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Late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) allows noninvasive detection of left atrial fibrosis in patients with atrial fibrillation (AF). However, whether the same methodology can be used in the right atrium (RA) remains unknown. Our aim was to define a standardized threshold to characterize RA fibrosis in LGE-CMR.A 3 Tesla LGE-CMR was performed in 53 individuals; the RA was segmented, and the image intensity ratio (IIR) calculated for the RA wall using 1 557 767 IIR pixels (40 994±10 693 per patient). The upper limit of normality of the IIR (mean IIR+2 standard deviations) was estimated in healthy volunteers (n=9), and patients who had undergone previous typical atrial flutter ablation (n=9) were used to establish the dense scar threshold. Paroxysmal and persistent AF patients (n=10 each) were used for validation. IIR values were correlated with a high-density bipolar voltage map in 15 patients undergoing AF ablation.The upper normality limit (total fibrosis threshold) in healthy volunteers was set at an IIR = 1.21. In the postablation group, 60% of the maximum IIR pixel (dense fibrosis threshold) was calculated as IIR = 1.29. Endocardial bipolar voltage showed a weak but significant correlation with IIR. The overall accuracy between the electroanatomical map and LGE-CMR to characterize fibrosis was 56%.An IIR 1.21 was determined to be the threshold for the detection of right atrial fibrosis, while an IIR 1.29 differentiates interstitial fibrosis from dense scar. Despite differences between the left and right atria, fibrosis could be assessed with LGE-CMR using similar thresholds in both chambers.

AimsElectrical reconnection of pulmonary veins (PVs) is considered an important determinant of recurrent atrial fibrillation (AF) after pulmonary vein isolation (PVI). To date, AF recurrences almost automatically trigger invasive repeat procedures, required to assess PVI durability. With recent technical advances, it is becoming increasingly common to find all PVs isolated in those repeat procedures. Thus, as ablation of extra-PV targets has failed to show benefit in randomized trials, more and more often these highly invasive procedures are performed only to rule out PV reconnection. Here we aim to define the ability of late gadolinium enhancement (LGE)-magnetic resonance imaging (MRI) to rule out PV reconnection non-invasively.Methods and resultsThis study is based on a prospective registry in which all patients receive an LGE-MRI after AF ablation. Included were all patients that—after an initial PVI and post-ablation LGE-MRI—underwent an invasive repeat procedure, which served as a reference to determine the predictive value of non-invasive lesion assessment by LGE-MRI.: 152 patients and 304 PV pairs were analysed. LGE-MRI predicted electrical PV reconnection with high sensitivity (98.9%) but rather low specificity (55.6%). Of note, LGE lesions without discontinuation ruled out reconnection of the respective PV pair with a negative predictive value of 96.9%, and patients with complete LGE lesion sets encircling all PVs were highly unlikely to show any PV reconnection (negative predictive value: 94.4%).ConclusionLGE-MRI has the potential to guide selection of appropriate candidates and planning of the ablation strategy for repeat procedures and may help to identify patients that will not benefit from a redo-procedure if no ablation of extra-PV targets is intended.

Aims: Neither the long-term development of ablation lesions nor the capability of late gadolinium enhancement (LGE)-MRI to detect ablation-induced fibrosis at late stages of scar formation have been defined. We sought to assess the development of atrial ablation lesions over time using LGE-MRI and invasive electroanatomical mapping (EAM). Methods and results: Ablation lesions and total atrial fibrosis were assessed in serial LGE-MRI scans 3 months and >12 months post pulmonary vein (PV) isolation. High-density EAM performed in subsequent repeat ablation procedures served as a reference. Serial LGE-MRI of 22 patients were analyzed retrospectively. The PV encircling ablation lines displayed an average LGE, indicative of ablation-induced fibrosis, of 91.7% ± 7.0% of the circumference at 3 months, but only 62.8% ± 25.0% at a median of 28 months post ablation (p < 0.0001). EAM performed in 18 patients undergoing a subsequent repeat procedure revealed that the consistent decrease in LGE over time was owed to a reduced detectability of ablation-induced fibrosis by LGE-MRI at time-points > 12 months post ablation. Accordingly, the agreement with EAM regarding detection of ablation-induced fibrosis and functional gaps was good for the LGE-MRI at 3 months (κ .74; p < .0001), but only weak for the LGE-MRI at 28 months post-ablation (κ .29; p < .0001). Conclusion: While non-invasive lesion assessment with LGE-MRI 3 months post ablation provides accurate guidance for future redo-procedures, detectability of atrial ablation lesions appears to decrease over time. Thus, it should be considered to perform LGE-MRI 3 months post-ablation rather than at later time-points > 12 months post ablation, like for example, prior to a planned redo-ablation procedure.

