Identifying the optimal regional predictor of right ventricular global function: a high-resolution three-dimensional cardiac magnetic resonance study.

Right ventricular (RV) function has prognostic value in acute, chronic and peri-operative disease, although the complex RV contractile pattern makes rapid assessment difficult. Several two-dimensional (2D) regional measures estimate RV function, however the optimal measure is not known. High-resolution three-dimensional (3D) cardiac magnetic resonance cine imaging was acquired in 300 healthy volunteers and a computational model of RV motion created. Points where regional function was significantly associated with global function were identified and a 2D, optimised single-point marker (SPM-O) of global function developed. This marker was prospectively compared with tricuspid annular plane systolic excursion (TAPSE), septum-freewall displacement (SFD) and their fractional change (TAPSE-F, SFD-F) in a test cohort of 300 patients in the prediction of RV ejection fraction. RV ejection fraction was significantly associated with systolic function in a contiguous 7.3 cm2 patch of the basal RV freewall combining transverse (38%), longitudinal (35%) and circumferential (27%) contraction and coinciding with the four-chamber view. In the test cohort, all single-point surrogates correlated with RV ejection fraction (p < 0.010), but correlation (R) was higher for SPM-O (R = 0.44, p < 0.001) than TAPSE (R = 0.24, p < 0.001) and SFD (R = 0.22, p < 0.001), and non-significantly higher than TAPSE-F (R = 0.40, p < 0.001) and SFD-F (R = 0.43, p < 0.001). SPM-O explained more of the observed variance in RV ejection fraction (19%) and predicted it more accurately than any other 2D marker (median error 2.8 ml vs 3.6 ml, p < 0.001). We conclude that systolic motion of the basal RV freewall predicts global function more accurately than other 2D estimators. However, no markers summarise 3D contractile patterns, limiting their predictive accuracy.

Acute myocardial infarction: susceptibility-weighted cardiac MRI for the detection of reperfusion haemorrhage at 1.5 T.

AIM: To assess whether susceptibility-weighted imaging (SWI) provides better image contrast for the detection of haemorrhagic ischaemia-reperfusion injury in the heart. MATERIALS AND METHODS: Thirty patients (all men; mean age 53 years) underwent cardiac magnetic resonance imaging (MRI) within 7 days of primary percutaneous intervention for acute ST elevation myocardial infarction (STEMI). Multiple gradient-echo T2* sequences with magnitude and phase reconstructions were acquired. A high-pass filtered phase map was used to create a mask for the SWI reconstructions. The difference in image contrast was assessed in those patients with microvascular obstruction. A mixed effects regression model was used to test the effect of echo time and reconstruction method on phase and contrast-to-noise ratio (CNR). Medians and interquartile ranges (IQR) are reported. RESULTS: T2* in haemorrhagic infarcts was shorter than in non-haemorrhagic infarcts (33.5 ms [24.9-43] versus 49.9 ms [44.6-67.6]; p=0.0007). The effect of echo time on phase was significant (p<0.0001), as was the effect of haemorrhage on phase (p=0.0016). SWI reconstruction had a significant effect on the CNR at all echo times (echoes 1-5, p<0.0001; echo 6, p=0.01; echo 7, p=0.02). The median echo number at which haemorrhage was first visible was less for SWI compared to source images (echo 2 versus echo 5, p=0.0002). CONCLUSION: Cardiac SWI improves the contrast between myocardial haemorrhage and the surrounding tissue following STEMI and has potential as a new tool for identifying patients with ischaemia-reperfusion injury.

LINC01013 Is a Determinant of Fibroblast Activation and Encodes a Novel Fibroblast-Activating Micropeptide.

Myocardial fibrosis confers an almost threefold mortality risk in heart disease. There are no prognostic therapies and novel therapeutic targets are needed. Many thousands of unannotated small open reading frames (smORFs) have been identified across the genome with potential to produce micropeptides (< 100 amino acids). We sought to investigate the role of smORFs in myocardial fibroblast activation.Analysis of human cardiac atrial fibroblasts (HCFs) stimulated with profibrotic TGFß1 using RNA sequencing (RNA-Seq) and ribosome profiling (Ribo-Seq) identified long intergenic non-coding RNA LINC01013 as TGFß1 responsive and containing an actively translated smORF. Knockdown of LINC01013 using siRNA reduced expression of profibrotic markers at baseline and blunted their response to TGFß1. In contrast, overexpression of a codon-optimised smORF invoked a profibrotic response comparable to that seen with TGFß1 treatment, whilst FLAG-tagged peptide associated with the mitochondria.Together, these data support a novel LINC01013 smORF micropeptide-mediated mechanism of fibroblast activation. TGFß1 stimulation of atrial fibroblasts induces expression of LINC01013, whose knockdown reduces fibroblast activation. Overexpression of a smORF contained within LINC01013 localises to mitochondria and activates fibroblasts.

