Assessment of patients with a suspected cardioembolic ischemic stroke. A national consensus statement.

OBJECTIVES: Several cardiovascular, structural, and functional abnormalities have been considered as potential causes of cardioembolic ischemic strokes. Beyond atrial fibrillation, other sources of embolism clearly exist and may warrant urgent action, but they are only a minor part of the many stroke mechanisms and strokes that seem to be of embolic origin remain without a determined source. The associations between stroke and findings like atrial fibrillation, valve calcification, or heart failure are confounded by co-existing risk factors for atherosclerosis and vascular disease. In addition, a patent foramen ovale which is a common abnormality in the general population is mostly an innocent bystander in patients with ischemic stroke. For these reasons, experts from the national Danish societies of cardiology, neurology, stroke, and neuroradiology sought to develop a consensus document to provide national recommendations on how to manage patients with a suspected cardioembolic stroke. Design: Comprehensive literature search and analyses were done by a panel of experts and presented at a consensus meeting. Evidence supporting each subject was vetted by open discussion and statements were adjusted thereafter. Results: The most common sources of embolic stroke were identified, and the statement provides advise on how neurologist can identify cases that need referral, and what is expected by the cardiologist. Conclusions: A primary neurological and neuroradiological assessment is mandatory and neurovascular specialists should manage the initiation of secondary prophylactic treatment. If a cardioembolic stroke is suspected, a dedicated cardiologist experienced in the management of cardioembolism should provide a tailored clinical and echocardiographic assessment.

Lymphatic drainage efficiency: a new parameter of lymphatic function.

Background Following convection from blood capillaries, plasma proteins are transported to loco-regional lymph nodes in two stages: first, uptake into peripheral lymphatics, and second, transport to nodes. Purpose To introduce a new parameter of lymphatic function that quantifies stage 2 - lymphatic drainage efficiency (LDE). Material and Methods Percentage injected activity (IIQ) in ilio-inguinal nodes 150 min following subcutaneous foot web-space injection of Tc-99 m-nanocolloid was measured in 102 patients undergoing lymphoscintigraphy using a method in which a standard is placed by image guidance over the nodes. Percentage activity leaving the injection depot by 150 min ( k) was measured in 60/102 patients. LDE (%) = 100 × (IIQ/ k). Abnormal lymphoscintigraphy was defined qualitatively as: (i) no activity in ilio-inguinal nodes at 45 min or negligible activity at 150 min (delay); (ii) lymph diversion through skin and/or deep system; and (iii) focal tracer accumulation suggesting cellulitis. Results Scintigraphy was bilaterally normal in 82 limbs, unilaterally normal in 40 limbs and abnormal in 82 limbs. IIQ correlated with k in bilaterally normal (r = 0.86; n = 52), unilaterally normal (r = 0.67; n = 27), and abnormal (r = 0.82; n = 41) limbs. IIQ, k, and LDE were significantly lower in unilaterally normal (9.3 ± 5.4%, 13.8 ± 7.1%, and 65 ± 30%) compared with bilaterally normal limbs (15.4 ± 8.4% [ P > 0.0001], 18.3 ± 8.9% [ P = 0.025], and 84 ± 30% [ P = 0.01]). LDE was lower in limbs displaying skin diversion and/or delay. Conclusion LDE is a new quantitative index that has potential value in clinical research but requires further clinical evaluation. Abnormal quantitative indices indicate that limbs unilaterally normal on lymphoscintigraphy are not functionally normal.

Quantitative [123]I-Ioflupane DaTSCAN single-photon computed tomography-computed tomography in Parkinsonism.