AimsWith recurrence rates up to 50% after pulmonary vein isolation (PVI) in persistent atrial fibrillation (AF), predictive tools to improve patient selection are needed. Patient selection based on left atrial late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) has been proposed previously (UTAH-classification). However, this approach has not been widely established, in part owed to the lack of standardization of the LGE quantification method. We have recently established a standardized LGE-CMR method enabling reproducible LGE-quantification. Here, the ability of this method to predict outcome after PVI was evaluated.Methods and resultsThis dual-centre study (n = 219) consists of a prospective derivation cohort (n = 37, all persistent AF) and an external validation cohort (n = 182; 66 persistent, 116 paroxysmal AF). All patients received an LGE-CMR prior to first-time PVI-only ablation. LGE was quantified based on the signal-intensity-ratio relative to the blood pool, applying a uniform LGE-defining threshold of >1.2. In patients with persistent AF in the derivation cohort, left atrial LGE-extent above a cut-off value of 12% was found to best predict relevant low-voltage substrate (≥2 cm two with 12%: 55% and 44%; P = 0.007 and P = 0.029, respectively).ConclusionThis dual-centre study established and validated a standardized, reproducible LGE-CMR method discriminating PVI responders from non-responders, which may improve choice of therapeutic approach or ablation strategy for patients with persistent AF.

Die Katheterablation von Herzrhythmusstorungen hat sich fur die meisten tachykarden Arrhythmieformen als primare Behandlungsform etabliert. Hierbei ist die interventionelle Behandlung eines symptomatischen Vorhofflimmerns der medikamentosen Therapie uberlegen, sodass die Durchfuhrung einer Katheterablation zunehmend zum klinischen Alltag vieler Kliniken gehort. Die elektrische Isolation der Pulmonalvenen (PVI) stellt den Eckpfeiler der interventionellen Therapie sowohl von paroxysmalem als auch von persistierendem Vorhofflimmern dar. Dieser Artikel beschreibt die Durchfuhrung einer Pulmonalvenenisolation mittels Radiofrequenzablation in Punkt-fur-Punkt-Technik und soll eine praktische Anleitung fur die Arbeit im Herzkatheterlabor sein. Diese Arbeit setzt eine Reihe von Artikeln fort, die fur eine Weiterbildung im Bereich der speziellen Rhythmologie erstellt worden sind.

Aufgrund guter Ergebnisse, zunehmender Standardisierung und Fehlen von gleichwertigen Alternativen gehort die Durchfuhrung einer Katheterablation zunehmend zum klinischen Alltag vieler Kliniken. Dieser Artikel beschreibt die Durchfuhrung haufiger oder notwendiger Punktionen (Punktion der Leistengefase, transseptale Punktion, Perikardpunktion) im Rahmen einer Katheterablation und soll eine praktische Anleitung fur die Arbeit im Herzkatheterlabor darstellen. Diese Arbeit setzt eine Reihe von Artikeln fort, die fur eine Weiterbildung im Bereich der speziellen Rhythmologie konzipiert sind.

Aims Myocardial fibrosis is a hallmark of atrial fibrillation (AF) and its characterization could be used to guide ablation procedures. Late gadolinium enhanced-magnetic resonance imaging (LGE-MRI) detects areas of atrial fibrosis. However, its accuracy remains controversial. We aimed to analyse the accuracy of LGE-MRI to identify left atrial (LA) arrhythmogenic substrate by analysing voltage and conduction velocity at the areas of LGE. Methods and results Late gadolinium enhanced-magnetic resonance imaging was performed before ablation in 16 patients. Atrial wall intensity was normalized to blood pool and classified as healthy, interstitial fibrosis, and dense scar tissue depending of the resulting image intensity ratio. Bipolar voltage and local conduction velocity were measured in LA with high-density electroanatomic maps recorded in sinus rhythm and subsequently projected into the LGE-MRI. A semi-automatic, point-by-point correlation was made between LGE-MRI and electroanatomical mapping. Mean bipolar voltage and local velocity progressively decreased from healthy to interstitial fibrosis to scar. There was a significant negative correlation between LGE with voltage (r = −0.39, P Conclusions Areas with higher LGE show lower voltage and slower conduction in sinus rhythm. The enhancement intensity correlates with bipolar voltage and conduction velocity in a point-by-point analysis. The performance of LGE-MRI in assessing local velocity might be reduced in patients with dilated atria (LA diameter ≥45).

