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All Publications

  • Repolarization in systemic sclerosis: a meta-analysis. Clinical rheumatology Wexler, Y., Nussinovitch, U. 2021


    OBJECTIVES: Systemic sclerosis (SSc) is a rare connective tissue disease characterized by immune dysregulation, vascular damage, and increased deposition of extracellular matrix. In SSc, cardiac manifestations are common and account for 14% of deaths. Numerous studies have examined electrocardiographic findings in SSc patients yielding conflicting reports regarding QTc duration. We conducted a systematic review and meta-analysis of existing studies to investigate whether QTc duration may aid in diagnosis and risk stratification of SSc patients.METHODS: Two electronic databases (PubMed and Embase) were searched for case-control and cohort studies assessing QTc duration in SSc patients published before March 1, 2021. A random-effects model was used to meta-analyze the results, and included studies were tested for heterogeneity. Linear regression was performed to determine correlations between comorbidities, and QTc duration.RESULTS: Ninety-six studies, abstracts, and posters were identified. After abstract review and duplicate removal, 23 manuscripts remained. After application of the inclusion and exclusion criteria, 10 studies remained which were quantitatively analyzed. The weighted mean QTc was found to be 422.21ms for SSc patients and 411.43ms for control subjects. A significant increase in QTc duration among SSc patients was found, with a standardized mean difference of 0.59 (p<0.01, 95% CI 0.27-0.92). No significant correlation was found between underlying traits and QTc values. Substantial heterogeneity was found between the studies (I2=83%, p<0.01).CONCLUSION: A significant increase in QTc duration is observed in SSc patients, though the absolute prolongation is not extreme. Therefore, the clinical utility of this finding is unclear and merits large prospective observations. Key Points A statistically significant prolongation of the QTc interval exists in patients with systemic sclerosis. Absolute QTc differences between healthy controls and scleroderma patients are not extreme, and, as such, may be of limited clinical utility. When assessing the underlying traits of systemic sclerosis patients, no statistically significant correlations were found between underlying parameters and QTc duration.

    View details for DOI 10.1007/s10067-021-05996-x

    View details for PubMedID 34843000

  • Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker. Nature biotechnology Protze, S. I., Liu, J., Nussinovitch, U., Ohana, L., Backx, P. H., Gepstein, L., Keller, G. M. 2017; 35 (1): 56-68


    The sinoatrial node (SAN) is the primary pacemaker of the heart and controls heart rate throughout life. Failure of SAN function due to congenital disease or aging results in slowing of the heart rate and inefficient blood circulation, a condition treated by implantation of an electronic pacemaker. The ability to produce pacemaker cells in vitro could lead to an alternative, biological pacemaker therapy in which the failing SAN is replaced through cell transplantation. Here we describe a transgene-independent method for the generation of SAN-like pacemaker cells (SANLPCs) from human pluripotent stem cells by stage-specific manipulation of developmental signaling pathways. SANLPCs are identified as NKX2-5- cardiomyocytes that express markers of the SAN lineage and display typical pacemaker action potentials, ion current profiles and chronotropic responses. When transplanted into the apex of rat hearts, SANLPCs are able to pace the host tissue, demonstrating their capacity to function as a biological pacemaker.

    View details for DOI 10.1038/nbt.3745

    View details for PubMedID 27941801

  • Optogenetics for suppression of cardiac electrical activity in human and rat cardiomyocyte cultures. Neurophotonics Nussinovitch, U., Gepstein, L. 2015; 2 (3): 031204


