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Emmanuel Messas

Publications and source records attributed to Emmanuel Messas.

14 recordsLinked to original sources
PubMed2006

Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients.

BACKGROUND: Skeletal myoblast (SM) transplantation (Tx) in a post-myocardial infarction (MI) scar experimentally improves left ventricular (LV) ejection fraction (EF). Short-term follow-up (FU) studies have suggested that a similar benefit could clinically occur despite an increased risk of LV arrhythmias. METHODS AND RESULTS: We report the long-term FU of the first worldwide cohort of grafted patients (n = 9, 61.8+/-11.6 years, previous MI, EF < or = 35%) operated on (autologous SM Tx and bypass surgery) in 2000 to 2001 and evaluated before Tx, at 1 month (M1) and at a median FU of 52 (18 to 58) months after Tx (37 patient-years). NYHA class improved from 2.5+/-0.5 to 1.8+/-0.4 at M1 (P=0.004 versus baseline) and 1.7+/-0.5 at FU (P=not significant versus M1; P=0.0007 versus baseline). EF increased from 24.3+/-4% to 31+/-4.1% at M1 (+28%, P=0.001 versus baseline) and remained stable thereafter (28.7+/-8.1%, +18% versus baseline). There were 5 hospitalizations for heart failure in 3 patients at 28.6+/-9.9 months, allowing implant in 2 patients with a resynchronization pacemaker. An automatic cardiac defibrillator (ACD) was implanted in 5 patients for nonsustained (n =1) or sustained (n =4) ventricular tachycardia at 12.2+/-18.6 (1 to 45) months. Despite a beta-blocker/amiodarone combination therapy, there were 14 appropriate shocks for 3 arrhythmic storms in 3 patients at 6, 7, and 18 months after ACD implantation. CONCLUSIONS: In this cohort of severe heart failure patients both clinical status and EF stably improve over time with a strikingly low incidence of hospitalizations for heart failure (0.13/patient-years) and the arrhythmic risk can be controlled by medical therapy and/or on-request ACD implantation.

Adrenergic beta-Antagonists↗
PubMed2006

Chordal cutting does not adversely affect left ventricle contractile function.

BACKGROUND: Severing a limited number of second-order chordae to the anterior leaflet can improve ischemic mitral regurgitation (MR). Some concerns have been raised regarding possible influence on regional and global left ventricle (LV) function. We evaluated changes in cardiac function in 5 normal sheep with cutting of pre-instrumented chords in the beating heart to maintain constant load. METHODS AND RESULTS: Under cardiopulmonary bypass, wires were placed around the 2 central basal chordae and brought outside the heart, which was restarted. Hemodynamic and imaging data were collected before and after chordal cutting by radiofrequency ablation using those wires. Segmental contractility was assessed invasively using sonomicrometers and noninvasively using Doppler tissue velocity and strain rate (with strain rate viewed as less load-dependent than ejection fraction) at 6 sites: base, mid-ventricle, and apex along the anteroseptal and posterolateral walls. We found no changes from before to after chordal cutting in LV end-diastolic volume (47.2+/-3.3 after cutting versus 48.4+/-4.6 mL before cutting, P=0.66), end-systolic volume (21.5+/-1.2 versus 22.3+/-2.8 mL, P=0.68), ejection fraction (54.2+/-1.8 versus 54.2+/-2.7%, P=0.96), systolic ventricular elastance (7.28+/-1.68 versus 7.66+/-2.11 mm Hg/mL, P=0.64), preload-recruitable stroke work (46.6+/-7.7 versus 50.2+/-10.7 mm Hg, P=0.76), and LVdP/dt (1480+/-238 versus 1392+/-250 mm Hg/s, P=0.45). Doppler tissue velocities and longitudinal strain rates surrounding the papillary muscles were unchanged, as were sonomicrometer longitudinal and mediolateral absolute strains. No wall motion abnormalities were visible around the papillary muscles, and no MR developed. CONCLUSIONS: We find no evidence for acutely decreased global or segmental LV contractility with chordal cutting. This absence of adverse effects is consistent with long-term clinical experience with cutting these chords in valve repair.

Animals↗
PubMed2006

Autologous myoblast transplantation for chronic ischemic mitral regurgitation.