Two novel alleles of tottering with distinct Ca(v)2.1 calcium channel neuropathologies.

The calcium channel CACNA1A gene encodes the pore-forming, voltage-sensitive subunit of the voltage-dependent calcium Ca(v)2.1 type channel. Mutations in this gene have been linked to several human disorders, including familial hemiplegic migraine, episodic ataxia 2 and spinocerebellar ataxia type 6. The mouse homologue, Cacna1a, is associated with the tottering, Cacna1a(tg), mutant series. Here we describe two new missense mutant alleles, Cacna1a(tg-4J) and Cacna1a(Tg-5J). The Cacna1a(tg-4J) mutation is a valine to alanine mutation at amino acid 581, in segment S5 of domain II. The recessive Cacna1a(tg-4J) mutant exhibited the ataxia, paroxysmal dyskinesia and absence seizures reminiscent of the original tottering mouse. The Cacna1a(tg-4J) mutant also showed altered activation and inactivation kinetics of the Ca(v)2.1 channel, not previously reported for other tottering alleles. The semi-dominant Cacna1a(Tg-5J) mutation changed a conserved arginine residue to glutamine at amino acid 1252 within segment S4 of domain III. The heterozygous mouse was ataxic and homozygotes rarely survived. The Cacna1a(Tg-5J) mutation caused a shift in both voltage activation and inactivation to lower voltages, showing that this arginine residue is critical for sensing Ca(v)2.1 voltage changes. These two tottering mouse models illustrate how novel allelic variants can contribute to functional studies of the Ca(v)2.1 calcium channel.

Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential.

Cardiac myocyte apoptosis is potentially important in many cardiac disorders. In other cells, Bcl-2 family proteins and mitochondrial dysfunction are probably key regulators of the apoptotic response. In the present study, we characterized the regulation of antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bad, Bax) Bcl-2 family proteins in the rat heart during development and in oxidative stress-induced apoptosis. Bcl-2 and Bcl-xL were expressed at high levels in the neonate, and their expression was sustained during development. In contrast, although Bad and Bax were present at high levels in neonatal hearts, they were barely detectable in adult hearts. We confirmed that H(2)O(2) induced cardiac myocyte cell death, stimulating poly(ADP-ribose) polymerase proteolysis (from 2 hours), caspase-3 proteolysis (from 2 hours), and DNA fragmentation (from 8 hours). In unstimulated neonatal cardiac myocytes, Bcl-2 and Bcl-xL were associated with the mitochondria, but Bad and Bax were predominantly present in a crude cytosolic fraction. Exposure of myocytes to H(2)O(2) stimulated rapid translocation of Bad (<5 minutes) to the mitochondria. This was followed by the subsequent degradation of Bad and Bcl-2 (from approximately 30 minutes). The levels of the mitochondrial membrane marker cytochrome oxidase remained unchanged. H(2)O(2) also induced translocation of cytochrome c from the mitochondria to the cytosol within 15 to 30 minutes, which was indicative of mitochondrial dysfunction. Myocytes exposed to H(2)O(2) showed an early loss of mitochondrial membrane potential (assessed by fluorescence-activated cell sorter analysis) from 15 to 30 minutes, which was partially restored by approximately 1 hour. However, a subsequent irreversible loss of mitochondrial membrane potential occurred that correlated with cell death. These data suggest that the regulation of Bcl-2 and mitochondrial function are important factors in oxidative stress-induced cardiac myocyte apoptosis.

Influence of left ventricular mass on the diagnostic accuracy of myocardial perfusion imaging using positron emission tomography with dipyridamole stress.

