David Rosenbaum

Targeted Sarcoplasmic Reticulum Ca2+ ATPase 2a Gene Delivery to Restore Electrical Stability in the Failing Heart

Background— Recently, we reported that sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart. Methods and Results— Adult guinea pigs were divided into 3 groups: control, HF, and HF+AAV9.SERCA2a gene transfer. HF resulted in a decrease in left ventricular fractional shortening compared with controls (P<0.001). As expected, isolated HF myocytes demonstrated slower sarcoplasmic reticulum calcium uptake, decreased Ca2+ release, and increased diastolic Ca2+ (P<0.05) compared with controls. Moreover, SERCA2a, cardiac ryanodine receptor 2, and sodium-calcium exchanger protein expression was decreased in HF compared with control (P<0.05). As predicted, HF increased susceptibility to cardiac alternans, as evidenced by decreased heart rate thresholds for both Vm alternans and Ca alternans compared with controls (P<0.01). Interestingly, in vivo gene transfer of AAV9.SERCA2a in the failing heart improved left ventricular contractile function (P<0.01), suppressed cardiac alternans (P<0.01), and reduced ryanodine receptor 2 Po secondary to reduction of ryanodine receptor 2–PS2814 (P<0.01). This ultimately resulted in a decreased incidence of inducible ventricular arrhythmias (P=0.05). Conclusions— These data show that SERCA2a gene transfer in the failing heart not only improves contractile function but also directly restores electric stability through the amelioration of key arrhythmogenic substrate (ie, cardiac alternans) and triggers (ie, sarcoplasmic reticulum Ca2+ leak).

The genetics of idiopathic generalized epilepsies of adolescent onset: Differences between juvenile myoclonic epilepsy and epilepsy with random grand mal and with awakening grand mal

Article abstract—Both linkage and association studies provide strong evidence that a gene locus on chromosome 6 is involved in the expression of juvenile myoclonic epilepsy (JME), an adolescent-onset form of primary idiopathic generalized epilepsy (IGE). This epilepsy-related gene locus, designated EJM-1, may also influence the expression of other forms of IGE. We report here evidence that at least one form of epilepsy that is similar to JME—pure, adolescent-onset grand mal epilepsy in which the seizures occur at any time during waking—is not linked to the EJM-1 locus. However, we also have evidence that another form of pure, adolescent-onset grand mal that occurs on awakening is linked to the EJM-1 locus and may be genetically the same as JME. This work suggests that clinically similar epileptic syndromes may have different genetic bases and underscores the critical importance of careful clinical observations in studying the genetics of the epilepsies.

The complementary roles of dynamic contrast-enhanced MRI and 18F-fluorodeoxyglucose PET/CT for imaging of carotid atherosclerosis

PurposeInflammation and neovascularization in vulnerable atherosclerotic plaques are key features for severe clinical events. Dynamic contrast-enhanced (DCE) MRI and FDG PET are two noninvasive imaging techniques capable of quantifying plaque neovascularization and inflammatory infiltrate, respectively. However, their mutual role in defining plaque vulnerability and their possible overlap has not been thoroughly investigated. We studied the relationship between DCE-MRI and 18F-FDG PET data from the carotid arteries of 40 subjects with coronary heart disease (CHD) or CHD risk equivalent, as a substudy of the dal-PLAQUE trial (NCT00655473).MethodsThe dal-PLAQUE trial was a multicenter study that evaluated dalcetrapib, a cholesteryl ester transfer protein modulator. Subjects underwent anatomical MRI, DCE-MRI and 18F-FDG PET. Only baseline imaging and biomarker data (before randomization) from dal-PLAQUE were used as part of this substudy. Our primary goal was to evaluate the relationship between DCE-MRI and 18F-FDG PET data. As secondary endpoints, we evaluated the relationship between (a) PET data and whole-vessel anatomical MRI data, and (b) DCE-MRI and matching anatomical MRI data. All correlations were estimated using a mixed linear model.ResultsWe found a significant inverse relationship between several perfusion indices by DCE-MRI and 18F-FDG uptake by PET. Regarding our secondary endpoints, there was a significant relationship between plaque burden measured by anatomical MRI with several perfusion indices by DCE-MRI and 18F-FDG uptake by PET. No relationship was found between plaque composition by anatomical MRI and DCE-MRI or 18F-FDG PET metrics.ConclusionIn this study we observed a significant, weak inverse relationship between inflammation measured as 18F-FDG uptake by PET and plaque perfusion by DCE-MRI. Our findings suggest that there may be a complex relationship between plaque inflammation and microvascularization during the different stages of plaque development. 18F-FDG PET and DCE-MRI may have complementary roles in future clinical practice in identifying subjects at high risk of cardiovascular events.

Vascular imaging with positron emission tomography.

