Ca(2+) elevations are fundamental to cardiac physiology-stimulating contraction and regulating the gene transcription that underlies hypertrophy. How Ca(2+) specifically controls gene transcription on the background of the rhythmic Ca(2+) increases required for contraction is not fully understood. Here we identify a hypertrophy-signaling module in cardiac myocytes that explains how Ca(2+) discretely regulates myocyte hypertrophy and contraction. We show that endothelin-1 (ET-1) stimulates InsP(3)-induced Ca(2+) release (IICR) from perinuclear InsP(3)Rs, causing an elevation in nuclear Ca(2+). Significantly, we show that IICR, but not global Ca(2+) elevations associated with myocyte contraction, couple to the calcineurin (CnA)/NFAT pathway to induce hypertrophy. Moreover, we found that activation of the CnA/NFAT pathway and hypertrophy by isoproterenol and BayK8644, which enhance global Ca(2+) fluxes, was also dependent on IICR and nuclear Ca(2+) elevations. The activation of IICR by these activity-enhancing mediators was explained by their ability to stimulate secretion of autocrine/paracrine ET-1.

Cardiac hypertrophy is a growth response of the heart to increased hemodynamic demand or damage. Accompanying this heart enlargement is a remodeling of Ca 2؉ signaling. Due to its fundamental role in controlling cardiomyocyte contraction during every heartbeat, modifications in Ca 2؉ fluxes significantly impact on cardiac output and facilitate the development of arrhythmias. Using cardiomyocytes from spontaneously hypertensive rats (SHRs), we demonstrate that an increase in Ca 2؉ release through inositol 1,4,5-trisphosphate receptors (InsP 3Rs) contributes to the larger excitation contraction coupling (ECC)-mediated Ca 2؉ transients characteristic of hypertrophic myocytes and underlies the more potent enhancement of ECCmediated Ca 2؉ transients and contraction elicited by InsP3 or endothelin-1 (ET-1). Responsible for this is an increase in InsP 3R expression in the junctional sarcoplasmic reticulum. Due to their close proximity to ryanodine receptors (RyRs) in this region, enhanced Ca 2؉ release through InsP 3Rs served to sensitize RyRs, thereby increasing diastolic Ca 2؉ levels, the incidence of extra-systolic Ca 2؉ transients, and the induction of ECC-mediated Ca 2؉ elevations. Unlike the increase in InsP 3R expression and Ca 2؉ transient amplitude in the cytosol, InsP3R expression and ECC-mediated Ca 2؉ transients in the nucleus were not altered during hypertrophy. Elevated InsP 3R2 expression was also detected in hearts from human patients with heart failure after ischemic dilated cardiomyopathy, as well as in aortic-banded hypertrophic mouse hearts. Our data establish that increased InsP 3R expression is a general mechanism that underlies remodeling of Ca 2؉ signaling during heart disease, and in particular, in triggering ventricular arrhythmia during hypertrophy.calcium ͉ ECC ͉ IP3 ͉ SHR ͉ signalling

Radiofrequency (RF)-related heating of cardiac pacemaker leads is a serious concern in magnetic resonance imaging (MRI).

The purpose of this study was to assess the distribution of RF-induced E-fields inside a gel-filled phantom of the human head and torso and compare the results with the RF-induced temperature rise at the tip of a straight conductive implant, specifically examining the dependence of the temperature rise on the position of the implant inside the gel. MRI experiments were performed in two different 1.5T MR systems of the same manufacturer. E-field distribution inside the liquid was assessed using a custom measurement system. The temperature rise at the implant tip was measured in various implant positions and orientations using fluoroptic thermometry. The results show that local E-field strength in the direction of the implant is a critical factor in RF-related tissue heating. The actual E-field distribution, which is dependent on phantom/ body properties and the MR-system employed, must be considered when assessing the effects of RF power deposition in implant safety investigations. Magn Reson Med 60:312-319, 2008.

Pharmacological S1P receptor agonists have distinct effects on ischaemia-reperfusion injury. Their efficacy when applied during reperfusion makes them potential candidates for pharmaceutical postconditioning therapy after cardiac ischaemia.

