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  • 1
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    Mitochondrial Hsp90 exerts pro‐survival functions in Pulmonary Arterial Hypertension
    Wiley ; 2017
    In:  The FASEB Journal Vol. 31, No. S1 ( 2017-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 31, No. S1 ( 2017-04)
    Abstract: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a poor prognosis and no therapeutic option. Although the causal pathomechanisms contributing to remodeling of the pulmonary vascular bed in PAH are still unclear, several features, including hyperproliferation and resistance to apoptosis of pulmonary smooth muscle cells (PASMCs) sustained by oncogenic pathways activation and metabolic alterations, have led to the emergence of the cancer‐like concept. The molecular chaperone heat shock protein 90 (Hsp90), by interacting with its client proteins, is directly associated with malignant growth and proliferation. In addition to be highly expressed in the cytosol, Hsp90 exists in a subcellular pool compartimentalized in the mitochondria (mtHsp90) of tumor cells, but not in normal cells, where it promotes cell survival. OBJECTIVE We hypothesized that Hsp90 up‐regulation in PAH triggers PASMC proliferation and resistance to apoptosis. METHODS AND RESULTS We showed that Hsp90 is up‐regulated in lungs and PASMCs isolated from distal pulmonary arteries from PAH patients compared to control donors. Using pharmacological inhibitors (AT13387 and 17‐AAG), we demonstrated that cytosolic Hsp90 stabilizes the expression of numerous clients proteins overexpressed in PAH that promote cell growth and survival. More importantly, we demonstrated that Hsp90 is specifically expressed in PAH‐PASMCs mitochondria (immunoblot, dual immunofluorescence and immunogold electronic microscopy), and not in healthy cells. Whereas cytosolic Hsp90 inhibition displays a lack of absolute specificity for PAH‐PASMCs, selective inhibition of mtHsp90 activity using Gamitrinib decreased PAH‐PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) without affecting control cells. In PAH‐PASMCs, mtHSP90 accumulation prevents the accumulation of mitochondrial DNA damage and maintains bioenergetics functions (Seahorse). In the fawn‐hooded rat and monocrotaline‐induced models of PAH, mtHsp90 inhibition reduces PA remodeling thus improving pulmonary hemodynamic parameters. CONCLUSION We demonstrated for the first time that accumulation of mtHsp90 is a cardinal feature of PAH‐PASMCs, contributing to the development of vascular lesions. Support or Funding Information ENTELLIGENCE young investigator program
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v31.S1
    DOI: 10.1096/fasebj.31.1_supplement.1073.10
    Language: English
    Publisher: Wiley
    Publication Date: 2017
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  • 2
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    Implication of the Histone Deacetylase 6 in pulmonary arterial hypertension
    Wiley ; 2017
    In:  The FASEB Journal Vol. 31, No. S1 ( 2017-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 31, No. S1 ( 2017-04)
    Abstract: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of complex etiology. Despite environmental stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) and endothelial cells (PAECs) exhibit a pro‐proliferative and anti‐apoptotic phenotype. Histone deacetylase 6 (HDAC6) is a cytoplasmic histone deacetylase overexpressed in response to stress and implicated in the regulation of multiple pro‐survival mechanisms in cancer cells. Therefore, we hypothesized that HDAC6 expression is increased in PAH‐PASMCs and PAH‐PAECs allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH. OBJECTIVE Using a multidisciplinary and translational approach we aimed to demonstrate that HDAC6 inhibition is a promising strategy to improve PAH. METHODS AND RESULTS HDAC6 is significantly up‐regulated (immunoblot) in lungs, distal PAs, and isolated PASMCs and PAECs from 10 PAH patients and 15 experimental PAH animal (5 Sugen/hypoxia rats; 5 monocrotaline rats and 5 chronic hypoxic mice) compared to controls. Molecular (siRNA) and pharmacological inhibition (Tubastatin and ACY‐775) of HDAC6 reduces dose‐dependently PAH‐PASMC/PAEC proliferation (Ki67 assay) and