Till F. Althoff

Head-to-Head Comparison of Left Ventricular Function Assessment with 64-Row Computed Tomography, Biplane Left Cineventriculography, and Both 2- and 3-Dimensional Transthoracic Echocardiography Comparison With Magnetic Resonance Imaging as the Reference Standard

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 < 0.005, 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 (p < 0.001), whereas 2D Echo and 3D Echo significantly underestimated the EDV (p < 0.05). 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 coefficient >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.

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP3 receptors

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 EP3 prostanoid receptor is specifically activated by ricinoleic acid and that it mediates the pharmacological effects of castor oil. In mice lacking EP3 receptors, the laxative effect and the uterus contraction induced via ricinoleic acid are absent. Although a conditional deletion of the EP3 receptor gene in intestinal epithelial cells did not affect castor oil-induced diarrhea, mice lacking EP3 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 EP3 prostanoid receptors. These findings identify the cellular and molecular mechanism underlying the pharmacological effects of castor oil and indicate a role of the EP3 receptor as a target to induce laxative effects.

Long-term Follow-up of a Fenestrated Amplatzer Atrial Septal Occluder in Pulmonary Arterial Hypertension

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.

G13-Mediated Signaling Pathway Is Required for Pressure Overload–Induced Cardiac Remodeling and Heart Failure

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 Gq/11 family of heterotrimeric G proteins. Most Gq/11-coupled receptors, however, can also activate G proteins of the G12/13 family, but the role of G12/13 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 G12/13 family in pressure overload–induced cardiac remodeling. We show in detail that inducible cardiomyocyte-specific inactivation of the &agr; subunit of G13, G&agr;13, does not affect basal heart function but protects mice from pressure overload–induced hypertrophy and fibrosis as efficiently as inactivation of G&agr;q/11. Furthermore, inactivation of G&agr;13 prevents the development of heart failure up to 1 year after overloading. On the molecular level, we show that G&agr;13, but not G&agr;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 G12/13 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.

Procontractile G protein–mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling

The G proteins Gα12/Gα13 and Gαq/Gα11 have opposing effects on vascular remodeling by differentially regulating vascular smooth muscle cell differentiation.

Sustained enhancement of residual platelet reactivity after coronary stenting in patients with myocardial infarction compared to elective patients

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 (100mg) 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.

Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein signalling

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.

G-protein-mediated signaling in vascular smooth muscle cells — implications for vascular disease

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.

Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation

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-&kgr;B 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-&kgr;B activation. Mice with induced endothelium-specific deficiency of Piezo1 or G&agr;q/G&agr;11 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.