Joshi F, Rosenbaum D, Bordes S, Rudd JHF (University of Cambridge, Cambridge, UK; Groupe Hospitalier Pitié‐Salpêtrière, Assistance Publique‐Hôpitaux de Paris, Paris, France; and Instituto Cardiovascular, Madrid, Spain). Vascular imaging with positron emission tomography (Review). J Intern Med 2011; 270: 99–109.

A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome

OBJECTIVEnArachidonate 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes. VIA-2291 is a potent 5-LO inhibitor, which has been shown to reduce hsCRP and noncalcified coronary plaque volume following an acute coronary syndrome (ACS). We aim to evaluate the effect of VIA-2291 on vascular inflammation compared to placebo using FDG-PET.nnnMETHODSnA Phase II, randomized, double-blind, parallel-group study was conducted in 52 patients with recent ACS assigned 1:1 to either 100 mg VIA-2291 or placebo for 24 weeks. The primary outcome was the effect of VIA-2291 relative to placebo on arterial inflammation detected by (18)fluorodeoxyglucose positron emission tomography (FDG-PET) within the index vessel after 24 weeks of daily treatment, compared to baseline.nnnRESULTSnVIA-2291 was relatively well tolerated and was associated with a significant inhibition of the potent chemo-attractant LTB4, with a mean inhibition of activity of 92.8% (p<0.0001) at 6 weeks in the VIA-2291 group, without further significant change in inhibition at 24 weeks. However, for VIA-2291 was not associated with significant difference in inflammation (target-to-background ratio) compared to placebo at 24 weeks or 6 weeks of treatment. Further, VIA-2291 was not associated with a significant reduction in hsCRP from baseline after either 6 or 24 weeks of treatment.nnnCONCLUSIONSnVIA-2291 is well-tolerated and effectively reduces leukotriene production. However, inhibition of 5-LO with VIA-2291 is not associated with significant reductions in vascular inflammation (by FDG-PET) or in blood inflammatory markers. Accordingly, this study does not provide evidence to support a significant anti-inflammatory effect of VIA-2291 in patients with recent ACS.

Association of HLA class II alleles in patients with juvenile myoclonic epilepsy compared with patients with other forms of adolescent-onset generalized epilepsy.

Reports have suggested an association of juvenile myoclonic epilepsy (JME) with an HLA-DR allele. We examined the HLA-DR and DQ frequencies in two populations of epilepsy patients: (1) JME patients and (2) patients with other forms of adolescent-onset, idiopathic generalized epilepsy (IGE). We did DNA-based HLA typing on 24 JME patients and 24 patients with non-JME forms of adolescent-onset IGE, forms that are clinically similar to JME. In typing the HLA region, we paid particular attention to the alleles contributing to the HLA-DR13 type and also to the DQB1 locus alleles that are in linkage disequilibrium with the alleles that comprise the DR13 type. We also examined the HLA-DP locus, which is centromeric to the DR locus. The frequency of DR13 was significantly higher in JME compared with the non-JME patients. Nine JME patients, compared with two non-JME patients, carried that type (chi2 = 5.78 [p < 0.017, 1 df]). The odds ratio was 6.6. Furthermore, the DQB1 alleles in linkage disequilibrium with the alleles contributing to the DR13 type were also more frequent in JME than in non-JME epilepsy patients. The chi2 is highly significant (8.1, p < 0.005) with an odds ratio of 13.8. These results confirm that JME is an HLA-associated form of epilepsy. They also show that the JME locus probably lies within the HLA region, most likely between the HLA-DP and HLA-B loci. The association studies also confirm linkage results showing that JME is genetically different from some other IGEs and emphasize that careful diagnosis is critical to genetic studies of the epilepsies. NEUROLOGY 1996;47: 750-755

Long-term outcome in 53 patients with homozygous familial hypercholesterolaemia in a single centre in France.

BACKGROUND AND AIMSnHomozygous familial hypercholesterolaemia (HoFH) is a rare inherited condition characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels, severe, accelerated atherosclerosis and premature coronary heart disease. We evaluated cardiovascular complications in HoFH patients over extended follow-up and investigated their association with changes in cholesterol over time, as well as total cholesterol burden.nnnMETHODSnIn this retrospective single-centre study, 53 patients (baseline meanxa0±xa0standard deviation [SD], total cholesterol 15.5xa0±xa03.7xa0mmol/L and LDL-C 13.2xa0±xa02.6xa0mmol/L) were followed for up to 38 years (21.2xa0±xa010 years). The primary outcome was an adverse clinical event, defined as cardiovascular death, nonfatal myocardial infarction, or angina.nnnRESULTSnTwenty-eight patients experienced an event, of whom 8 died due to complications of major surgery (4), myocardial infarction (3) or stroke (1). While total cholesterol levels were comparable in patients with and without an event at baseline (20xa0mmol/L), those who subsequently experienced an event showed a slower decline in total cholesterol. Cumulative total cholesterol (i.e. total-cholesterol year score) was highly associated with the incidence of an adverse clinical event in a linear dose-response relation. A 100xa0mmol/L increase in cumulative total cholesterol (i.e. an average exposure of 10xa0mmol/L per 10 years or 20xa0mmol/L per 5 years) was associated with a doubling of the risk of a cardiovascular event (age-adjusted incidence rate ratio: 1.99, 95% CI, 1.16-3.41).nnnCONCLUSIONSnOur findings reinforce the importance of early diagnosis and initiation of maximal treatment, including lipoprotein apheresis, to ensure long-term reduction in the cholesterol burden, expressed as the total-cholesterol year score, and risk of cardiovascular complications in HoFH.