Late gadolinium enhancement (LGE) MRI is capable of detecting not only native cardiac fibrosis, but also ablation-induced scarring. Thus, it offers the unique opportunity to assess ablation lesions non-invasively. In the atrium, LGE-MRI has been shown to accurately detect and localise gaps in ablation lines. With a negative predictive value close to 100% it can reliably rule out pulmonary vein reconnection non-invasively and thus may avoid unnecessary invasive repeat procedures where a pulmonary vein isolation only approach is pursued. Even LGE-MRI-guided repeat pulmonary vein isolation has been demonstrated to be feasible as a standalone approach. LGE-MRI-based lesion assessment may also be of value to evaluate the efficacy of ventricular ablation. In this respect the elimination of LGE-MRI-detected arrhythmogenic substrate may serve as a potential endpoint, but validation in clinical studies is lacking. Despite holding great promise, the widespread use of LGE-MRI is still limited by the absence of standardised protocols for image acquisition and post-processing. In particular, reproducibility across different centres is impeded by inconsistent thresholds and internal references to define fibrosis. Thus, uniform methodological and analytical standards are warranted to foster a broader implementation in clinical practice.

The shape of the left atrium (LA) and left atrial appendage (LAA) have been shown to predict stroke in patients with atrial fibrillation (AF). Prior studies rely on qualitative assessment of shape, which limits reproducibility and clinical utility. Statistical shape analysis (SSA) allows for quantitative assessment of shape. We use this method to assess the shape of the LA and LAA and predict stroke in patients with AF. From a database of AF patients who had previously undergone MRI of the LA, we identified 43 patients with AF who subsequently had an ischemic stroke. We also identified a cohort of 201 controls with AF who did not have a stroke after the MRI. We performed SSA of the LA and LAA shape to quantify the shape of these structures. We found three of the candidate LAA shape parameters to be predictive of stroke, while none of the LA shape parameters predicted stroke. When the three predictive LAA shape parameters were added to a logistic regression model that included the CHA

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Spanish Government, Madrid, Spain [FIS_PI16/00435 Background Late gadolinium enhancement MRI (LGE-MRI) is increasingly used to detect native as well as ablation-induced atrial fibrosis in the context of atrial fibrillation (AF). However, cardiac fibrotic tissue including ablation lesions is subject to sustained remodeling, and neither the development of ablation-induced fibrosis over time nor the capability of LGE-MRI to detect it at different stages of scar formation have been defined. We sought to define the long-term development of ablation-induced atrial fibrosis and to validate LGE-MRI for the assessment of ablation lesions at different time points. Methods Patients with first-time AF ablation and an early follow-up LGE-MRI (3 months post ablation) and a late follow-up LGE-MRI (>12 months post ablation) were included. LGE-MRI data were postprocessed for quantification of fibrotic tissue using the ADAS 3D software. In the majority of patients high-density electroanatomical mapping (EAM), performed in a repeat procedure served as a reference. Results 22 consecutive patients fulfilling the inclusion criteria were analysed retrospectively. In the LGE-MRI 3 months post ablation an average of 91.7 ± 7.0% of the ablation lines" circumference displayed late gadolinium enhancement (LGE) reflecting ablation-induced fibrosis, whereas in the late follow-up LGE-MRI, at a median of 28 months post ablation, only 62.8 ± 25.0% of the ablation lines" circumference was covered by LGE (p Conclusions Our results indicate that while ablation-induced atrial fibrosis appears to remain rather constant over time, LGE-MRI loses some of its capability to detect it. Thus, LGE-MRI 3 months post ablation may be more accurate in the detection of durable ablation lesions than LGE-MRI at later time points more than 12 months after ablation. Abstract Figure

Aims Left atrial (LA) fibrosis is present in patients with atrial fibrillation (AF) and can be visualized by magnetic resonance imaging with late gadolinium enhancement (LGE-MRI). Previous studies have shown that LA fibrosis is not randomly distributed, being more frequent in the area adjacent to the descending aorta (DAo). The objective of this study is to analyse the relationship between fibrosis in the atrial area adjacent to the DAo and the distance to it, as well as the prognostic implications of this fibrosis. Methods and results Magnetic resonance imaging with late gadolinium enhancement was obtained in 108 patients before AF ablation to analyse the extent of LA fibrosis and the distance DAo-to-LA. A high-density electroanatomic map was performed in a subgroup of 16 patients to exclude the possibility of an MRI artifact. Recurrences after ablation were analysed at 1 year of follow-up. The extent of atrial fibrosis in the area adjacent to the DAo was inversely correlated with the distance DAo-to-LA (r = −0.34, P Conclusions Atrial fibrosis was predominantly located in the area adjacent to the DAo, and increased with the proximity between the two structures. Furthermore, this regional fibrosis better predicted recurrence after AF ablation than total atrial fibrosis.