This study assesses the influence of left ventricular hypertrophy (LVH) on the accuracy of myocardial perfusion imaging using pharmacologic coronary vasodilation. Seventy-five patients without previous infarction, and with known coronary anatomy, were studied by echocardiography and PET. LVH (defined by mass greater than 131 g/m2 in males or greater than 100 g/m2 in females) was identified in 25 patients; this group did not differ significantly from the remainder in terms of clinical or angiographic parameters. Twenty patients with hypertrophy had significant coronary artery stenoses, which were identified correctly by PET in 11 (55%), in contrast to 29 of 34 patients (85%, p = 0.03) with coronary disease but normal LV mass. Normal perfusion images were obtained in three of five patients (60%) with hypertrophy but no coronary disease; in contrast, 14 of 16 patients without either coronary disease or hypertrophy (88%, p = ns) had normal scans. The accuracy of PET was 14/25 (56%) in those with hypertrophy, and 43/50 (86%, p = 0.01) in patients with normal LV mass. In this group, the presence of hypertrophy was associated with reduction in the diagnostic accuracy of PET using dipyridamole stress. These findings may account for the phenomenon of "dipyridamole nonresponsiveness" in some patients.

Thallium-20 1 myocardial imaging in young adults with anomalous left coronary artery arising from the pulmonary artery.

Anomalous origin of the left coronary artery from the pulmonary artery (Bland-Garland-White syndrome) may produce myocardial ischemia, infarction, and frequently death in infancy. Some patients, however, develop satisfactory coronary artery collaterals and are relatively asymptomatic into adulthood. Very little is known about their myocardial perfusion patterns. We studied three young adults with this condition using stress thallium-20 1 myocardial imaging. Electrocardiograms in two patients demonstrated old anterolateral myocardial infarctions. Preoperative stress exercise tests were positive in all three patients. Marked perfusion abnormalities were found in the proximal anterolateral wall in all patients, and one patient also had a posterolateral defect. Postoperatively, all stress tests returned to normal. Thallium imaging demonstrated improvement in ischemic areas, but old scars persisted.

Automated computer program for radionuclide cardiac output determination.

Radionuclides have provided a safe, reliable, and minimally invasive method for repeated determinations of cardiac output. A completely automated computer program for data analysis is described. Cardiac output values obtained by this technique correlated closely with values obtained by manual determination of the region of interest (r = 0.90 for right-ventricular and 0.98 for left-ventricular outputs, p less than 0.001 for both). Further, cardiac output determined by computer selection of either left-ventricular area of interest or of the "whole heart region" correlated significantly with that simultaneously determined by dye-dilution technique (indocyanine green; r = 0.86, p less than 0.001 for both). The automated approach allows greater objectivity in the selection of the regions of interest, faster turnaround of calculated results, and use of a smaller dose of radionuclide.

Recirculation subtraction for analysis of left-to-right-cardiac shunts: concise communication.

The object of this study is to improve the techniques for describing the lung dilution curve for shunt quantification by separating the effects of systemic recirculation on the curve form those of direct shunt return. The time of the systemic recirculation peak was estimated by determination of transit times from the right and left ventricles and lung. A gamma variate fit based on the distribution of points at that segment was applied to the recirculation curve and subtracted from the original lung dilution curve. Similar gamma variate fitting was performed for both primary and shunt curves. Rather than fitting the gamma variate of the shunt curve by the leading edge only, a larger portion could now be used since the trailing edge of the curve is clearer following recirculation subtraction. The algorithm is completely automatic, requiring no operator intervention or selection of curve-fitting regions. The correlation coefficient for comparison of the dilution-curve analysis with oximetry determinations was 0.92 in a series of 29 patients.

Clinical outcome of cardiac patients with negative thallium-201 SPECT and positive rubidium-82 PET myocardial perfusion imaging.

In a previous comparison of 202 consecutive patients who underwent myocardial perfusion imaging with both 201Tl SPECT and 82Rb PET, 27 patients were identified as having true-positive 82Rb images, but false-negative 201Tl images. The purpose of this report is to determine the effect of correct image interpretation of coronary artery disease on the final management of those patients and compare it to the previous management scheme wherein a negative image was usually accepted as the end point unless clinical symptoms dictated otherwise. A follow-up study of the clinical course and outcome of these studies showed that 63% (17/27) of the patients with a true-positive 82Rb PET image were recommended for revascularization procedures. It is doubtful that this majority of patients would have received either surgical or interventional management based on the false-negative 201Tl SPECT procedure alone.

Myocardial viability studies using fluorine-18-FDG SPECT: a comparison with fluorine-18-FDG PET.

