Admittance-based pressure-volume loop measurements in a porcine model of chronic myocardial infarction.

The aim of this study was to validate admittance-based pressure-volume (PV) loop measurements for the assessment of cardiac function in a porcine model of chronic myocardial infarction. The traditional PV loop measurement technique requires hypertonic saline injections for parallel conductance correction prior to signal conversion into volume. Furthermore, it assumes a linear relationship between conductance and volume. More recently, an admittance-based technique has been developed, which continuously measures parallel conductance and uses a non-linear equation for volume calculation. This technique has not yet been evaluated in a large-animal model of myocardial ischaemia. Eleven pigs underwent invasive PV measurements with the admittance system (AS) and the traditional conductance system followed by three-dimensional echocardiography (3DE). After baseline measurements, pigs were subjected to 90 min left anterior descending coronary artery occlusion, followed by the same measurements at 8 weeks follow-up. In the healthy heart, the AS showed good agreement with 3DE for left ventricular volumes and a reasonable correlation for ejection fraction (r = 0.756, P = 0.007). At follow-up, an increase in end-systolic volume was observed with 3DE (+15.4 ± 14.4 ml, P = 0.005) and the AS (+34.6 ± 36.1 ml, P = 0.010). The ejection fraction measured with 3DE (-13.2 ± 5.2%, P < 0.001) and the AS (-20.3 ± 11.2%, P < 0.001) significantly decreased. We conclude that the AS can be used for quantitative monitoring of changes in cardiac function induced by myocardial infarction and provides comparable results to 3DE, rendering it a useful tool for functional testing in large-animal cardiac models.

Adipose-derived cells.

Heart failure is by far the most common cause of hospitalization in Western countries, with onerous economic consequences. Cell therapy holds great promise for use in tissue regeneration and is increasingly used in an effort to improve outcomes in cardiac disease. Recently it has been shown that adipose tissue, in addition to committed adipogenic, endothelial progenitor cells and pluripotent vascular progenitor cells, also contains multipotent cell types (adipose-derived stem cells, ADSCs) that, in cell culture conditions, have shown to have an impressive developmental plasticity including the ability to undergo multilineage differentiation and self-renewal. ADSCs express multiple CD marker antigens similar to those observed on MSCs and are also capable of secreting a large number of angiogenesis-related cytokines, including vascular endothelial growth factor, granulocyte/macrophage colony stimulating factor, stromal-derived factor-1alpha, and hepatocyte growth factor. Adipose tissue can be harvested in large quantities with minimal morbidity in several regions of the body and, on average, 100 ml of human adipose tissue yields about 1 x 10(6) stem cells. Studies conducted in porcine AMI models have shown a significant LV functional improvement, with no report of any potentially fatal arrhythmias. The APOLLO trial, a prospective, double blind, randomized, placebo-controlled trial currently in the recruiting phase, is a "first-in-man" study that explores the safety and feasibility of ADSC transplantation in patients with acute MI.

Heme oxygenase-1 protects against vascular constriction and proliferation.

Heme oxygenase (HO-1, encoded by Hmox1) is an inducible protein activated in systemic inflammatory conditions by oxidant stress. Vascular injury is characterized by a local reparative process with inflammatory components, indicating a potential protective role for HO-1 in arterial wound repair. Here we report that HO-1 directly reduces vasoconstriction and inhibits cell proliferation during vascular injury. Expression of HO-1 in arteries stimulated vascular relaxation, mediated by guanylate cyclase and cGMP, independent of nitric oxide. The unexpected effects of HO-1 on vascular smooth muscle cell growth were mediated by cell-cycle arrest involving p21Cip1. HO-1 reduced the proliferative response to vascular injury in vivo; expression of HO-1 in pig arteries inhibited lesion formation and Hmox1-/- mice produced hyperplastic arteries compared with controls. Induction of the HO-1 pathway moderates the severity of vascular injury by at least two adaptive mechanisms independent of nitric oxide, and is a potential therapeutic target for diseases of the vasculature.

Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury.

Here we defined the main viral determinant of Ebola virus pathogenicity; synthesis of the virion glycoprotein (GP) of Ebola virus Zaire induced cytotoxic effects in human endothelial cells in vitro and in vivo. This effect mapped to a serine-threonine-rich, mucin-like domain of this type I transmembrane glycoprotein, one of seven gene products of the virus. Gene transfer of GP into explanted human or porcine blood vessels caused massive endothelial cell loss within 48 hours that led to a substantial increase in vascular permeability. Deletion of the mucin-like region of GP abolished these effects without affecting protein expression or function. GP derived from the Reston strain of virus, which causes disease in nonhuman primates but not in man, did not disrupt the vasculature of human blood vessels. In contrast, the Zaire GP induced endothelial cell disruption and cytotoxicity in both nonhuman primate and human blood vessels, and the mucin domain was required for this effect. These findings indicate that GP, through its mucin domain, is the viral determinant of Ebola pathogenicity and likely contributes to hemorrhage during infection.

Prospects for genetic therapy of cardiovascular disease.