Aims While the CLOSE protocol proposes a maximally tolerable interlesion distance (ILD) of 6 mm for ablation index ablation index-guided atrial fibrillation (AF) ablation, a target ILD has never been defined. This randomized study sought to establish a target ILD for ablation index-guided AF ablation. Methods and results Consecutive patients scheduled for first-time pulmonary vein (PV) isolation (PVI) were randomly assigned to ablation protocols with a target ILD of 5.0–6.0 mm or 3.0–4.0 mm, with the primary endpoint of first-pass PVI. In compliance with the CLOSE protocol, the maximum tolerated ILD was 6.0 mm in both study protocols. A target ablation index of ≥550 (anterior) or ≥400 (posterior) was defined for the ‘5–6 mm’ protocol and ≥500 (anterior) or ≥350 (posterior) for the ‘3–4 mm’ protocol. The study was terminated early for superiority of the ‘3–4 mm’ protocol. Forty-two consecutive patients were randomized and 84 ipsilateral PV pairs encircled according to the study protocol. First-pass PVI was accomplished in 35.0% of the ‘5–6 mm’ group and 90.9% of the ‘3–4 mm’ group (P Conclusion In ablation index-guided AF ablation, an ILD of 3.0–4.0 mm should be targeted rather than 5.0–6.0 mm. Moreover, the lower target ILD may allow for less extensive ablation at each given point.

Atherosclerosis preferentially develops in areas of disturbed flow. Albarrán-Juárez et al. provide evidence that this depends on at least two different endothelial mechanosignaling pathways, a flow direction-independent pathway involving Piezo1 and Gq/G11, as well as integrin signaling, which is only initiated in response to disturbed flow., The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-κB activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 receptor, and Gq/G11-mediated signaling. However, only disturbed flow leads to Piezo1- and Gq/G11-mediated integrin activation resulting in focal adhesion kinase-dependent NF-κB activation. Mice with induced endothelium-specific deficiency of Piezo1 or Gαq/Gα11 show reduced integrin activation, inflammatory signaling, and progression of atherosclerosis in atheroprone areas. Our data identify critical steps in endothelial mechanotransduction, which distinguish flow pattern-dependent activation of atheroprotective and atherogenic endothelial signaling and suggest novel therapeutic strategies to treat inflammatory vascular disorders such as atherosclerosis.

Introduction Endothelial inflammation plays a pivotal role in atherosclerosis. Many inflammatory and metabolic signals converge upon mechanistic target of rapamycin (mTOR), and inhibition of mTOR has been shown to reduce atherosclerosis. However, clinical use of mTOR-inhibitors is limited by serious adverse effects, of which insulin resistance and dyslipidemia are particularly troubling in the context of atherosclerosis. In that respect, targeting PRAS40, an endogenous modulator of mTOR complex 1 (mTORC1) with highly cell type-specific effects on mTOR signaling, may be a more promising approach. In fact, we have previously demonstrated that, in contrast to conventional mTOR inhibitors, PRAS40 gene therapy substantially improves metabolic profile in obese mice. However, the function of PRAS40 in endothelial cells and its role in atherosclerosis have never been investigated. Methods and results To define the impact of PRAS40 on endothelial mTORC1-signaling in this context, cultured human umbilical vein endothelial cells (HUVECs) were exposed to the atherogenic cytokine TNFα. TNFα induced mTOR signaling as evidenced by increased phosphorylation of S6 kinase and ribosomal S6 protein. Interestingly, this effect was strongly augmented upon siRNA-mediated knock-down of PRAS40, indicating a negative regulation of mTORC1 by PRAS40 in endothelial cells. Moreover, PRAS40-knockdown promoted TNFα-induced inflammatory signaling as reflected by increased proliferative activity, upregulation of atherogenic markers like CCL2 and VCAM-1, as well as enhanced monocyte recruitment in the THP-1 adhesion assay. In contrast, PRAS40-overexpression blocked TNFα-induced activation of mTORC1 and consistently suppressed all of these measures of inflammatory activation. All effects of PRAS40-overexpression could be reproduced by the mTORC1 inhibitors rapamycin and torin1. Thus, our in vitro studies suggest that in endothelial cells PRAS40 exerts anti-atherogenic effects by negative regulation of mTORC1. To validate these findings in vivo in the context of atherosclerosis we created transgenic mice with tamoxifen-inducible endothelium-specific PRAS40-deficiency (EC-PRAS40-KO). These mice were exposed to a model of accelerated atherosclerosis based on western diet and partial carotid ligation: Four weeks after partial carotid ligation, neointimal and atherosclerotic lesion formation was strongly enhanced in EC-PRAS40-KO mice. Moreover, mTORC1 activity as well as CCL2 and VCAM-1 expression were markedly increased compared to control mice. Conclusion Our data indicate that PRAS40 suppresses atherosclerosis via inhibition of mTORC1-mediated inflammatory signaling in endothelial cells. In conjunction with its favourable effects on metabolic homeostasis, the overall therapeutic profile of PRAS40-treatment appears to be beneficial compared to conventional mTOR-inhibitors. Taken together PRAS40 may qualify as a promising therapeutic target for the treatment of atherosclerosis. Acknowledgement/Funding German Federal Ministry of Education and Research, DZHK (German Centre for Cardiovascular Research)