UNLABELLED: Multidetector SPECT systems equipped with a high-energy, or 511-keV collimator, have been proposed to offer a less expensive alternative to PET in myocardial viability studies with [18F]FDG. The objectives of this investigation included: (a) measuring the physical imaging characteristics of SPECT systems equipped with either a high-energy general-purpose collimator (HE), or the dedicated 511-keV collimator (UH), when imaging 511-keV photons, and comparing them with conventional FDG PET; and (b) directly and quantitatively comparing the diagnostic accuracy of SPECT, with either an UH or HE collimator, to that of PET in myocardial viability studies using 18F-FDG. METHODS: Physical imaging characteristics of SPECT and PET were measured and compared. Both SPECT and PET studies were performed in two groups of 18 patients each, with Group I using HE SPECT and Group II using UH SPECT. Myocardial perfusion studies were also performed using 82Rb PET at rest and during dipyridamole stress to identify areas of persistent hypoperfusion. For each myocardial region with a persistent perfusion defect, a perfusion-metabolism match or mismatch pattern was established independently, based on the results of 18F-FDG SPECT as well as PET. RESULTS: PET is superior to SPECT in all physical imaging characteristics, particularly in sensitivity and contrast resolution. PET had a sensitivity 40-80 times higher than that of SPECT, and its contrast resolution was 40-100% better than SPECT. Between FDG-SPECT using an HE collimator and that using a 511-keV collimator, the latter showed marked reduction in septal penetration (from 56% to 38%), improvement in spatial resolution (from 17 mm to 11 mm FWHM) as well as contrast resolution (from 34% to 45%), while suffering reduced system sensitivity (from 75 to 34 cpm/microCi). Patient studies demonstrated that although FDG-SPECT, using a HE or UH collimator, provided concordant viability information as FDG PET in a large majority of myocardial segments with persistent perfusion defects (88% and 90%, respectively), there is an excellent statistical agreement (kappa = 0.736) between SPECT with UH collimator and PET, while the agreement between SPECT using HE collimator and PET are moderate (kappa = 0.413). CONCLUSION: Despite its markedly inferior physical imaging characteristics compared with PET, SPECT with the dedicated 511-keV collimator offers a low-cost, practical alternative to PET in studying myocardial viability using [18F]FDG. SPECT systems with a high-energy, general-purpose collimator, on the other hand, are inadequate in such studies.

Outcome of temporal lobe epilepsy surgery predicted by statistical parametric PET imaging.

UNLABELLED: PET is useful in the presurgical evaluation of temporal lobe epilepsy. The purpose of this retrospective study is to assess the clinical use of statistical parametric imaging in predicting surgical outcome. METHODS: Interictal 18FDG-PET scans in 17 patients with surgically-treated temporal lobe epilepsy (Group A-13 seizure-free, group B = 4 not seizure-free at 6 mo) were transformed into statistical parametric imaging, with each pixel representing a z-score value by using the mean and s.d. of count distribution in each individual patient, for both visual and quantitative analysis. RESULTS: Mean z-scores were significantly more negative in anterolateral (AL) and mesial (M) regions on the operated side than the nonoperated side in group A (AL: p < 0.00005, M: p = 0.0097), but not in group B (AL: p = 0.46, M: p = 0.08). Statistical parametric imaging correctly lateralized 16 out of 17 patients. Only the AL region, however, was significant in predicting surgical outcome (F = 29.03, p < 0.00005). Using a cut-off z-score value of -1.5, statistical parametric imaging correctly classified 92% of temporal lobes from group A and 88% of those from Group B. CONCLUSION: The preliminary results indicate that statistical parametric imaging provides both clinically useful information for lateralization in temporal lobe epilepsy and a reliable predictive indicator of clinical outcome following surgical treatment.

Prediction of improvement in left ventricular function after ventricular aneurysmectomy using Fourier phase and amplitude analysis of radionuclide cardiac blood pool scans.

Postoperative improvement in left ventricular (LV) function is a common objective of LV aneurysmectomy, but is difficult to predict. The first Fourier component of time-activity curves of pre- and postoperative gated radionuclide angiographic studies was evaluated for this purpose in 20 patients who had undergone aneurysmectomy. LV aneurysms had portions that characteristically exhibited marked phase delay with varying degrees of amplitude. Total aneurysmal amplitude was obtained preoperatively by summing the amplitude component of all pixels that exhibited phase delay, suggesting paradoxical motion. LV ejection fraction (EF) before and after aneurysmectomy and the absolute postoperative increase in LVEF were calculated. Nine of 20 patients had an absolute increase of EF less than 10% despite resection of large aneurysms. A strong correlation was found between the absolute increase in EF after aneurysmectomy and the total amplitude within paradoxically moving areas (r = 0.93, p less than 0.0001). Thus, preoperative measurement of the total paradoxical amplitude predicts absolute change in EF and may be important in selecting patients for aneurysmectomy. The data also suggest that the total aneurysmal amplitude reflects the stroke volume ejected into an aneurysm in systole and that paradoxical expansion of an aneurysm contributes to LV dysfunction in some of these patients.