    Optogenetics has revolutionized neuroscience by enabling precise control of neural excitation. The development of similar optogenetics strategies in the heart is just emerging and mainly focused on pacing with light activation of channelrhodopsin-2. Here, we aimed to develop an optogenetic approach to suppress local cardiac electrical activity by using engineered cell-grafts (HEK293-cells) transfected to express the light-sensitive hyperpolarizing proton-pump archaerhodopsin-3 (Arch3). To evaluate the ability of the engineered cells to couple and modulate the electrical activity of cardiomyocytes, we co-cultured the Arch3-HEK293 cells with neonatal rat cardiomyocytes (NRCMs) or human embryonic stem cells derived cardiomyocytes (hESC-CMs). The co-cultures' conduction and chronotropic properties were evaluated prior, during, and following application of focused monochromatic light (590 nm) using a multielectrode array mapping system. Application of focused illumination completely silenced electrical activity at the illuminated area in all NRCM co-cultures, leading to development of localized functional conduction blocks. Similarly, illumination significantly slowed spontaneous beating-rate in the hESCs-CMs co-cultures (from [Formula: see text] to [Formula: see text], [Formula: see text]). Interestingly, a transient acceleration in beating-rate was noted immediately postillumination. In conclusion, a combined gene and cell therapy approach, using light-sensitive hyperpolarizing proteins, could be used to modulate conduction and automaticity in cardiomyocyte cultures, opening the way for future optogenetic treatments for cardiac tachyarrhythmias.

    View details for DOI 10.1117/1.NPh.2.3.031204

    View details for PubMedID 26158013

    View details for PubMedCentralID PMC4478752

  • Optogenetics for in vivo cardiac pacing and resynchronization therapies. Nature biotechnology Nussinovitch, U., Gepstein, L. 2015; 33 (7): 750-4


    Abnormalities in the specialized cardiac conduction system may result in slow heart rate or mechanical dyssynchrony. Here we apply optogenetics, widely used to modulate neuronal excitability, for cardiac pacing and resynchronization. We used adeno-associated virus (AAV) 9 to express the Channelrhodopsin-2 (ChR2) transgene at one or more ventricular sites in rats. This allowed optogenetic pacing of the hearts at different beating frequencies with blue-light illumination both in vivo and in isolated perfused hearts. Optical mapping confirmed that the source of the new pacemaker activity was the site of ChR2 transgene delivery. Notably, diffuse illumination of hearts where the ChR2 transgene was delivered to several ventricular sites resulted in electrical synchronization and significant shortening of ventricular activation times. These findings highlight the unique potential of optogenetics for cardiac pacing and resynchronization therapies.

    View details for DOI 10.1038/nbt.3268

    View details for PubMedID 26098449

  • Modulation of cardiac tissue electrophysiological properties with light-sensitive proteins. Cardiovascular research Nussinovitch, U., Shinnawi, R., Gepstein, L. 2014; 102 (1): 176-87


    Optogenetics approaches, utilizing light-sensitive proteins, have emerged as unique experimental paradigms to modulate neuronal excitability. We aimed to evaluate whether a similar strategy could be used to control cardiac-tissue excitability.A combined cell and gene therapy strategy was developed in which fibroblasts were transfected to express the light-activated depolarizing channel Channelrhodopsin-2 (ChR2). Patch-clamp studies confirmed the development of a robust inward current in the engineered fibroblasts following monochromatic blue-light exposure. The engineered cells were co-cultured with neonatal rat cardiomyocytes (or human embryonic stem cell-derived cardiomyocytes) and studied using a multielectrode array mapping technique. These studies revealed the ability of the ChR2-fibroblasts to electrically couple and pace the cardiomyocyte cultures at varying frequencies in response to blue-light flashes. Activation mapping pinpointed the source of this electrical activity to the engineered cells. Similarly, diffuse seeding of the ChR2-fibroblasts allowed multisite optogenetics pacing of the co-cultures, significantly shortening their electrical activation time and synchronizing contraction. Next, optogenetics pacing in an in vitro model of conduction block allowed the resynchronization of the tissue's electrical activity. Finally, the ChR2-fibroblasts were transfected to also express the light-sensitive hyperpolarizing proton pump Archaerhodopsin-T (Arch-T). Seeding of the ChR2/ArchT-fibroblasts allowed to either optogentically pace the cultures (in response to blue-light flashes) or completely suppress the cultures' electrical activity (following continuous illumination with 624 nm monochromatic light, activating ArchT).The results of this proof-of-concept study highlight the unique potential of optogenetics for future biological pacemaking and resynchronization therapy applications and for the development of novel anti-arrhythmic strategies.

    View details for DOI 10.1093/cvr/cvu037

    View details for PubMedID 24518144