Introduction Antagonists of the angiotensin II receptor type 1 (AT1) belong to the most successful treatments of cardiovascular disease. Besides G-protein-independent β-arrestin-mediated signaling, AT1 preferencially signals via G-proteins of the families Gq and G13. Conventional AT1-antagonists equally inhibit all of these pathways, even though the beneficial effects are generally attributed to the inhibition of Gq only. While data on β-arrestin signaling in the vascular disease context are conflicting, we found an excessive pathological remodeling and dramatic exacerbation of atherosclerosis upon interference with G13-mediated signaling. Against this background, selective inhibition of the Gq-pathway seems desirable. Thus, based on the novel concept of ligand-biased signaling, we aimed to identify biased AT1-antagonists that selectively inhibit the Gq-pathway, while allowing for continued signaling through G13. Methods and results We systematically profiled known AT1-ligands and identified the angiotensin analogue Sar-Arg-Val-Tyr-Lys-His-Pro-Ala-OH (TRV023) as a Gq-selective AT1-antagonist: TRV023 has recently been described as a β-arrestin-biased ligand; however its signaling properties regarding distinct G-protein isoforms have never been defined. Indeed, using bioluminescence reporter assays, we found that TRV023 inhibits Gq-signaling at least as potently as losartan and telmisartan, but unlike the conventional antagonists, it does not impair β-arrestin-signaling (Fig. 1A). Intriguingly, while the conventional antagonists effectively inhibited induction of a G13 luciferase reporter, TRV023 did not significantly interfere with G13-mediated signaling, indicating Gq-selective antagonistic effects. According to our hypothesis, these G-protein-biased signaling properties could render TRV023 superior to conventional antagonists in the treatment of vascular disease. In order to test this hypothesis, we exposed ApoE-deficient mice to one of two different atherosclerosis models: A novel model for accelerated atherosclosis based on partial carotid ligation and western diet, or a conventional atherosclerosis model based on 12 weeks of western diet. Using osmotic pumps, mice were continuously treated with vehicle control, TRV023 or losartan in doses that proved equipotent with respect to blood pressure lowering effects. In line with our hypothesis, TRV023 but not losartan significantly attenuated plaque development in both atherosclerosis models (Fig. 1B). Figure 1 Conclusion Our studies have identified TRV023 as a Gq-biased AT1-antagonist and indicate that selective inhibition of AT1-dependent Gq-mediated signaling by biased ligands may be a promising approach for the treatment of atherosclerosis. Hence, TRV023 qualifies as a drug candidate, particularly since it has already proven to be safe and well-tolerable in clinical phase I and II trials in the context of acute heart failure. Acknowledgement/Funding Else Kröner-Fresenius-Foundation