Intramedullary Spinal Cord Metastases from Lung Carcinoma: Simulatiug Primary Cervical Cord Tumor

PRIMARY CARCINOMA of the lung metastasizes frequently to the brain but infrequently to other portions of the nervous system. The incidence of metastases to the brain varies with different reports. Beeler and Ireyl found intracranial metastases in 21 of 35 cases with carcinoma of the lung. Fried2 found 11.1 per cent metastases in 319 such cases. Hematogenous spread to the vertebral column is not uncommon, and the spinal cord and nerve roots may be compressed by epidural metastatic lesions.3 However, metastases to the spinal cord itself are rare. The incidence cannot be stated accurately since examination of the spinal cord is omitted in many autopsies. Cantor and Stein4 recently reported a case presenting paraplegia resulting from intramedullary spinal cord metastasis from a bronchogenic carcinoma. They stated that only 13 verified cases of pure intramedullary metastasis could be found in reviewing the literature. In reporting a series of 100 cases of lung tumor with central nervous system metastases, King5 found that when the spinal column was involved the metastases were never found in the substance of the cord. Wilson and Ruppa reported two cases of intramedullary spinal cord involvement by metastases; one from a tumor of the adrenal medulla and the other a case of Hodgkin’s disease. In this same series the metastases from lung tumors compressed but did not involve the spinal cord. Craig‘ reported a case of lung tumor in which metastatic cells and necrosis were found in the thoracic portion of the spinal cord. Spencefl described a case of bronchiogenic carcinoma with a metastatic lesion in the lumbar spinal cord proven at autopsy.

Targeted Sarcoplasmic Reticulum Ca2+ ATPase 2a Gene Delivery to Restore Electrical Stability in the Failing HeartClinical Perspective

Background— Recently, we reported that sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart. Methods and Results— Adult guinea pigs were divided into 3 groups: control, HF, and HF+AAV9.SERCA2a gene transfer. HF resulted in a decrease in left ventricular fractional shortening compared with controls (P<0.001). As expected, isolated HF myocytes demonstrated slower sarcoplasmic reticulum calcium uptake, decreased Ca2+ release, and increased diastolic Ca2+ (P<0.05) compared with controls. Moreover, SERCA2a, cardiac ryanodine receptor 2, and sodium-calcium exchanger protein expression was decreased in HF compared with control (P<0.05). As predicted, HF increased susceptibility to cardiac alternans, as evidenced by decreased heart rate thresholds for both Vm alternans and Ca alternans compared with controls (P<0.01). Interestingly, in vivo gene transfer of AAV9.SERCA2a in the failing heart improved left ventricular contractile function (P<0.01), suppressed cardiac alternans (P<0.01), and reduced ryanodine receptor 2 Po secondary to reduction of ryanodine receptor 2–PS2814 (P<0.01). This ultimately resulted in a decreased incidence of inducible ventricular arrhythmias (P=0.05). Conclusions— These data show that SERCA2a gene transfer in the failing heart not only improves contractile function but also directly restores electric stability through the amelioration of key arrhythmogenic substrate (ie, cardiac alternans) and triggers (ie, sarcoplasmic reticulum Ca2+ leak).

Noninvasive atherosclerosis imaging modalities and their application to investigating cardiovascular drug effects in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that affects not only joints but also the cardiovascular (CV) system. Premature endothelial dysfunction and accelerated atherosclerosis are pertinent findings in patients with RA, resulting in increased CV morbidity and mortality. Thus, detection of subclinical atherosclerosis is important in RA management. A range of promising imaging modalities is currently available to visualize early vascular disease and monitor changes in atherosclerotic plaque burden, serving as important tools in CV risk stratifications and as surrogate markers for CV endpoints in intervention trials. This review summarizes various noninvasive imaging modalities, implemented in widespread clinical use, such as vascular ultrasonography and cardiac computer tomography, as well as novel emerging technologies, such as magnetic resonance imaging and positron emission tomography. These novel technologies make a step forward in the evaluation and quantification of atherosclerotic plaque features, permitting the detection of vulnerable plaque as well as functional assessment of vessel wall metabolic activity that was previously not achievable. Application of the imaging modalities to monitor CV drug effects in therapeutic clinical trials in both the general and RA population is further presented and discussed. Drug Dev Res 72:739–749, 2011.