Significant progress has been made in cardiovascular gene therapy. Further investigations are required to understand the basic science of vectors, mechanisms of gene delivery, vector-associated immunogenicity, and pathophysiology of vascular and myocardial diseases. In addition, catheter and stent devices will be required to deliver vectors to the vasculature and myocardium (Fig. 3). Despite these scientific challenges, molecular therapies for cardiovascular diseases are being implemented into clinical practice.

Neurotrophic ACTH4-9 analogue therapy normalizes electroencephalographic alterations in chronic experimental allergic encephalomyelitis.

Chronic experimental allergic encephalomyelitis (CEAE) is an established experimental model for multiple sclerosis (MS). The demyelinating lesions in the white matter of the central nervous system observed in CEAE and in MS are accompanied by various neurophysiological alterations. Among the best defined electrophysiological abnormalities are the changes in event-related potentials, in particular evoked potentials involving the spinal cord, i.e. motor and sensory evoked potentials. Less familiar are the changes observed in the electroencephalogram of CEAE-affected animals, which are also encountered in the human equivalent, MS. In the present experiment we evaluated the therapeutic value of a neurotrophic peptide treatment [H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH, an ACTH4-9 analogue] and its effect on the delayed flash visual evoked potentials (VEP) and power spectra of the electroencephalogram, during a 17-week follow-up of CEAE. CEAE animals treated with the neurotrophic peptide were protected against the development of neurological symptoms during the course of the demyelinating syndrome. VEPs of animals suffering from CEAE showed a delay of the latencies of the late components which was significantly counteracted by peptide treatment. The peak-to-peak amplitude of the VEP afterdischarge recorded from CEAE animals was significantly increased during the course of CEAE and correlated closely with the progression of the myelinopathy. Furthermore, CEAE animals showed an increase of electroencephalogram (EEG) beta activity of up to 500% as compared with the age-matched control group. This increase in beta power mainly consisted of a prevailing 20-21 Hz peak, a frequency that normally is not dominant in control EEG recordings of the rat during passive wakefulness. All these electrophysiological phenomena were absent in ACTH4-9 analogue-treated animals. The present findings underscore the potential importance of a neurotrophic peptide treatment in the pharmacotherapy of central demyelinating syndromes, and possibly of MS.

Gene therapy for coronary artery disease: The University of Michigan Program.

Recent studies show that the cyclin dependent kinase inhibitor KIP/CIP family members function as regulators of VSMC proliferation. The prevention and treatment of cell proliferation in arteries after percutaneous intervention, represents an attractive target for gene therapy. Targeting of cell cycle regulatory proteins might inhibit cell proliferation and migration, and induce withdrawal from the cell cycle. Furthermore, these studies suggest that genetic approaches are feasible and that local expression of a regulatory gene is sufficient to abrogate lesion formation in different animal models of vascular diseases.

Longitudinal in vivo magnetic resonance imaging studies in experimental allergic encephalomyelitis: effect of a neurotrophic treatment on cortical lesion development.

Proton magnetic resonance imaging enables non-invasive monitoring of lesion formation in multiple sclerosis and has an important role in assessing the potential effects of therapy. T2-weighted and short tau inversion recovery magnetic resonance imaging were used to assess the effect of a neurotrophic adrenocorticotrophic hormone analogue [H-Met(O(2))-Glu-His-Phe-D-Lys-Phe-OH] on the volume of lesions in the brains of rats suffering from chronic experimental allergic encephalomyelitis, an animal equivalent of multiple sclerosis. Lesion volume was monitored during a five-month period. Magnetic resonance imaging indicated that treatment with the adrenocorticotrophic hormone analogue significantly reduced the lesion volume by 84 and 85% 10 and 20 weeks after lesion induction, respectively. Furthermore, peptide treatment significantly reduced chronic experimental allergic encephalomyelitis-related neurological symptoms during the chronic phase of the disease (week 3 until week 20 after lesion induction). Both functional and morphological recovery were considerably advanced by peptide treatment. Twenty weeks after lesion induction rats with chronic experimental allergic encephalomyelitis were killed for histological analysis, to correlate magnetic resonance imaging findings with morphological changes. The regions of abnormally high signal intensities on T2-weighted magnetic resonance images coincided with areas of demyelination and concomitant widespread inflammatory infiltration, oedema formation and enlarged ventricles. The improved neurological status and the 84% reduction in the lesion volume in the cerebrum of rats chronic experimental allergic encephalomyelitis point to the potential value of trophic peptides in the development of strategies for limiting the damage caused by central demyelinating lesions in syndromes such as multiple sclerosis.

Effective use of a novel rate-smoothing algorithm in atrial fibrillation by ventricular pacing.