OBJECTIVES: This study was designed to assess whether post-myocardial infarction (MI) in-scar transplantation of skeletal myoblasts (SM) could reduce chronic ischemic mitral regurgitation (MR) by decreasing left ventricular (LV) remodeling. BACKGROUND: Extensive work has confirmed the relationship between ischemic MR and post-myocardial infarction (MI) remodeling of the LV. METHODS: An infero-posterior MI was created in 13 sheep, thereby resulting in increasing MR. Two months post-MI, the animals were randomized and in-scar injected with expanded autologous SM (n = 6, mean: 251 x 10(6) cells) or culture medium only (n = 7). Three-dimensional echocardiography was performed at baseline, before transplantation, and for two months thereafter (sacrifice), with measurements of LV end-diastolic and end-systolic volumes (ESV), ejection fraction (EF), MR stroke volume, and leaflet tethering distance; wall motion score index (WMSi) was assessed by two-dimensional echo. RESULTS: Measurements were similar between groups at baseline and before transplantation. At sacrifice, transplantation was found to have reduced MR progression (regurgitant volume change: -1.83 +/- 0.32 ml vs. 5.9 +/- 0.7 ml in control group, p < 0.0001) and tethering distance (-0.41 +/- 0.09 cm vs. 0.44 +/- 0.12 cm in control group, p < 0.001), with significant improvement of EF (2.01 +/- 0.94% vs. -4.86 +/- 2.23%, p = 0.02), WMSi (-0.25 +/- 0.11 vs. 0.13 +/- 0.03 in controls, p < 0.01) and a trend to a lesser increase in ESV (23.3 +/- 3.5 ml vs. 35.4 +/- 4.2 ml in control group, p = 0.055). CONCLUSIONS: Autologous skeletal myoblast transplantation attenuates mild-to-moderate chronic ischemic MR, which otherwise is progressive, by decreasing tethering distance and improving EF and wall motion score, thereby enhancing valve coaptation. These data shed additional light on the mechanism by which skeletal myoblast transplantation may be cardioprotective.

Animals↗
PubMed2006

Doxycycline affects diet- and bacteria-associated atherosclerosis in an ApoE heterozygote murine model: cytokine profiling implications.

BACKGROUND: It has been postulated that systemic infection with pathogens such as Porphyromonas gingivalis (Pg) elevates the inflammatory response and increases susceptibility to atherosclerosis. We hypothesized that Doxycycline would be beneficial in diet- and/or Pg-induced atherosclerosis given its role in various cell functions and matrix remodeling. METHODS AND RESULTS: ApoE+/- mice were inoculated weekly with Pg and treated with either Doxycycline or saline; animals were fed either a high-fat or chow diet. Animals were euthanized at 14 or 24 weeks and histomorphometric analysis of atheromatous lesions in proximal aorta, levels of SAA and serum cytokine profiling were performed. Histomorphometric analysis demonstrated that in non-infected mice fed a high fat diet, Doxycycline treatment resulted in a reduction of mean lesions from 10.5%+/-.49 to 1.09%+/-0.102 (p<0.05) at 14 weeks and a reduction from 21.5%+/-6.49 to 8.26%+/-0.162 (p=0.106) at 24 weeks. Chow-fed Pg mice treated with Doxyclycline also resulted in a reduction from 0.62%+/-0.128 to 0.0%+/-0.0 (p<0.05) at 14 weeks and a reduction from 0.92%+/-0.23 to 0.0%+/-0.0 (p<0.05) at 24 weeks. Administration of Doxycycline to mice fed a high fat diet and Pg-inoculated resulted in a reduction of mean percentage of atheromatous lesions from 16.46%+/-1.69 to 1.141%+/-0.23 (p<0.05) at 14 weeks and a reduction from 25.27%+/-1.734 to 0.428%+/-0.033 (p<0.05) at 24 weeks. At this timepoint, SAA levels in Pg-infected animals were reduced by five-fold and three-fold in Doxycycline-treated chow and high fat-diet groups, respectively. Cytokine antibody arrays revealed a marked reduction in the levels of pro-inflammatory cytokines in Doxycycline-treated groups whether Pg-infected or fed a high fat diet while anti-inflammatory cytokines were not affected. Consistent with the role of Doxycycline on matrix proteases, at 24 weeks MMP-9 Serum levels were markedly reduced by 60% (p<0.05) and 30% (p<0.05) with Doxycycline treatment in Pg-infected high fat and chow diet groups, respectively. CONCLUSIONS: Doxycycline decreases pro-inflammatory cytokines and results in reduction of atherosclerosis in ApoE+/-Pg-inoculated and/or high fat diet fed mice.