AIM: [123]I-Ioflupane (DaTSCAN) binds to the presynaptic dopamine transporter (DAT) and with a lower affinity to the serotonin transporter (SERT). We aimed to develop a novel method to quantify absolute uptake in the striatal (predominantly DAT binding) and extra-striatal regions (mainly SERT binding) using single-photon computed tomography-computed tomography (SPECT-CT) DaTSCAN and to improve DaTSCAN image quality. METHOD: Twenty-six patients with Parkinsonism underwent DaTSCAN SPECT-CT prospectively. The scans were visually analyzed independently by two experienced reporters. Specific binding ratios (SBRs) from Chang attenuation corrected SPECT were obtained using GE DaTQuant. Normalized concentrations and specific uptakes (NSU) from measured attenuation and modelled scatter-corrected SPECT-CT were obtained using HERMES Hybrid Recon and Affinity and modified EARL volumes of interest. RESULTS: Striatal NSU and SBR positively correlate ( R  = 0.65-0.88, P  = 0.00). SBR, normalized concentrations, and NSU box plots differentiated between scans without evidence of dopaminergic deficit and abnormal scans. Interestingly, body weight inversely correlated with normalized concentrations values in extra-striatal regions [frontal ( R  = 0.81, P  = 0.00); thalamus ( R  = 0.58, P  = 0.00); occipital ( R  = 0.69, P  = 0.00)] and both caudate nuclei [ R  = 0.42, P  = 0.03 (Right), R  = 0.52, P  = 0.01 (Left)]. Both reporters noted improved visual quality of SPECT-CT versus SPECT images for all scans. CONCLUSION: DaTSCAN SPECT-CT resulted in more accurate quantification, improved image quality, and enabled absolute quantification of extra-striatal regions. More extensive studies are required to establish the full value of absolute quantification for diagnosis and monitoring the progression of neurodegenerative disease, to assess an interplay between DAT and SERT, and to verify whether serotonin and DATs are potentially dysfunctional in obesity.

Association between body mass index (BMI) and [123I]Ioflupane (DaTSCAN) availabilities in patients with parkinsonism using single-photon emission computed tomography-computed tomography (SPECT-CT).

AIM: [123I]Ioflupane (DaTSCAN) has a high binding affinity to the dopamine (DA) transporter (DaT) and tenfold less affinity to serotonin (5-HT) transporter (SERT). Both neurotransmitters are considered to contribute to body weight regulation. This study assesses the association between body mass index (BMI) and DaTSCAN availability in brain. METHOD: Scans from 74 consecutive patients who had undergone DaTSCAN single-photon emission computed tomography-computed tomography (SPECT-CT) were used to obtain semi- and absolute quantitative data in several volumes of interest (VOIs). Relative semi-quantitative specific binding ratios (SBRs) from Chang attenuated SPECT were obtained from GE DaTQUANT. Absolute normalised concentration (NC) was calculated from attenuation/scatter corrected SPECT-CT images, using an adapted version of the EARL Ltd (European Association of Nuclear Medicine (EANM) Research 4 Life) template. Scans were subdivided into either degenerative parkinsonism (abnormal = 49), borderline (n = 14) or scan without evidence of dopaminergic deficit (SWEDD = 11) using visual assessment and SBR values by two nuclear medicine consultants. RESULTS: SBRs did not correlate with BMI. However, NC values correlated negatively in the entire cohort, with the strongest correlation in the frontal (r = - 0.649. p = 0.000), occipital (r = - 0.555, p = 0.000) regions and pons (r = - 0.555, p = 0.000). In the abnormal (n = 49) and SWEDD group (n = 11), NC of the frontal region was the most correlated with BMI (r = - 0.570, p = 0.000; r = - 0.813, p = 0.002, respectively). In the borderline group (n = 14), the left posterior putamen displayed the strongest correlation (r = - 0.765, p = 0.001). CONCLUSION: Absolute NC values demonstrate a strong inverse correlation with BMI, strongest in the extrastriatal regions. Due to the predominately non-overlapping distribution of DaT and SERT, this study suggests greater involvement of SERT in obesity with possible interplay with DA transmission.

Left atrial late gadolinium enhancement in patients with ischaemic stroke.