resistance to apoptosis (Annexin V assay) in vitro sparing control cells. Mechanistically, we demonstrated that HDAC6 deacetylates Ku70, blocking the translocation of Bax to mitochondria and preventing apoptosis. In vivo inhibition of HDAC6 (Tubastatin A 25mg/kg/day for 2 weeks) significantly improved (n=5 to 10 p 〈 0.05) established PAH by decreasing mean PA pressure, total pulmonary resistance and increasing cardiac output in two experimental models (Sugen/hypoxia and monocrotaline). In addition, we showed that HDAC6 inhibitor can be safely given in combination with currently approved PAH therapies (macitentan and tadalafil). Finally, Hdac6 K.O mice have significantly lower right ventricle systolic pressure in response to 3 weeks of chronic‐hypoxia compared to wild‐type mice. CONCLUSION We showed for the first time that HDAC6 is implicated in PAH development and represents a new promising therapeutic target to improve PAH. Support or Funding Information None
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v31.S1
    DOI: 10.1096/fasebj.31.1_supplement.1073.11
    Language: English
    Publisher: Wiley
    Publication Date: 2017
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    detail.hit.zdb_id: 639186-2
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  • 3
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    The Chaperone Protein Hsp90 is Upregulated in Human Pulmonary Hypertension
    Wiley ; 2015
    In:  The FASEB Journal Vol. 29, No. S1 ( 2015-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 29, No. S1 ( 2015-04)
    Abstract: Human and animal pulmonary arterial hypertension (PAH) is characterized by a selective activation of several transcription factors including STAT3, NFAT and HIF‐1α, which regulates pulmonary artery smooth muscle cells (PASMC) proliferation and apoptosis. The activation mechanisms of these factors in PAH remain elusive. Hsp90 is a major molecular chaperone that is plays a pivotal role in assisting correct folding and functionality of its client proteins. The Hsp90 client proteins include a wide variety of transcription factors like NFAT, STAT3 and HIF‐1α. Recent evidences have shown that miR‐223 may regulates HsP90 expression in cancer, which share many similarities with PAH. We thus hypothesized that the miR‐223/Hsp90 axis is aberrantly expressed in PAH patients, contributing to PAH‐PASMC phenotype. METHODS and RESULTS Using immunoblot, we showed that Hsp90 is upregulated in lungs, and PASMC of PAH patients compared to non‐PAH donors. This upregulation in Hsp90 is associated with a significant downregulation of miR223 in PAH; upregulation of HIF‐1α, NFAT and STAT3 activation measured by immunoblot and nuclear translocation assay. In primary cultured PASMC from 3 PAH and 3 control patients, we demonstrated that miR‐223 upregulation using mimic or Hsp90 molecular inhibition using siRNAs significantly reduces PAH‐PASMC proliferation and resistance to apoptosis. Finally, using monocrotaline‐induced PAH, we showed that miR223 nebulization decreases total pulmonary resistance by decreasing distal PA wall thickness. CONCLUSION The miR223/Hsp90 may represent a new signal hub in PAH, accounting for the activation of several transcription factors contributing to PAH‐PASMC phenotype and thus vascular remolding seen in PAH.
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v29.S1
    DOI: 10.1096/fasebj.29.1_supplement.662.21
    Language: English
    Publisher: Wiley
    Publication Date: 2015
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    detail.hit.zdb_id: 639186-2
    SSG: 12
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  • 4
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    HDAC6‐Hsp90 interplay in Pulmonary Arterial Hypertension
    Wiley ; 2016
    In:  The FASEB Journal Vol. 30, No. S1 ( 2016-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 30, No. S1 ( 2016-04)