BACKGROUND: It is still unknown whether a fast heart rate or an irregular ventricular response in atrial fibrillation causes tachycardiomyopathy. Reduction in the variability of RR intervals without an increase in heart rate might be an alternative treatment when antiarrhythmic drugs fail to control the irregularity accompanying atrial fibrillation. SUBJECTS AND METHODS: Eight patients underwent temporary right ventricular pacing, using a novel rate-smoothing algorithm prior to DC cardioversion or His bundle ablation. A rate-smoothing algorithm was utilized by right ventricular apical stimulation. Spontaneous and paced RR intervals during atrial fibrillation were quantified and processed for statistical analysis. RESULTS: The rate-smoothing algorithm resulted in a substantial reduction in the variance of the RR intervals (slow mode 73.1%, fast mode 40.0%) and RR range (slow mode 49.3%, fast mode 34.3%). In contrast to previous algorithms, the mean heart rate during pacing intervention in atrial fibrillation did not change significantly to the heart rate directly preceding the pacemaker intervention (+2%). CONCLUSIONS: This initial study of the novel rate-smoothing algorithm shows that pacing intervention is a relatively safe, rapid and reliable alternative therapy for controlling irregular ventricular rhythms due to atrial fibrillation. Incorporation of the algorithm in implantable pacemakers appears justified, but demands further prospective studies in patients to evaluate relief of symptoms and reduction of tachycardiomyopathy due to atrial fibrillation.

Functional and neurophysiological evidence of the efficacy of trophic pharmacotherapy using an adrenocorticotrophic hormone4-9 analog in experimental allergic encephalomyelitis, an animal model of multiple sclerosis.

Chronic experimental allergic encephalomyelitis (CEAE) is a well-established animal model for the human syndrome, multiple sclerosis. CEAE has striking histological, electrophysiological and clinical analogies with multiple sclerosis and is a valuable animal model for the preclinical pharmacotherapeutical development of new putative therapeutic agents. In this paper, we describe a neurotrophic repair approach in Lewis rats suffering from CEAE. The neurotrophic peptide used is a degradation resistant adrenocorticotrophic hormone4-9 analog. The development of CEAE was examined using a combination of clinical, functional and electrophysiological parameters including somatosensory and motor evoked potentials. The latencies and amplitudes of the various evoked potentials can provide quantitative, objective data regarding the involvement of different nerve tracts in CEAE and the effectiveness of the neurotrophic peptide. Repeated subcutaneous injections of the neurotrophic peptide suppressed the development of CEAE-related clinical symptoms, markedly improved motor performance and reduced the reaction time upon thermal stimulation as compared to saline-treated CEAE animals during a 17 week follow-up study. Prolonged onset latencies of corticomotor evoked potentials and peak latencies of somatosensory evoked potentials due to the demyelination were normalized upon peptide treatment. In addition, peptide treatment substantially prevented total blocking of the corticomotor pathway in CEAE-animals and reduced the attenuation of sensory evoked potentials-related peak amplitudes as compared to saline-treated animals. The functional and electrophysiological improvements observed in CEAE-animals treated with the adrenocorticotrophic hormone4-9 analog, suggest that a neurotrophic repair approach could be of great value to promote the restoration of function in a disabling demyelinating disorder.

Effective use of a neurotrophic ACTH4-9 analogue in the treatment of a peripheral demyelinating syndrome (experimental allergic neuritis). An intervention study.

Demyelinating syndromes are an important group of nerve disorders for which no effective therapy exists and which are life threatening in a substantial proportion of the patients. In the present experiments we assessed the ameliorative effect of Org 2766, a degradation resistant ACTH4-9 analogue devoid of corticotrophic and melanotrophic action in experimental allergic neuritis (EAN), an animal model for a human demyelinating disease, the Guillain-Barré syndrome (GBS). In order to mimic the clinical situation, peptide treatment was initiated at the first appearance of neurological symptoms in each animal. The ACTH4-9 analogue treatment substantially suppressed the neurological symptoms in animals with EAN, as assessed by clinical scoring and resulted in a significant improvement of motor performance. Furthermore, histological examination of the sural nerve provided a morphological basis for the beneficial functional effect of peptide treatment: more myelinated fibres were present in EAN animals treated with the ACTH4-9 analogue in comparison with EAN animals treated with saline. Further analysis of the sural nerve indicated a complete preservation of the diameter distribution of myelinated fibres in sural nerves of peptide-treated animals. In contrast, saline-treated EAN animals exhibited a significant loss of small and intermediate size myelinated fibres in the sural nerves. This study provides first evidence for the amelioration of the functional and anatomical deficits in an animal model of the GBS syndrome by an interventive synthetic neurotrophic peptide treatment.

The neurotrophic analogue of ACTH(4-9), Org 2766, protects against experimental allergic neuritis.

Demyelinating diseases such as multiple sclerosis or the Guillain-Barré syndrome originate from an autoimmune response resulting in the degradation of myelin and impaired neuronal function. Prophylactic administration of the neurotrophic peptide, H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH [an ACTH(4-9) analogue], to rats with experimental allergic neuritis, a model for the Guillain-Barré syndrome, markedly suppresses the clinical symptoms, protects against loss of motor coordination and prevents the degeneration of myelinated axons in the affected peripheral nerve. Therefore, this peptide may provide a new approach to the therapy of peripheral demyelinating polyneuropathies.