AIMS: To evaluate the extent of left atrial (LA) fibrosis in patients with a recent stroke without atrial fibrillation and controls without established cardiovascular disease. METHODS AND RESULTS: This prospectively designed study used cardiac magnetic resonance to detect LA late gadolinium enhancement as a proxy for LA fibrosis. Between 2019 and 2021, we consecutively included 100 patients free of atrial fibrillation with recent ischaemic stroke (<30 days) and 50 age- and sex-matched controls. LA fibrosis assessment was achieved in 78 patients and 45 controls. Blinded to the cardiac magnetic resonance results, strokes were adjudicated according to modified Trial of Org 10172 in Acute Stroke Treatment classification as undetermined aetiology (n = 42) or as attributable to large- or small-vessel disease (n = 36). Patients with stroke had a larger extent of LA fibrosis [6.9%, interquartile range (IQR) 3.6-15.4%] than matched controls (4.2%, IQR 2.3-7.5%; P = 0.007). No differences in LA fibrosis were observed between patients with stroke of undetermined aetiology and those with large- or small-vessel disease (6.6%, IQR 3.8-16.0% vs. 6.9%, IQR 3.4-14.6%; P = 0.73). CONCLUSION: LA fibrosis was more extensive in patients with stroke than in age- and sex-matched controls. A similar extent of LA fibrosis was observed in patients with stroke of undetermined aetiology and stroke classified as attributable to large- or small-vessel disease. Our findings suggest that LA structural abnormality is more frequent in patients with stroke than in controls independent of aetiological classification.

Functionally selective AT(1) receptor activation reduces ischemia reperfusion injury.

Angiotensin II (AngII) is a key peptide in cardiovascular homeostasis and is a ligand for the Angiotensin II type 1 and 2 seven transmembrane receptors (AT(1)R and AT(2)R). The AT(1) receptor is a seven-transmembrane (7TM) G protein-coupled receptor (GPCR) mediating the majority of the physiological functions of AngII. The AT(1)R mediates its effects through both G protein-dependent and independent signaling, which can be separated by functionally selective agonists. In the present study we investigate the effect of AngII and the ß-arrestin biased agonist [SII]AngII on ischemia-reperfusion injury in rat hearts. Isolated hearts mounted in a Langendorff perfused rat heart preparations showed that preconditioning with [SII]AngII reduced the infarct size induced by global ischemia from 46±8.4% to 22±3.4%. In contrast, neither preconditioning with AngII nor postconditioning with AngII or [SII]AngII had a protective effect. Together these results demonstrate a cardioprotective effect of simultaneous blockade of G protein signaling and activation of G protein independent signaling through AT(1) receptors.

Left Atrial Volumes and Function, and Long-Term Incidence of Ischemic Stroke in the General Population.

Background Left atrial (LA) volumes and emptying fraction in the general population may address structural and functional aspects of atrial cardiomyopathy associated with long-term risk of ischemic stroke in the absence of atrial fibrillation or prior stroke. We investigated the association between LA volumes and function and ischemic stroke. Methods and Results In a community-based cohort, we measured LA minimal volume, LA maximal volume, and LA emptying fraction by transthoracic echocardiography. The primary end point was ischemic stroke. Participants with known atrial fibrillation or prior ischemic stroke were excluded, which resulted in 1866 participants. The mean age was 58±16 years, and 57% were women. During a median follow-up of 16.5 years (interquartile range: 11.4-16.8 years), 176 (9.4%) ischemic strokes occurred. In multivariable cause-specific regression models and competing risk models with death as a competing risk, LA emptying fraction was associated with ischemic stroke (hazard ratio [HR], 1.14 per 10% decrease [95% CI, 1.02-1.28]) and (subdistribution HR, 1.14 [95% CI, 1.01-1.29]). This association remained when adjusting for participants who developed atrial fibrillation during follow-up (HR, 1.12 per 10% decrease [95% CI, 1.00-1.26]). Indexed LA volumes were not associated with ischemic stroke in the same models. LA emptying fraction and indexed LA volumes were not associated with all-cause mortality. Conclusions Lower LA emptying fraction measured by transthoracic echocardiography was associated with future ischemic stroke independently of incident atrial fibrillation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993172.

Atrial cardiomyopathy in patients with ischaemic stroke: a cross-sectional and prospective cohort study-the COAST study.