Failure of LeVeen shunting in refractory ascites--a view from the other side.

We have reviewed our experience with 11 patients treated with LeVeen peritoneovenous shunts during a 22-month period from March, 1976, through December, 1977, to assess long-term results and shunt patency. Nine patients had follow-up studies to assess shunt patency at a mean of 26 months. After insertion of the shunt, the mean weight loss was 7.9 kg at hospital discharge. At 26-month follow-up evaluation, six patients had minimal ascites (responders), whereas five had massive ascites (nonresponders). Of the six responders, three patients with nonfunctioning shunts lost an average of 15.8 kg of ascites, three whereas with patent shunts lost an average of 15.0 kg. Eight of 11 patients (73%) required revision or replacement of the shunt because of malfunction; clotting was the most common cause of failure. We conclude that the role and effectiveness of LeVeen peritoneovenous shunts remain questionable. They may cause diuresis, maintain it, or not be responsible for it all. Clinical reports that cite their effectiveness should document patency of these shunts.

Current status of the clinical applications of cardiac positron emission tomography.

At the present time, positron emission tomography (PET) has evolved into an accurate clinical diagnostic imaging procedure for coronary artery disease that provides unique information, presently unavailable from other imaging modalities, for the management of patients with previous myocardial infarction. The superior accuracy of PET for the diagnosis of coronary artery disease has had a positive influence on the management decision process to perform revascularization. In addition to the superior accuracy of PET compared with single photon emission computed tomography, PET has the advantage of being able to identify viable hibernating myocardium.

Evaluation of cAMP involvement in cannabinoid-induced antinociception.

It has been proposed that cannabinoids act at a Gi protein-coupled receptor to produce antinociception. One action of Gi-proteins is to decrease intracellular cAMP via inhibition of adenylyl cyclase activity. Although cannabinoid inhibition of forskolin-stimulated adenylyl cyclase is used as a confirmation of functional cannabinoid receptors, it is unknown whether this second messenger system specifically mediates cannabinoid-induced antinociception. This in vivo study was conducted using enantiomeric cAMP analogs, Rp-cAMPS (an antagonist) and Sp-cAMPS (an agonist), and the cAMP agonist Cl-cAMP to test the hypothesis that cannabinoid-induced antinociception is due to decreased adenylyl cyclase activity. None of the cAMP analogs, forskolin, or 1,9-dideoxy-forskolin affected delta 9-THC or CP-55,940-induced antinociception produced by intrathecal (i.t.) or intracerebroventricular (i.c.v.) injections in mice. Experiments were also conducted to investigate whether i.c.v. administration of Sp-cAMPS would block i.c.v. cannabinoid-induced antinociception in rats. Sp-cAMPS failed to block CP-55,940-induced antinociception. However, Sp-cAMPS produced hyper-excitability and reactive behavior indicating that it did elicit a pharmacological effect. Although, adenylyl cyclase may mediate other cannabinoid-induced actions, these results do not support the hypothesis that it is involved in cannabinoid-induced antinociception. Alternatively, other effector systems such as calcium or potassium channels coupled to cannabinoid receptors may mediate cannabinoid-induced antinociception.

A major gene affecting age-related hearing loss in C57BL/6J mice.

A major gene responsible for age-related hearing loss (AHL) in C57BL/6J mice was mapped by analyses of a (C57BL/6J x CAST/Ei) x C57BL/6J backcross. AHL, as measured by elevated auditory-evoked brainstem response (ABR) thresholds, segregated among backcross mice as expected for a recessive, primarily single-gene trait. Both qualitative and quantitative linkage analyses gave the same genetic map position for the AHL gene (Ahl on chromosome 10, near D10Mit5. Marker assisted selection was then used to produce congenic lines of C57BL/6J that contain different CAST-derived segments of chromosome 10. ABR test results and cochlear histopathology of aged progenitors of these congenic lines are presented. Ahl is the first gene causing late-onset, non-syndromic hearing loss that has been reported in the mouse.