Animals↗
PubMed2005

Skeletal myoblast transplantation through a catheter-based coronary sinus approach: an effective means of improving function of infarcted myocardium.

AIMS: This study was designed to assess the functional effects of a transvenous coronary sinus technique of skeletal myoblast delivery in infarcted myocardium. METHODS AND RESULTS: An anterior myocardial infarction was created percutaneously in 14 sheep. Simultaneously, a muscle biopsy was harvested and expanded. Two weeks later, sheep were instrumented percutaneously with a dedicated catheter incorporating an extendable needle for puncture of the venous wall and, under endovascular ultrasound guidance, a microcatheter was advanced through the needle into the target scar for cell delivery. Following the baseline echocardiographic assessment of left ventricular (LV) function, sheep were randomly allocated to receive four-staged in-scar injections of either autologous cells (n=7) or culture medium (n=7). Two months later, LV function was reassessed blindly and hearts were explanted for subsequent histological and immunohistochemical analysis. There were no acute procedural complications. Baseline LV ejection fraction (EF) was significantly lower in transplanted sheep than in controls [38% (35-48) vs. 51% (38-55), respectively, P=0.03; median (range)]. Two months later, LVEF was significantly higher in the transplanted group than in controls [50% (47-56) vs. 39% (36-47), respectively, P=0.002]. Clusters of myoblasts were identified by histology and immunohistochemistry in three of the seven transplanted sheep. CONCLUSION: These data suggest the functional efficacy of the transvenous coronary sinus technique as a less invasive means of cell delivery to infarcted myocardium.

Animals↗
PubMed2004

Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model: pharmacotherapeutic implications.

BACKGROUND: Current data demonstrate that progressive atherosclerosis is associated with activation of the inflammatory process, as evidenced by systemic elevations of molecules such as tumor necrosis factor, interleukin (IL)-6, and IL-1. It has been postulated that inflammatory events within an atherogenic lesion are induced by oxidized LDL. Recent evidence suggests that infectious agents, including those that cause periodontal disease, may also play an important role. Studies presented here tested the hypothesis that IL-1 receptor (IL-1R1) signaling plays a crucial role in bacteria- and/or high-fat diet (HFD)-enhanced atherogenesis. METHODS AND RESULTS: Ten-week-old ApoE+/- mice lacking either 1 IL-1R1 allele (ApoE+/-/IL-1R1+/-) or 2 IL-1R1 alleles (ApoE+/-/IL-1R1-/-) fed either an HFD or regular chow were inoculated intravenously with live Porphyromonas gingivalis (P gingivalis) (10(7) CFU), an important periodontal pathogen, or vehicle once per week for 14 or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, and ELISA for systemic proinflammatory mediators were performed. Atherosclerotic lesions of proximal aortas and aortic tree were substantially reduced in ApoE+/-/IL-1R1-/- mice than in ApoE+/-/IL-1R1+/- mice challenged with P gingivalis. At 24 weeks after P gingivalis inoculation, proximal aortic lesion size quantified by histomorphometry was 5-fold-reduced in chow-fed ApoE+/-/IL-1R1-/- mice than in ApoE+/-/IL-1R1+/- mice (P<0.05). In the HFD group, ApoE+/-/IL-1R1-/- mice exhibited marked attenuation of the progression of atherosclerotic lesions (78% to 97%), with and without P gingivalis inoculation (P<0.05). CONCLUSIONS: Ablation of IL-1R1 under P gingivalis challenge and/or an HFD reduced the progression of atherosclerotic plaques. These results indicate that IL-1 plays a crucial role in bacteria- and/or HFD-enhanced atherogenesis.

Animals↗
PubMed2003

Efficacy of chordal cutting to relieve chronic persistent ischemic mitral regurgitation.