Aims Arterial hypertension is a major risk factor for cardiovascular diseases. The kidney and its natriuretic function are in the centre of the prevailing models to explain the pathogenesis of hypertension; however, the mechanisms underlying blood pressure elevation remain unclear in most patients. Development of hypertension is strongly correlated with age, and this blood pressure increase typically accelerates in the fourth decade of life. The cause of age-dependent blood pressure elevation is poorly understood. This study aims to understand the role of procontractile G-protein-mediated signalling pathways in vascular smooth muscle in age-dependent hypertension. Methods and results Similar to humans at mid-life, we observed in 1-year-old mice elevated blood pressure levels without any evidence for increased vessel stiffness, impaired renal function, or endocrine abnormalities. Hypertensive aged mice showed signs of endothelial dysfunction and had an increased vascular formation of reactive oxygen species (ROS) and elevated endothelial ET-1 expression. Age-dependent hypertension could be normalized by ETA receptor blockade, smooth muscle-specific inactivation of the gene encoding the ETA receptor, as well as by acute disruption of downstream signalling via induction of smooth muscle-specific Gα12/Gα13, Gαq/Gα11, or LARG deficiency using tamoxifen-inducible smooth muscle-specific conditional mouse knock-out models. Induction of smooth muscle-specific ETA receptor deficiency normalized the blood pressure in aged mice despite the continuous presence of signs of endothelial dysfunction. Conclusion Age-dependent blood pressure elevation is due to a highly reversible activation of procontractile signalling in vascular smooth muscle cells indicating that increased vascular tone can be a primary factor in the development of hypertension.

Background— Cardiac remodeling in response to pressure or volume overload plays an important role in the pathogenesis of heart failure. Various mechanisms have been suggested to translate mechanical stress into structural changes, one of them being the release of humoral factors such as angiotensin II and endothelin-1, which in turn promote cardiac hypertrophy and fibrosis. A large body of evidence suggests that the prohypertrophic effects of these factors are mediated by receptors coupled to the G q/11 family of heterotrimeric G proteins. Most G q/11 -coupled receptors, however, can also activate G proteins of the G 12/13 family, but the role of G 12/13 in cardiac remodeling is not understood. Methods and Results— We use siRNA-mediated knockdown in vitro and conditional gene inactivation in vivo to study the role of the G 12/13 family in pressure overload–induced cardiac remodeling. We show in detail that inducible cardiomyocyte-specific inactivation of the α subunit of G 13 , Gα 13 , does not affect basal heart function but protects mice from pressure overload–induced hypertrophy and fibrosis as efficiently as inactivation of Gα q/11 . Furthermore, inactivation of Gα 13 prevents the development of heart failure up to 1 year after overloading. On the molecular level, we show that Gα 13 , but not Gα q/11 , controls agonist-induced expression of hypertrophy-specific genes through activation of the small GTPase RhoA and consecutive activation of myocardin-related transcription factors. Conclusion— Our data show that the G 12/13 family of heterotrimeric G proteins is centrally involved in pressure overload–induced cardiac remodeling and plays a central role in the transition to heart failure.

Objectives This study was designed to compare the accuracy of 64-row contrast computed tomography (CT), invasive cineventriculography (CVG), 2-dimensional echocardiography (2D Echo), and 3-dimensional echocardiography (3D Echo) for left ventricular (LV) function assessment with magnetic resonance imaging (MRI). Background Cardiac function is an important determinant of therapy and is a major predictor for long-term survival in patients with coronary artery disease. A number of methods are available for assessment of function, but there are limited data on the comparison between these multiple methods in the same patients. Methods A total of 36 patients prospectively underwent 64-row CT, CVG, 2D Echo, 3D Echo, and MRI (as the reference standard). Global and regional LV wall motion and ejection fraction (EF) were measured. In addition, assessment of interobserver agreement was performed. Results For the global EF, Bland-Altman analysis showed significantly higher agreement between CT and MRI (p 0.8), whereas agreement was lower for CVG (intraclass correlation coefficient = 0.58). Conclusions 64-row CT may be more accurate than CVG, 2D Echo, and 3D Echo in comparison with MRI as the reference standard for assessment of global LV function.

Differentiated vascular smooth muscle cells (VSMCs) are critical determinants of vascular tone and blood pressure. However, during vascular remodeling processes, which occur in response to changing hemodynamics or vascular injury, VSMCs lose most of their contractile functions in a dedifferentiation process, which goes along with cell proliferation and cell migration. VSMCs are under the constant control of a variety of mediators with vasocontractile or vasodilatory properties. Most of these mediators act through G-protein-coupled receptors, which, via different downstream signaling pathways, regulate the phosphorylation of myosin light chain and thereby control vascular tone. Recent work indicates that procontractile G-protein-mediated signal transduction pathways are also critical regulators of vascular smooth muscle dedifferentiation and redifferentiation. This review describes some of the key G-protein-mediated signal transduction pathways regulating vascular tone and VSMC differentiation and their involvement in cardiovascular diseases.