INTRODUCTION: Despite workup for the aetiology of ischaemic stroke, about 25% of cases remain unexplained. Paroxysmal atrial fibrillation is typically suspected but often not detected. Even if atrial fibrillation (AF) is detected, the quantitative threshold of clinically relevant AF remains unclear. Emerging evidence suggests that left atrial (LA) functional and structural abnormalities may convey a risk of ischaemic stroke in which AF is only one of several features. These abnormalities have been termed 'atrial cardiomyopathy'. This study uses cardiac magnetic resonance (CMR) to evaluate atrial cardiomyopathy among patients with stroke of undetermined aetiology compared with those with an attributable mechanism and controls without established cardiovascular disease. METHODS AND ANALYSIS: This cross-sectional and prospective cohort study included 100 patients with recent ischaemic stroke and 50 controls with no established cardiovascular disease. The study will assess LA structural and functional abnormalities with CMR. Inclusion began in March 2019, and follow-up is planned to be complete in January 2023. There are two scheduled follow-ups: (1) 18 months after individual inclusion, counting from the index diagnostic MRI of the brain, (2) end of study follow-up at 18 months after inclusion of the last patient, assessing the incidence of recurrent ischaemic stroke, AF and cardiovascular death. The primary endpoint is the extent of CMR-assessed atrial fibrosis in the LA at baseline. The study is powered to detect a difference of 6% fibrosis between stroke of undetermined aetiology and stroke of known mechanism with a SD of 9%, a significance level of 0.05, and power of 80%. ETHICS AND DISSEMINATION: This study has been approved by the Danish National Committee on Health Research Ethics (H-18055313). All participants in the study signed informed consent. Results from the study will be published in peer-reviewed journals regardless of the outcome. TRIAL REGISTRATION NUMBER: NCT03830983.

Excessive supraventricular ectopic activity and risk of incident atrial fibrillation in a consecutive population referred to ambulatory cardiac monitoring.

BACKGROUND: Excessive supraventricular ectopic activity (ESVEA), defined as ≥720 premature atrial contractions (PAC) per day or any runs of ≥20 PACs, has been proposed as a surrogate marker for paroxysmal atrial fibrillation (PAF). OBJECTIVE: We aimed to estimate the prognostic impact of ESVEA on the future development of PAF in consecutive patients referred to ambulatory cardiac monitoring. METHODS: The cohort consists of a population with comorbidities referred to 48-hour ambulatory electrocardiogram aged 30-98 (n = 1316) between 2009 and 2011. After exclusion of known or current atrial fibrillation (AF) (n = 527) and patients with pacemakers (n = 7), 782 patients were included, with a median follow-up of 8.1 years. Events of incident AF and death were retrieved from patient records. RESULTS: Mean age was 58.6 ± 15.5 years and 56.5% were women. A total of 101 patients had ESVEA at baseline (12.9%). During follow-up, 69 (8.9%) developed incidental AF. Twenty-three patients with ESVEA developed AF (23%). Incidence rate of AF in patients with and without ESVEA was 37.1/1000 person-years and 9.1 per 1000 person-years, respectively (P < .001). ESVEA was associated with incident AF after adjustment for potential confounders in Cox regression analysis (hazard ratio [HR]: 2.39; 95% confidence interval [CI]: 1.40-4.09) and in competing risk analysis with death as competing risk (subdistribution HR: 2.35; 95% CI: 1.30-4.17). CONCLUSION: ESVEA increases the risk of incident AF substantially in a population referred to ambulatory cardiac monitoring.

Molecular determinants of angiotensin II type 1 receptor functional selectivity.