    Abstract: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the elevation of mean pulmonary arterial pressure. Pulmonary arterial smooth muscle cells (PASMCs) from PAH patients exhibit a cancer‐like metabolic‐dependent pro‐proliferative, pro‐migratory and anti‐apoptotic phenotype leading to development of progressive pulmonary artery remodeling. The histone deacetylase 6 (HDAC6) is mainly cytoplasmic and involved primarily in “non‐histone” functions. HDAC6 interacts and deacetylates various proteins such as α‐tubulin and Hsp90 promoting proto‐oncogene activation such as Survivin (implicated in PAH) to carry out cancerous functions. We hypothesize that HDAC6/Hsp90 axis is up‐regulated in PAH and contributes to the development of the cancer‐like phenotype through in part Survivin stabilization. Method/Results Using a translational molecule‐cell‐organ‐animal and multidisciplinary approach, we demonstrated that both HDAC6 and HSP90 are up‐regulated (immunofluorescence and immunoblot; p 〈 0.01) in the lungs and PASMCs isolated from PAH patients (n=5) compared to age‐matched controls (n=5). HDAC6 inhibition via a pharmacological (Tubastatin A) or molecular (siHDAC6) approach dose dependently increased α‐tubulin acetylation and decreased PAH‐PASMC migration (wound healing assay; p 〈 0.05), resistance to apoptosis (Annexin‐V; p 〈 0.05) and proliferation (Ki67; p 〈 0.01). Increased apoptosis following Tubastatin A treatment was associated with mitochondrial membrane depolarization (TMRM) of PAH‐PASMCs and inhibition of the oxygen consumption rate in a concentration‐dependent manner (Seahorse XFe 24 system). All these effects were associated with a down‐regulation of Survivin. Similarly, inhibition of Hsp90 (AT13387 or siHsp90) reverses the cancer‐like phenotype and this effect was associated with a down‐regulation of HDAC6, suggesting that HDAC6 up‐regulation in PAH is Hsp90‐mediated. In vivo, HDAC6 inhibition in monocrotaline‐induced PAH decreases both mean pulmonary artery pressure (right heart catheterization, p 〈 0.01) and right ventricular hypertrophy (Fulton index). Conclusion We provide evidence that Hsp90 and HDAC6 are specifically up‐regulated in human PAH and contributes to the proliferative, migratory and anti‐apoptotic phenotype seen in PAH‐PASMCs. As HDAC6 inhibitors have been tested in cancer, this offers a short‐term new therapeutic avenue for PAH patients. Support or Funding Information Canada Research Chairs and CIHR grants to S. Bonnet and S. Provencher supported this work
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v30.S1
    DOI: 10.1096/fasebj.30.1_supplement.774.4
    Language: English
    Publisher: Wiley
    Publication Date: 2016
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    detail.hit.zdb_id: 639186-2
    SSG: 12
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  • 5
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    Role for RUNX2/HDAC6 Axis in Pulmonary Arterial Hypertension
    Wiley ; 2015
    In:  The FASEB Journal Vol. 29, No. S1 ( 2015-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 29, No. S1 ( 2015-04)
    Abstract: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation, migration, calcification and suppressed apoptosis. Numerous biological pathways have been implicated in this phenotype, including HIF‐1α. Recent studies have shown that miR‐204 downregulation upregulates the expression of RUNX2. RUNX2 is implicated in many features seen in PAH‐PASMC in part through the activation of HIF‐1α by a HDAC6‐depepdent mechanism. Thus we hypothesis that miR‐204‐dependent upregulation of RUNX2/HDAC6 axis promotes HIF‐1 α and development of PAH. Results Using human lungs, distal PAs and isolated PASMC from both control and PAH patients, we demonstrated a significant upregulation of RUNX2 and HDAC6 in PAH. Gain and loss of functions experiments in PASMC showed that downregulation of miR‐204 in controls PASMC increase RUNX2 expression, while increases miR‐204 in PAH‐PASMC decrease it. In controls PASMC, RUNX2 upregulation increases calcification,migration, proliferation, resistance to apoptosis through an HDAC6 and HIF‐1α dependent mechanism, as both tubastatin A (HDAC6 inhibitor) and siHIF‐1α blocks RUNX2 effects. Similarly in PAH‐PASMC siRUNX2 has the opposite effects. Finally, in sugen/hypoxia rat model of PAH, nebulization of siRUNX2 decreased mean PA pressure, pulmonary vascular resistance and increased compliance and cardiac output. Conclusion Taken together, our study uncovers a new miR‐204 dependent up regulation of RUNX2/HDAC6 axis contributing to calcification and to normoxic activation of HIF‐1α leading to proliferation, migration and resistance to apoptosis in PAH‐PASMC.