Pulmonary arterial hypertension (PAH) is a progressive disease, with right-heart failure being the main cause of death. In patients refractory to conventional drug therapy, atrial septostomy can serve as palliative treatment or as a bridge to transplantation. A 41-year-old woman with a 15-year history of PAH associated with a corrected atrial septal defect presented with severe deterioration of symptoms. Echocardiography confirmed reocclusion of an atrial septal stoma that had been created several months before. After performing a repeat atrial septostomy, we implanted a custom-made atrial septostomy device, an Amplatzer septal occluder that had been fenestrated to serve as a custom-made atrial septostomy device. This resulted in an improvement in cardiac output and a marked symptomatic relief. During the 6-year follow-up, the patient was clinically stable with limited but constant exercise tolerance, under specific medical therapy. Repeated echocardiography confirmed long-term patency of the device.

Atrial fibrillation (AF) is a common arrhythmia with relevant impact on mortality and morbidity. Pulmonary vein isolation (PVI) is an established therapy in patients who remain symptomatic under optimal medical therapy. However, up to 70 % of patients present with recurrence of AF after PVI. Therefore, identifying ideal candidates is an unmet clinical need. Left atrial (LA) fibrosis is associated with reduced LA function. Analysis of LA mechanics using 2D speckle tracking echocardiography (STE) might give more insight into LA substrates and be therefore of predictive value. This prospective single-center pilot study included 31 patients (mean age, 62.3 ± 9.1 years; 19 males) with AF who underwent PVI and 20 matched healthy controls (mean age, 60.6 ± 6.6 years; 10 males). 2D STE strain indices of LA reservoir (RLA), conduit, and, if feasible, contractile function, were analyzed before and 6 months after PVI. Assessment of the LV diastolic function was based on standard indices. Responders to PVI were defined as being asymptomatic and free of AF in a 7-day Holter-ECG after 6 months. At baseline, all patients with AF had significantly lower reservoir and contractile function compared with controls. After 6 months, 17 patients (54.8 %) were identified as responders. At baseline, the reservoir function was significantly higher in responders compared with nonresponders (32.7 ± 11.1 vs. 22.9 ± 10.9 %; P = 0.019). Only in responders, RLA and contractile LA function improved and reached normal values whereas LA function remained unchanged in nonresponders. In a ROC analysis, a RLA value of ≥19.5 % discriminated responders and nonresponders in patients with persistent AF with a sensitivity of 86 % and a specificity of 100 % (P = 0.012; area under the curve 0.943; CI, 0.81–1.0). LA reservoir function helps to predict efficacy of PVI after 6 months. Only in responders, reservoir, and contractile function normalized within 6 months after PVI indicating a lower level of atrial remodeling at baseline. No deleterious effects of ablation were detected in nonresponders.

The G proteins Gα12/Gα13 and Gαq/Gα11 have opposing effects on vascular remodeling by differentially regulating vascular smooth muscle cell differentiation., Vascular smooth muscle (Sm) cells (VSMCs) are highly plastic. Their differentiation state can be regulated by serum response factor (SRF), which activates genes involved in Sm differentiation and proliferation by recruiting cofactors, such as members of the myocardin family and ternary complex factors (TCFs), respectively. However, the extracellular cues and upstream signaling mechanisms regulating SRF-dependent VSMC differentiation under in vivo conditions are poorly understood. In this study, we show that the procontractile signaling pathways mediated by the G proteins G12/G13 and Gq/G11 antagonistically regulate VSMC plasticity in different models of vascular remodeling. In mice lacking Gα12/Gα13 or their effector, the RhoGEF protein LARG, RhoA-dependent SRF-regulation was blocked and down-regulation of VSMC differentiation marker genes was enhanced. This was accompanied by an excessive vascular remodeling and exacerbation of atherosclerosis. In contrast, Sm-specific Gαq/Gα11 deficiency blocked activation of extracellular signal-regulated kinase 1/2 and the TCF Elk-1, resulting in a reduced VSMC dedifferentiation in response to flow cessation or vascular injury. These data show that the balanced activity of both G protein–mediated pathways in VSMCs is required for an appropriate vessel remodeling response in vascular diseases and suggest new approaches to modulate Sm differentiation in vascular pathologies.