The angiotensin AT(1) receptor is an important pharmacological target in the treatment of cardiovascular disorders, such as hypertension, diabetic nephropathy, cardiac hypertrophy, arrhythmia and failure. Simultaneously, the AT(1) receptor has emerged to be a prominent model for the emerging concept that receptors may attain multiple active states with differentiated functional outcomes. Two major signalling pathways are employed by the AT(1) receptor, namely 1) the canonical G(q) protein-dependent activation of inositol phosphate turnover and intracellular calcium release, and 2) G protein-independent recruitment of beta-arrestin-scaffolded signalling complexes that activate protein kinase pathways. Different states of receptor activation with preference for individual downstream pathways (functional selectivity) have been demonstrated in mutational studies of the AT(1) receptor and by pharmacological probing with analogues of angiotensin II. These studies also provide clues about the conformational changes that underlie different functional outcomes. In this review, we evaluate current knowledge of the molecular determinants of AT(1) receptor activation, which may distinguish G protein-dependent and -independent behaviour. While G protein activation is known to be detrimental, G protein-independent signalling by the AT(1) receptor has been associated with phenotypes such as cell survival and renewal, regulation of cardiac contraction and cell migration. It is therefore currently hypothesized that selective blockade of G protein actions and simultaneous activation of G protein-independent signalling will prove to be a feasible strategy for improved cardiovascular therapy. The pharmacological perspectives of functional selectivity by receptors, such as the AT(1) receptor, urge the elucidation of molecular mechanisms that govern disparate signalling events.

Relationship between regional hepatic glucose metabolism and regional distribution of hepatic fat.

AIM: Hepatic steatosis is associated with insulin resistance and hyperinsulinaemia. Insulin stimulates hepatic glucokinase, even in insulin resistance, so hepatic glucose uptake is increased in hepatic steatosis. The study hypothesis was that hepatic glucose uptake is also influenced locally by fat, the hepatic distribution of which is heterogeneous. PATIENTS AND METHODS: Sixty patients undergoing PET/CT using fluorine-18-fluorodeoxyglucose (F-FDG) had dynamic imaging of the liver for 30 min after injection before undergoing whole-body PET/CT at 60 min after injection. Hepatic F-FDG uptake was measured using Gjedde-Patlak-Rutland graphical analysis. Plot gradient (Ki), which represents hepatic blood clearance of F-FDG to phosphorylation, was normalized to intercept [V(0)], which represents the hepatic F-FDG distribution volume. The 60 min computed tomography (CT) was co-registered on to each of the 30 dynamic PET frames. This failed in 20 patients. A further seven patients with lymphoma and three with hepatic metastases were excluded. Within transaxial sections, the liver was divided into small regions of interest (ROIs) of 5×5 pixels each in sections of 5 mm (range: 118-586 ROIs/liver). CT density and Ki/V(0) were measured in each ROI. RESULTS: Throughout the 25-pixel ROIs in the individual liver, CT density and Ki/V(0) showed a significant negative correlation in 15/30 patients. It was significantly positive in only three (P=0.01). In some patients, parametric imaging showed regional concordance between Ki/V(0) and hepatic fat, identified as reduced CT density. CONCLUSION: In addition to systemic influences, hepatic glucose uptake is regionally linked to the distribution of hepatic fat. Increased metabolism could be the cause or result of local fat deposition.

The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation.

The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.

S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes.

OBJECTIVE: The multifunctional Ca2+-binding protein S100A4 (also known as Mts1 and Fsp1) is involved in fibrosis and tissue remodeling in several diseases including cancer, kidney fibrosis, central nervous system injury, and pulmonary vascular disease. We previously reported that S100A4 mRNA expression was increased in hypertrophic rat hearts and that it has pro-cardiomyogenic effects in embryonic stem cell-derived embryoid bodies. We therefore hypothesized that S100A4 could play a supportive role in the injured heart. METHODS AND RESULTS: Here we verify by quantitative real-time PCR and immunoblotting that S100A4 mRNA and protein is upregulated in hypertrophic rat and human hearts and show by way of confocal microscopy that S100A4 protein, but not mRNA, appears in cardiac myocytes only in the border zone after an acute ischemic event in rat and human hearts. In normal rat and human hearts, S100A4 expression primarily colocalizes with markers of fibroblasts. In hypertrophy elicited by aortic banding/stenosis or myocardial infarction, this expression is increased. Moreover, invading macrophages and leucocytes stain strongly for S100A4, further increasing cardiac levels of S100A4 protein after injury. Promisingly, recombinant S100A4 protein elicited a robust hypertrophic response and increased the number of viable cells in cardiac myocyte cultures by inhibiting apoptosis. We also found that ERK1/2 activation was necessary for both the hypertrophy and survival effects of S100A4 in vitro. CONCLUSIONS: Along with proposed angiogenic and cell motility stimulating effects of S100A4, these findings suggest that S100A4 can act as a novel cardiac growth and survival factor and may have regenerative effects in injured myocardium.

