Yair Feld

Evolution of action potential propagation and repolarization in cultured neonatal rat ventricular myocytes.

Maturation of Cultured Neonatal Rat Ventricular Myocytes. Introduction: Cultured neonatal rat ventricular myocytes (NRVM) reestablish gap junctions as they form synchronously and spontaneously beating monolayers, thus providing a useful model for studying activation and repolarization.

Cell Therapy for Modification of the Myocardial Electrophysiological Substrate

Background— Traditional antiarrhythmic pharmacological therapies are limited by their global cardiac action, low efficacy, and significant proarrhythmic effects. We present a novel approach for the modification of the myocardial electrophysiological substrate using cell grafts genetically engineered to express specific ionic channels. Methods and Results— To test the aforementioned concept, we performed ex vivo, in vivo, and computer simulation studies to determine the ability of fibroblasts transfected to express the voltage-sensitive potassium channel Kv1.3 to modify the local myocardial excitable properties. Coculturing of the transfected fibroblasts with neonatal rat ventricular myocyte cultures resulted in a significant reduction (68%) in the spontaneous beating frequency of the cultures compared with baseline values and cocultures seeded with naive fibroblasts. In vivo grafting of the transfected fibroblasts in the rat ventricular myocardium significantly prolonged the local effective refractory period from an initial value of 84±8 ms (cycle length, 200 ms) to 154±13 ms (P<0.01). Margatoxin partially reversed this effect (effective refractory period, 117±8 ms; P<0.01). In contrast, effective refractory period did not change in nontransplanted sites (86±7 ms) and was only mildly increased in the animals injected with wild-type fibroblasts (73±5 to 88±4 ms; P<0.05). Similar effective refractory period prolongation also was found during slower pacing drives (cycle length, 350 to 500 ms) after transplantation of the potassium channels expressing fibroblasts (Kv1.3 and Kir2.1) in pigs. Computer modeling studies confirmed the in vivo results. Conclusions— Genetically engineered cell grafts, transfected to express potassium channels, can couple with host cardiomyocytes and alter the local myocardial electrophysiological properties by reducing cardiac automaticity and prolonging refractoriness.

Future strategies for the treatment of diastolic heart failure

It is estimated that 30% to 50% of heart failure patients have preserved systolic left ventricular (LV) function, often referred to as diastolic heart failure (DHF). Mortality is high in this patient population, and morbidity and rate of hospitalization are similar to those of patients with systolic heart failure. The management of patients with diastolic heart failure is essentially empirical, limited, and disappointing. New drugs, devices, and gene therapy based treatment options are currently under investigation. In this review, future strategies for the treatment of diastolic heart failure are discussed.

Energy transfer from systole to diastole: A novel device-based approach for the treatment of diastolic heart failure

We hypothesized that attachment of elastic coil to the left ventricular (LV) wall, capable of exerting outward forces may allow the transfer of energy from systole to diastole and improve diastolic function. Methods and results: An extra-ventricular-device, composed of a series of elastic elements interposed between spiral screws attached to the epimyocardium of the LV free-wall was developed. The hemodynamic and mechanical effects of the device were tested using a computerized model, an in vitro model utilizing a computerized-controlled fluid pump, eight healthy sheep and 10 mini-pigs induced with diastolic dysfunction by renal wrapping. The computerized and in vitro models predicted a reduction of the LV diastolic pressure curve and partial normalization of the pressure-volume loop. The sheep study demonstrated preservation of animals wellbeing including maintaining cardiac mechanical function with stable energy transfer from systole to diastole throughout the 6 months follow-up. The mini-pigs study showed an increase in the early diastolic to systolic strain-rate ratio in the mid-endocardial level (23 ± 10%, P = 0.008) and an increase in early apical reverse rotation rate of 50% (P = 0.016 compared to control). Conclusions: This study presents a novel concept of using a mechanical device to transfer energy from systole to diastole, potentially enhancing diastolic function.

Modulation of excessive neuronal activity by fibroblasts: Potential use in treatment of Parkinson's disease

PURPOSE A number of neurological disorders are marked by increased or aberrant frequency of neuronal discharge in specific parts of the brain. Administration of drugs such as antiepileptic compounds results in the depression of neuronal activity in the whole brain, with the potential for serious side-effects. In the search for additional therapies to reduce the unphysiological electrical activity of over-active brain foci, we have examined the effect of fibroblasts transplanted to areas responsible for motor dysfunction in hemi-parkinsonian rats, since bursting synchronous discharges in internal segment of globus pallidus (GPi) are thought to be partially responsible for the movement disorders of PD. Fibroblasts express gap junctions and ion channels, and so, when transplanted to brain tissue, can potentially modulate excessive electrical activity. METHODS Neonatal cortical neurons were cultured on multi-electrode arrays, and their electrical activity was evaluated before and after fibroblast seeding. Unilateral 6-hydroxydopamine (6-OHDA) lesion was carried out in Fischer rats. Lesioned or control rats were transplanted with either syngeneic dermal fibroblasts, microfine glass beads, ibotenic acid, or physiological saline, in the entopeduncular nucleus (EP). Apomorphine-induced rotational behavior and L-dopa-induced dyskinetic movements were evaluated before transplantation (baseline) and 2, 4, 8, 12, and 24 weeks following transplantation. Following behavioral experiments, rats were perfused with 4% formaldehyde in PBS for immunohistochemical study of the brain. RESULTS We demonstrate in vitro that the introduction of fibroblasts into a network of neurons does not interfere with overall functional measures of activity, while moderately altering the characteristics of synchronous neuronal discharge. In rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal dopaminergic pathway, apomorphine-induced rotations were reduced by more than 60% following ipsilateral transplantation of fibroblasts to the EP. L-Dopa-induced dyskinesia was also significantly reduced. Transplantation of inert microspheres, or chemical lesion of the same area with ibotenic acid, did not produce beneficial effects on parkinsonian symptomatology. CONCLUSION Fibroblast transplantation could be an alternative treatment strategy for the parkinsonian patient.

Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates.

Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson’s disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6–8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.

A Novel Intra-aortic Device Designed for Coronary Blood Flow Amplification in Unrevascularizable Patients

Patients with unrevascularizable coronary artery disease represent a substantial number of all patients with coronary disease. However, their therapeutic options are limited; they endure recurrent hospitalizations, a poor quality of life and prognosis. We aim to investigate a novel alternative approach to the treatment of this common medical condition by using a specialized intra-aortic device with coiling properties capable of enhancing diastolic coronary flow. Both a mathematical analysis and in vitro study presented in the current study have yielded enhanced coronary diastolic blood flow and energetic advantages. We suggest that this original approach might be implicated in severely symptomatic unrevascularizable patients.