Castor oil is one of the oldest drugs. When given orally, it has a laxative effect and induces labor in pregnant females. The effects of castor oil are mediated by ricinoleic acid, a hydroxylated fatty acid released from castor oil by intestinal lipases. Despite the wide-spread use of castor oil in conventional and folk medicine, the molecular mechanism by which ricinoleic acid acts remains unknown. Here we show that the EP 3 prostanoid receptor is specifically activated by ricinoleic acid and that it mediates the pharmacological effects of castor oil. In mice lacking EP 3 receptors, the laxative effect and the uterus contraction induced via ricinoleic acid are absent. Although a conditional deletion of the EP 3 receptor gene in intestinal epithelial cells did not affect castor oil-induced diarrhea, mice lacking EP 3 receptors only in smooth-muscle cells were unresponsive to this drug. Thus, the castor oil metabolite ricinoleic acid activates intestinal and uterine smooth-muscle cells via EP 3 prostanoid receptors. These findings identify the cellular and molecular mechanism underlying the pharmacological effects of castor oil and indicate a role of the EP 3 receptor as a target to induce laxative effects.

This study was designed to compare the accuracy of 64-row contrast computed tomography (CT), invasive cineventriculography (CVG), 2-dimensional echocardiography (2D Echo), and 3-dimensional echocardiography (3D Echo) for left ventricular (LV) function assessment with magnetic resonance imaging (MRI).Cardiac function is an important determinant of therapy and is a major predictor for long-term survival in patients with coronary artery disease. A number of methods are available for assessment of function, but there are limited data on the comparison between these multiple methods in the same patients.A total of 36 patients prospectively underwent 64-row CT, CVG, 2D Echo, 3D Echo, and MRI (as the reference standard). Global and regional LV wall motion and ejection fraction (EF) were measured. In addition, assessment of interobserver agreement was performed.For the global EF, Bland-Altman analysis showed significantly higher agreement between CT and MRI (p0.005, 95% confidence interval: ±14.2%) than for CVG (±20.2%) and 3D Echo (±21.2%). Only CVG (59.5 ± 13.9%, p = 0.03) significantly overestimated EF in comparison with MRI (55.6 ± 16.0%). CT showed significantly better agreement for stroke volume than 2D Echo, 3D Echo, and CVG. In comparison with MRI, CVG-but not CT-significantly overestimated the end-diastolic volume (p0.001), whereas 2D Echo and 3D Echo significantly underestimated the EDV (p0.05). There was no significant difference in diagnostic accuracy (range: 76% to 88%) for regional LV function assessment between the 4 methods when compared with MRI. Interobserver agreement for EF showed high intraclass correlation for 64-row CT, MRI, 2D Echo, and 3D Echo (intraclass correlation coefficient0.8), whereas agreement was lower for CVG (intraclass correlation coefficient = 0.58).64-row CT may be more accurate than CVG, 2D Echo, and 3D Echo in comparison with MRI as the reference standard for assessment of global LV function.

Introduction Elevated platelet reactivity despite antiplatelet therapy is associated with an increased cardiovascular risk after percutaneous coronary interventions. Current guidelines recommend uniform antiplatelet maintenance regimen after percutaneous coronary interventions for patients with myocardial infarction and elective patients. We sought to demonstrate that there is a persistent enhancement of residual platelet reactivity after myocardial infarction, requiring an intensified antiplatelet maintenance therapy. Materials and Methods A total of 66 patients after coronary stenting for myocardial infarction (n = 36) or elective coronary stenting (n = 30) were included in this prospective, controlled study. Platelet reactivity to adenosine-5-diphosphate and arachidonic acid under treatment with clopidogrel (75 mg) and acetyl salicylic acid (100 mg) were assessed 48 hours and 30 days after coronary stenting using light transmission aggregometry and multiple electrode platelet aggregometry (Multiplate analyzer) simultaneously. Results Fourty-eight hours after coronary stenting all measures of residual platelet reactivity were significantly elevated in the infarction group. After a mean follow up of 37 days, residual platelet reactivity to adenosine-5-diphosphate was still consistently elevated, albeit statistically not significant. Contrarily, residual platelet reactivity to arachidonic acid significantly decreased and returned to normal by the time of follow up. Regression analyses revealed myocardial infarction, C-reactive protein and fibrinogen as predictors of enhanced platelet reactivity 48 hours after coronary stenting. Conclusions Patients undergoing coronary stenting for acute myocardial infarction exhibit an enhancement of residual platelet reactivity sustaining for at least 48 hours following coronary stenting. This finding provides a rationale for a continued intensified antiplatelet therapy after myocardial infarction.