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v29.S1
    DOI: 10.1096/fasebj.29.1_supplement.662.22
    Language: English
    Publisher: Wiley
    Publication Date: 2015
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  • 6
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    Cause‐specific mortality after diagnosis of cancer among HIV‐positive patients: A collaborative analysis of cohort studies
    Wiley ; 2020
    In:  International Journal of Cancer Vol. 146, No. 11 ( 2020-06), p. 3134-3146
    Details
    In: International Journal of Cancer, Wiley, Vol. 146, No. 11 ( 2020-06), p. 3134-3146
    Abstract: What's new? People with HIV live longer than they used to, thanks to advances in antiretroviral therapy. These improvements reduced the incidence of AIDS‐defining malignancies, such as Kaposi's sarcoma, but the increased life expectancy has led to more diagnoses of cancers not traditionally associated with HIV. Here, the authors studied cause‐specific mortality among people with HIV diagnosed with cancer. For those people, within 5 years after a cancer diagnosis, cause of death was more likely to be cancer than AIDS. Survival rates after diagnosis varied by cancer type, but were similar to rates among the general population.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v146.11
    DOI: 10.1002/ijc.32895
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 7
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    Contribution of alcohol use in HIV /hepatitis C virus co‐infection to all‐cause and cause‐specific mortality: A collaboration of cohort studies
    Wiley ; 2023
    In:  Journal of Viral Hepatitis Vol. 30, No. 9 ( 2023-09), p. 775-786
    Details
    In: Journal of Viral Hepatitis, Wiley, Vol. 30, No. 9 ( 2023-09), p. 775-786
    Abstract: Among persons with HIV (PWH), higher alcohol use and having hepatitis C virus (HCV) are separately associated with increased morbidity and mortality. We investigated whether the association between alcohol use and mortality among PWH is modified by HCV. Data were combined from European and North American cohorts of adult PWH who started antiretroviral therapy (ART). Self‐reported alcohol use data, collected in diverse ways between cohorts, were converted to grams/day. Eligible PWH started ART during 2001–2017 and were followed from ART initiation for mortality. Interactions between the associations of baseline alcohol use (0, 0.1–20.0, 〉 20.0 g/day) and HCV status were assessed using multivariable Cox models. Of 58,769 PWH, 29,711 (51%), 23,974 (41%) and 5084 (9%) self‐reported alcohol use of 0 g/day, 0.1–20.0 g/day, and  〉  20.0 g/day, respectively, and 4799 (8%) had HCV at baseline. There were 844 deaths in 37,729 person‐years and 2755 deaths in 443,121 person‐years among those with and without HCV, respectively. Among PWH without HCV, adjusted hazard ratios (aHRs) for mortality were 1.18 (95% CI: 1.08–1.29) for 0.0 g/day and 1.84 (1.62–2.09) for 〉 20.0 g/day compared with 0.1–20.0 g/day. This J‐shaped pattern was absent among those with HCV: aHRs were 1.00 (0.86–1.17) for 0.0 g/day and 1.64 (1.33–2.02) for 〉 20.0 g/day compared with 0.1–20.0 g/day (interaction p   〈  .001). Among PWH without HCV, mortality was higher in both non‐drinkers and heavy drinkers compared with moderate alcohol drinkers. Among those with HCV, mortality was higher in heavy drinkers but not non‐drinkers, potentially due to differing reasons for not drinking (e.g. illness) between those with and without HCV.
    Type of Medium: Online Resource
    ISSN: 1352-0504 , 1365-2893
    URL: Issue
    URL: Article
    DOI: 10.1111/jvh.v30.9
    DOI: 10.1111/jvh.13863
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1212497-7
    detail.hit.zdb_id: 2007924-2
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  • 8
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    Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV‐positive individuals
    Wiley ; 2019
    In:  Statistics in Medicine Vol. 38, No. 13 ( 2019-06-15), p. 2428-2446
    Details
    In: Statistics in Medicine, Wiley, Vol. 38, No. 13 ( 2019-06-15), p. 2428-2446
    Abstract: Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV‐positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first‐line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV‐positive individuals included in the HIV‐CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow‐up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the “no direct effect” assumption. We found little differences on survival and AIDS‐free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/μl compared with 500 cells/μl and where treatment was switched at an HIV‐RNA threshold of 1000 copies/ml compared with 200 copies/ml. The “no direct effect” assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7‐ to 53‐fold increase in the effective sample size.