ObjectiveCardiac diseases are established risk factors for ischemic stroke incidence and severity. Conversely, there is increasing evidence that brain ischemia can cause cardiac dysfunction. The mechanisms underlying this neurogenic heart disease are incompletely understood. Although it is established that ischemic stroke is associated with cardiac arrhythmias, myocardial damage, elevated cardiac enzymes, and plasma catecholamines in the acute phase, nothing is known about the delayed consequences of ischemic stroke on cardiovascular function.MethodsTo determine the long‐term cardiac consequences of a focal cerebral ischemia, we subjected young and aged mice to a 30‐minute transient middle cerebral artery occlusion and analyzed cardiac function by serial transthoracic echocardiography and hemodynamic measurements up to week 8 after surgery. Finally, animals were treated with metoprolol to evaluate a pharmacologic treatment option to prevent the development of heart failure.ResultsFocal cerebral ischemia induced a long‐term cardiac dysfunction with a reduction in left ventricular ejection fraction and an increase in left ventricular volumes; this development was associated with higher peripheral sympathetic activity. Metoprolol treatment prevented the development of chronic cardiac dysfunction by decelerating extracellular cardiac remodeling and inhibiting sympathetic signaling relevant to chronic autonomic dysfunction.InterpretationFocal cerebral ischemia in mice leads to the development of chronic systolic dysfunction driven by increased sympathetic activity. If these results can be confirmed in a clinical setting, treating physicians should be attentive to clinical signs of heart failure in every patient after ischemic stroke. Therapeutically, the successful β‐blockade with metoprolol in mice could also have future clinical implications. Ann Neurol 2017;82:729–743

Abstract-The role of the neuronal NO synthase (nNOS or NOS1) enzyme in the control of cardiac function still remains unclear. Results from nNOS Ϫ/Ϫ mice or from pharmacological inhibition of nNOS are contradictory and do not pay tribute to the fact that probably spatial confinement of the nNOS enzyme is of major importance. We hypothesize that the close proximity of nNOS and certain effector molecules like L-type Ca 2ϩ -channels has an impact on myocardial contractility. To test this, we generated a new transgenic mouse model allowing conditional, myocardial specific nNOS overexpression. Western blot analysis of transgenic nNOS overexpression showed a 6-fold increase in nNOS protein expression compared with noninduced littermates (nϭ12; PϽ0.01). Measuring of total NOS activity by conversion of [3 H]-L-arginine to [ 3 H]-L-citrulline showed a 30% increase in nNOS overexpressing mice (nϭ18; PϽ0.05). After a 2 week induction, nNOS overexpression mice showed reduced myocardial contractility. In vivo examinations of the nNOS overexpressing mice revealed a 17Ϯ3% decrease of ϩdp/dt max compared with noninduced mice (PϽ0.05). Likewise, ejection fraction was reduced significantly (42% versus 65%; nϭ15; PϽ0.05). Interestingly, coimmunoprecipitation experiments indicated interaction of nNOS with SR Ca 2ϩ ATPase and additionally with L-type Ca 2ϩ -channels in nNOS overexpressing animals. Accordingly, in adult isolated cardiac myocytes, I Ca,L density was significantly decreased in the nNOS overexpressing cells. Intracellular Ca 2ϩ -transients and fractional shortening in cardiomyocytes were also clearly impaired in nNOS overexpressing mice versus noninduced littermates. In conclusion, conditional myocardial specific overexpression of nNOS in a transgenic animal model reduced myocardial contractility. We suggest that nNOS might suppress the function of L-type Ca 2ϩ -channels and in turn reduces Ca 2ϩ -transients which accounts for the negative inotropic effect. (Circ Res. 2007;100:e32-e44.) Key Words: nNOS Ⅲ contractility Ⅲ excitation Ⅲ contraction coupling Ⅲ conditional overexpression S everal studies have demonstrated neuronal NO synthase (nNOS) protein expression within cardiac myocytes. 1 Specifically, nNOS has been localized to the sarcolemma 2,3 and the sarcoplasmatic reticulum (SR), 4 where it has been shown to be in close proximity to the SR Ca 2ϩ -release channel (RyR2) 5 and the SR Ca 2ϩ ATPase. However, the impact of nNOS on myocardial contractility remains largely controversial. Results from nNOS Ϫ/Ϫ mice and from pharmacological inhibition of nNOS provided insights into the role of nNOS in the cardiovascular system. But these approaches suffer from complete nNOS blockade and did not take into account a possible translocation of nNOS to specific subcellular sites. Some authors have shown, that inhibition of nNOS activity, via gene disruption or by pharmacological inhibition, enhanced basal contractility. 7,8 In the latter study, the positive inotropic effects of nNOS inhibition or gene disruption were related to ...

Magnetic resonance imaging (MRI) has long been regarded a general contraindication in patients with cardiovascular implanted electronic devices such as cardiac pacemakers or cardioverter defibrillators (ICDs) due to the risk of severe complications and even deaths caused by interactions of the magnetic resonance (MR) surrounding and the electric devices. Over the last decade, a better understanding of the underlying mechanisms responsible for such potentially life-threatening complications as well as technical advances have allowed an increasing number of pacemaker and ICD patients to safely undergo MRI. This review lists the key findings from basic research and clinical trials over the last 20 years, and discusses the impact on current day clinical practice. With ‘MR-conditional’ devices being the new standard of care, MRI in pacemaker and ICD patients has been adopted to clinical routine today. However, specific precautions and specifications of these devices should be carefully followed if possible, to avoid patient risks which might appear with new MR technology and further increasing indications and patient numbers.