple stable rotors. Destabilization of sustained VF could be beneficial by affecting VF complexity (defined by the number of rotors... Show moreAIMS Sustained ventricular fibrillation (VF) is maintained by multiple stable rotors. Destabilization of sustained VF could be beneficial by affecting VF complexity (defined by the number of rotors). However, underlying mechanisms affecting VF stability are poorly understood. Therefore, the aim of this study was to correlate changes in arrhythmia complexity with changes in specific electrophysiological parameters, allowing a search for novel factors and underlying mechanisms affecting stability of sustained VF. METHODS AND RESULTS Neonatal rat ventricular cardiomyocyte monolayers and Langendorff-perfused adult rat hearts were exposed to increasing dosages of the gap junctional uncoupler 2-aminoethoxydiphenyl borate (2-APB) to induce arrhythmias. Ion channel blockers/openers were added to study effects on VF stability. Electrophysiological parameters were assessed by optical mapping and patch-clamp techniques. Arrhythmia complexity in cardiomyocyte cultures increased with increasing dosages of 2-APB (n > 38), leading to sustained VF: 0.0 ± 0.1 phase singularities/cm(2) in controls vs. 0.0 ± 0.1, 1.0 ± 0.9, 3.3 ± 3.2, 11.0 ± 10.1, and 54.3 ± 21.7 in 5, 10, 15, 20, and 25 µmol/L 2-APB, respectively. Arrhythmia complexity inversely correlated with wavelength. Lengthening of wavelength during fibrillation could only be induced by agents (BaCl(2)/BayK8644) increasing the action potential duration (APD) at maximal activation frequencies (minimal APD); 123 ± 32%/117 ± 24% of control. Minimal APD prolongation led to transient VF destabilization, shown by critical wavefront collision leading to rotor termination, followed by significant decreases in VF complexity and activation frequency (52%/37%). These key findings were reproduced ex vivo in rat hearts (n = 6 per group). CONCLUSION These results show that stability of sustained fibrillation is regulated by minimal APD. Minimal APD prolongation leads to transient destabilization of fibrillation, ultimately decreasing VF complexity, thereby providing novel insights into anti-fibrillatory mechanisms. Show less
AIMS Cardiac hypertrophy and fibrosis are associated with potentially lethal arrhythmias. As these substrates often occur simultaneously in one patient, distinguishing between pro-arrhythmic... Show moreAIMS Cardiac hypertrophy and fibrosis are associated with potentially lethal arrhythmias. As these substrates often occur simultaneously in one patient, distinguishing between pro-arrhythmic mechanisms is difficult. This hampers understanding of underlying pro-arrhythmic mechanisms and optimal treatment. This study investigates and compares arrhythmogeneity and underlying pro-arrhythmic mechanisms of either cardiac hypertrophy or fibrosis in in vitro models. METHODS AND RESULTS Fibrosis was mimicked by free myofibroblast (MFB) proliferation in neonatal rat ventricular monolayers. Cultures with inhibited MFB proliferation were used as control or exposed to phenylephrine to induce hypertrophy. At Day 9, cultures were studied with patch-clamp and optical-mapping techniques and assessed for protein expression. In hypertrophic (n = 111) and fibrotic cultures (n = 107), conduction and repolarization were slowed. Triggered activity was commonly found in these substrates and led to high incidences of spontaneous re-entrant arrhythmias [67.5% hypertrophic, 78.5% fibrotic vs. 2.9% in controls (n = 102)] or focal arrhythmias (39.1, 51.7 vs. 8.8%, respectively). Kv4.3 and Cx43 protein expression levels were decreased in hypertrophy but unaffected in fibrosis. Depolarization of cardiomyocytes (CMCs) was only found in fibrotic cultures (-48 ± 7 vs. -66 ± 7 mV in control, P < 0.001). L-type calcium-channel blockade prevented arrhythmias in hypertrophy, but caused conduction block in fibrosis. Targeting heterocellular coupling by low doses of gap-junction uncouplers prevented arrhythmias by accelerating repolarization only in fibrotic cultures. CONCLUSION Cultured hypertrophic or fibrotic myocardial tissues generated similar focal and re-entrant arrhythmias. These models revealed electrical remodelling of CMCs as a pro-arrhythmic mechanism of hypertrophy and MFB-induced depolarization of CMCs as a pro-arrhythmic mechanism of fibrosis. These findings provide novel mechanistic insight into substrate-specific arrhythmicity. Show less
Bingen, B.O.; Askar, S.F.A.; Ypey, D.L.; Laarse, A. van der; Schalij, M.J.; Pijnappels, D.A. 2012
AIMS Arrhythmogenesis in cardiac fibrosis remains incompletely understood. Therefore, this study aims to investigate how heterocellular coupling between cardiomyocytes (CMCs) and myofibroblasts ... Show moreAIMS Arrhythmogenesis in cardiac fibrosis remains incompletely understood. Therefore, this study aims to investigate how heterocellular coupling between cardiomyocytes (CMCs) and myofibroblasts (MFBs) affects arrhythmogeneity of fibrotic myocardial cultures. Potentially, this may lead to the identification of novel anti-arrhythmic strategies. METHODS AND RESULTS Co-cultures of neonatal rat CMCs and MFBs in a 1:1 ratio were used as a model of cardiac fibrosis, with purified CMC cultures as control. Arrhythmogeneity was studied at day 9 of culture by voltage-sensitive dye mapping. Heterocellular coupling was reduced by transducing MFBs with lentiviral vectors encoding shRNA targeting connexin43 (Cx43) or luciferase (pLuc) as control. In fibrotic cultures, conduction velocity (CV) was lowered (11.2 ± 1.6 cm/s vs. 23.9 ± 2.1 cm/s; P < 0.0001), while action potential duration and ectopic activity were increased. Maximal diastolic membrane potential (MDP) of CMCs was less negative in fibrotic cultures. In fibrotic cultures, (n = 30) 30.0% showed spontaneous re-entrant tachyarrhythmias compared with 5% in controls (n = 60). Cx43 silencing in MFBs made the MDP in CMCs more negative, increased excitability and CV by 51% (P < 0.001), and reduced action potential duration and ectopic activity (P < 0.01), thereby reducing re-entry incidence by 40% compared with pLuc-silenced controls. Anti-arrhythmic effects of Cx43 down-regulation in MFBs was reversed by depolarization of CMCs through I(k1) inhibition or increasing extracellular [K(+)]. CONCLUSION Arrhythmogeneity of fibrotic myocardial cultures is mediated by Cx43 expression in MFBs. Reduced expression of Cx43 causes a more negative MDP of CMCs. This preserves CMC excitability, limits prolongation of repolarization and thereby strongly reduces the incidence of spontaneous re-entrant tachyarrhythmias. Show less