    Type of Medium: Online Resource
    ISSN: 0277-6715 , 1097-0258
    URL: Issue
    URL: Article
    DOI: 10.1002/sim.v38.13
    DOI: 10.1002/sim.8120
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2019
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    detail.hit.zdb_id: 1491221-1
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  • 9
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    Involvement of the TGFβ pathway in the regulation of α 5 β 1 integrins by caveolin‐1 in human glioblastoma
    Wiley ; 2012
    In:  International Journal of Cancer Vol. 131, No. 3 ( 2012-08), p. 601-611
    Details
    In: International Journal of Cancer, Wiley, Vol. 131, No. 3 ( 2012-08), p. 601-611
    Abstract: Caveolin‐1 plays a crucial role in the development of cancer and its progression. We previously reported that glioblastoma cells expressing low levels of caveolin‐1 exerted a more aggressive phenotype than cells expressing high levels. Such phenotype was due to the induction of α 5 β 1 integrin subsequent to the depletion of caveolin‐1. Caveolin‐1 was identified as a transcriptional repressor of α 5 β 1 integrin. The current study was designed to identify in vitro , the molecular mechanisms by which caveolin‐1 controls α 5 β 1 integrin expression and to determine if a negative correlation between caveolin‐1 and α 5 β 1 integrins also exists in biopsies and xenografted human brain tumors. We showed that depletion of caveolin‐1 lead to the activation of the TGFβ/TGFβRI/Smad2 pathway which in turn induced the expression of α 5 β 1 integrins. We showed that cells expressing the lowest levels of caveolin‐1 but the highest levels of α 5 β 1 integrins and TGFβRI were the most sensitive to a α 5 β 1 integrin antagonist and a TGFβRI inhibitor. Screening human glioma biopsies and human glioblastoma xenografts, we isolated subgroups with either low levels of caveolin‐1 but high levels of α 5 β 1 integrin and TGFβRI or high levels of caveolin‐1 but low levels of α 5 β 1 integrin and TGFβRI. In conclusion, caveolin‐1 controls α 5 β 1 integrin expression through the TGFβ/TGFβRI/Smad2 pathway. The status of caveolin‐1/α 5 β 1 integrins/TGFβRI might be a useful marker of the tumor evolution/prognosis as well as a predictor of anti‐TGFβ or anti‐α 5 β 1 integrin therapies.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v131.3
    DOI: 10.1002/ijc.26415
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 10
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    Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years
    Wiley ; 2019
    In:  European Journal of Heart Failure Vol. 21, No. 12 ( 2019-12), p. 1619-1627
    Details
    In: European Journal of Heart Failure, Wiley, Vol. 21, No. 12 ( 2019-12), p. 1619-1627
    Abstract: The MITRA‐FR trial showed that among symptomatic patients with severe secondary mitral regurgitation, percutaneous repair did not reduce the risk of death or hospitalization for heart failure at 12 months compared with guideline‐directed medical treatment alone. We report the 24‐month outcome from this trial. Methods and results At 37 centres, we randomly assigned 304 symptomatic heart failure patients with severe secondary mitral regurgitation (effective regurgitant orifice area 〉 20 mm 2 or regurgitant volume 〉 30 mL), and left ventricular ejection fraction between 15% and 40% to undergo percutaneous valve repair plus medical treatment (intervention group, n  = 152) or medical treatment alone (control group, n  = 152). The primary efficacy outcome was the composite of all‐cause death and unplanned hospitalization for heart failure at 12 months. At 24 months, all‐cause death and unplanned hospitalization for heart failure occurred in 63.8% of patients (97/152) in the intervention group and 67.1% (102/152) in the control group [hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.77–1.34]. All‐cause mortality occurred in 34.9% of patients (53/152) in the intervention group and 34.2% (52/152) in the control group (HR 1.02, 95% CI 0.70–1.50). Unplanned hospitalization for heart failure occurred in 55.9% of patients (85/152) in the intervention group and 61.8% (94/152) in the control group (HR 0.97, 95% CI 0.72–1.30). Conclusions In patients with severe secondary mitral regurgitation, percutaneous repair added to medical treatment did not significantly reduce the risk of death or hospitalization for heart failure at 2 years compared with medical treatment alone.
    Type of Medium: Online Resource
    ISSN: 1388-9842 , 1879-0844
    URL: Issue
    URL: Article
    DOI: 10.1002/ejhf.v21.12
    DOI: 10.1002/ejhf.1616
    Language: English
    Publisher: Wiley
    Publication Date: 2019
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