The angiotensin type 1 receptor activates extracellular signal-regulated kinases 1 and 2 by G protein-dependent and -independent pathways in cardiac myocytes and langendorff-perfused hearts.

The angiotensin II (AngII) type 1 receptor (AT(1)R) has been shown to activate extracellular signal-regulated kinases 1 and 2 (ERK1/2) through G proteins or G protein-independently through beta-arrestin2 in cellular expression systems. As activation mechanisms may greatly influence the biological effects of ERK1/2 activity, differential activation of the AT(1)R in its native cellular context could have important biological and pharmacological implications. To examine if AT(1)R activates ERK1/2 by G protein-independent mechanisms in the heart, we used the [Sar(1), Ile(4), Ile(8)]-AngII ([SII] AngII) analogue in native preparations of cardiac myocytes and beating hearts. We found that [SII] AngII does not activate G(q)-coupling, yet stimulates the beta-arrestin2-dependent ERK1/2. The G(q)-activated pool of ERK1/2 rapidly translocates to the nucleus, while the beta-arrestin2-scaffolded pool remains in the cytosol. Similar biased agonism was achieved in Langendorff-perfused hearts, where both agonists elicit ERK1/2 phosphorylation, but [SII] AngII induces neither inotropic nor chronotropic effects.

Differential extracellular signal-regulated kinases 1 and 2 activation by the angiotensin type 1 receptor supports distinct phenotypes of cardiac myocytes.

The angiotensin II (AngII) type 1 receptor (AT(1)R) is a seven-transmembrane receptor well established to activate extracellular signal-regulated kinases 1 and 2 (ERK1/2) by discrete G protein-dependent and beta-arrestin2-dependent pathways. The biological importance of this, however, remains obscure. Application of the modified analogue [Sar(1), Ile(4), Ile(8)]-AngII ([SII] AngII) allowed us to dissect the two pathways of ERK1/2 activation in native cardiac myocytes. Although cytosol-retained, the beta-arrestin2-bound pool of ERK1/2 represents an active signalling component that phosphorylates p90 Ribosomal S6 Kinase, a ubiquitous and versatile mediator of ERK1/2 signal transduction. Moreover, the beta-arrestin2-dependent ERK1/2 signal supports intact proliferation of cardiac myocytes. In contrast to G(q)-activated ERK1/2, and in keeping with its failure to translocate to the nucleus, the beta-arrestin2-scaffolded pool of ERK1/2 does not phosphorylate the transcription factor Elk-1, induces no increased transcription of the immediate-early gene c-Fos, and does not entail myocyte hypertrophy. These results clearly demonstrate the biological significance of differential signalling by the AT(1)R. The opportunity to separate desirable cardiac myocyte division from detrimental hypertrophy holds promise that novel pharmacological approaches will allow targeting of pathway-specific actions.

Role of G-protein-coupled receptor kinase 2 in the heart--do regulatory mechanisms open novel therapeutic perspectives?

G-protein-coupled receptor kinase (GRK) 2 regulates a plethora of cellular processes, including cardiac expression and function of key seven-transmembrane receptors (7TM receptors) such as the beta-adrenergic and angiotensin receptors (Penela P, Murga C, Ribas C, et al.: 2006. Mechanisms of regulation of G-protein-coupled receptor kinases [GRKs] and cardiovascular disease. Cardiovasc Res 69:46-56, Rockman HA, Koch WJ, Lefkowitz RJ: 2002. Seven-transmembrane-spanning receptors and heart function. Nature 415:206-212). Interestingly, these two G-protein-coupled receptor systems are targeted by modern heart failure treatment including beta-adrenergic blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Although GRK2 is ubiquitously expressed, its particular importance in the heart has been demonstrated by interesting phenotypes of genetically altered mice that suggest GRK2 inhibition can ameliorate heart failure. In essence, this work suggests GRK2 could be an endogenous receptor blocker targeting both the beta-adrenergic and angiotensin receptors in the heart. This notion immediately suggests it is important to understand the molecular mechanisms that regulate GRK2 activity in the heart. In this review, we provide a detailed presentation of the tight regulation of GRK2 expression levels and protein activity, and we discuss the cardiovascular GRK2 functions and possible therapeutic perspectives.

Importance of accurate ilio-inguinal quantification in lower extremity lymphoscintigraphy.

AIMS: The aims of this study were to improve the quantification of lower extremity lymphoscintigraphy, determine its value and lower limit of normal, and determine whether intermediate postinjection time imaging is necessary. PATIENTS AND METHODS: This was a study of 102 consecutive patients undergoing routine lower extremity lymphoscintigraphy using subcutaneous Tc-99m-nanocolloid with imaging at 5, 45 and 150 min after injection. Abnormal imaging criteria were delay (no activity in ilio-inguinal nodes at 45 min or negligible activity at 150 min), lymph diversion (through skin or deep system) and focal accumulation suggesting cellulitis. Lymphatic function was quantified as % injected activity in ilio-inguinal nodes at 150 min (IIQ) using a standard placed, by image guidance, exactly over the nodes. RESULTS: Forty-one patients had bilateral normal scintigraphy. IIQ was normally distributed in 15 limbs, with IIQ of 1-7.5%. In contrast, it was log-normally distributed in 68 limbs, with IIQ of at least 7.5%, suggesting 8% as the lower limit of normal. In 57 limbs, delay was the only scintigraphic abnormality at 45 min. Of these, 33 were abnormal at 150 min. Of the remaining 24 limbs, 17 had reduced IIQ; thus, 50 of these 57 (88%) limbs had lymphatic dysfunction. The seven limbs that remained normal at 150 min were in six patients. The contralateral limb was abnormal in five of these six patients; hence, lymphatic dysfunction would have been missed in only one patient without 45 min imaging. CONCLUSION: IIQ is strongly recommended. Isolated delay at 45 min is abnormal. However, 45 min imaging is not necessary if IIQ is performed.

Cardiac remodelling and function with primary mitral valve insufficiency studied by magnetic resonance imaging.

AIMS: Evaluation of patients with primary mitral valve insufficiency (MI) is best supported by quantitative measures. Cardiovascular magnetic resonance imaging (CMR) offers flow and cardiac chamber volume quantification. We studied cardiac remodelling with CMR to determine MI regurgitation volumes (MIVol) related to severe MI. METHODS AND RESULTS: In total, 24, 20, and 28 patients determined to have mild, moderate, and severe primary MI, respectively, were studied. Combining cine stacks with phase-contrast velocity mapping across the ascending aorta, CMR-determined MIVol was reproducibly obtained as the difference between left ventricular (LV) stroke volume and aortic forward flow (Aoflow). With increasing MI severity, MIVol, left heart volumes, and pulmonary venous diameters increased (P < 0.01). Severe MI with LV end-systolic diameter of 40 mm was signified by MIVol >40 mL, MI regurgitant fraction >0.30, LV end-diastolic volume (LVEDV(i)) >108 mL m(-2), and a total left heart volume >188 mL m(-2) with dilated pulmonary veins and a LVEDV/right ventricular EDV ratio >1.2. In severe MI, LV ejection fraction was unaffected, but the Aoflow and the peak ejection rate indexed to LVEDV were lowered (P < 0.05). In surgical patients, the MIVol correlated to the decrease in LV dimension after valve surgery (P < 0.02). CONCLUSION: CMR provides a reproducible quantitative technique for evaluation of MI, as MIVol and cardiac chamber volumes can be held against diagnostic cut-off values. The Aoflow and peak ejection rate indexed to LVEDV may reveal early LV systolic dysfunction in patients with severe MI. Severe MI is related to lower MI regurgitation volume and fraction than previously believed.