BACKGROUND: Mitral regurgitation (MR) conveys adverse prognosis in ischemic heart disease. Leaflet closure is restricted by tethering to displaced papillary muscles, and is, therefore, incompletely treated by annular reduction. In an acute ischemic model, we reduced such MR by cutting a limited number of critically positioned chordae to the leaflet base that most restrict closure but are not required to prevent prolapse. Whether this is effective without prolapse, recurrent MR, or left ventricular (LV) failure in chronic persistent ischemic MR, despite greater LV remodeling, remains to be established. Therefore, we studied 7 sheep with chronic inferobasal infarcts known to produce progressive MR over 2 months. In all of those sheep, after a mean of 4.1 months, the 2 central basal (intermediate) chordae were cut at the chronic ischemic MR stage. 3-Dimensional echo quantified MR, LV function, and valve geometry. Five other sheep were followed for a mean of 7.8+/-1.2 months after inferobasal infarction with chordal cutting. RESULTS: All 7 of the sheep with chronic ischemic MR (increased from 1.4+/-0.4 to 11.1+/-0.5 mL/beat, regurgitant fraction=39.0+/-4.2%, P<0.0001) showed anterior leaflet angulation at the basal chord insertion. Although end-systolic volume had doubled, cutting the 2 central basal chordae significantly decreased the MR to baseline (P<0.0001) without prolapse or decline in EF (41.1+/-1.5% to 42.6+/-1.6%, P=not significant [NS]). The five sheep with long-term follow-up showed no prolapse or MR, and no significant post-infarct decrease in LV ejection fraction (EF; 38.9+/-2.4% to 41.4+/-1.2%, P=NS). CONCLUSIONS: Cutting a minimum number of basal (intermediate) chordae can improve coaptation and reduce chronic persistent ischemic MR without impairing LVEF. No adverse effects were noted long-term after chordal cutting at the time of infarction.

Animals↗
PubMed2003

Transplantation of autologous fresh bone marrow into infarcted myocardium: a word of caution.

BACKGROUND: As the benefits of extemporaneous transplantation (Tx) of fresh (unfractionated) autologous bone marrow (BM) have been primarily studied in the setting of acute myocardial infarction, we assessed whether this approach could be effective for regenerating chronically infarcted myocardium. METHODS AND RESULTS: Myocardial infarction was created in 18 sheep by ligation of circumflex arterial branches. Three weeks later, BM was aspirated from the iliac crest, washed, labeled with the fluorescent dye Dil and reinjected (mean: 422 x 10(6) cells in 3 mL) in 10 sites across the infarcted area through the reopened thoracotomy (n=9). Nine controls received culture medium. Left ventricular (LV) function was assessed before and 2 months after Tx by two-dimensional echocardiography whereas transmural velocity gradients were measured using M-mode tissue Doppler imaging at the center of the infarcted/grafted area. Formalin-fixed hearts were processed for the detection of grafted cells and angiogenesis. LV ejection fraction deteriorated similarly in the Tx and control groups (from 42+/-5% to 30+/-4% and from 40+/-4% to 31+/-1%, respectively; P=0.86). Likewise, BM Tx failed to prevent LV dilatation and impairment of the global wall motion score. The decrease in regional systolic velocity gradients (s(-1)) featured a similar pattern (Tx group: from 0.77+/-0.11 to 0.31+/-0.07; control group: from 0.73+/-0.10 to 0.50+/-0.07; P=0.06). Histologically, there was neither BM tissue engraftment, except for a few scattered Dil-positive macrophages in the infarcted fibrotic areas nor transdifferentiation of BM cells into endothelial cells. CONCLUSIONS: These data caution against the functional efficacy of extemporaneous Tx of fresh unfractionated BM into postinfarction scars.

Animals↗
PubMed2003

Leaflet concavity: a rapid visual clue to the presence and mechanism of functional mitral regurgitation.

Repairing mitral regurgitation (MR) requires an understanding of its mechanism. Evaluating restricted leaflet closure in functional MR is challenging. Tenting area between leaflets and annulus in long-axis (LAX) views correlates with MR, but is positive even in control subjects; in the 4-chamber view, the incomplete mitral leaflet closure (IMLC) tenting pattern may be subtle and variable. We tested the hypothesis that leaflet concavity toward the left atrium in the LAX view, a rapid visual clue indicating abnormal tethering predominantly by intermediate chords, is a strong indicator of functional MR. We reviewed 90 patients: 40 with inferior myocardial infarction and ejection fraction > or = 50%; 40 with global left ventricular dysfunction and ejection fraction < 50%; and 10 control subjects. We assessed leaflet shape (concave or convex toward the left atrium) and maximum systolic proximal MR jet width in the LAX views. To quantify shape, we measured the leaflet concavity area between the anterior leaflet and a line connecting its ends. Conventional IMLC area was also assessed. Patients with leaflet concavity had significantly greater MR than those without this finding (jet width of 4.6 +/- 0.7 vs 0.5 +/- 0.1 mm, P <.0001), indicating mild-moderate versus trace MR, with differences comparable in those with inferior myocardial infarction and left ventricular dysfunction. Leaflet concavity area most strongly predicted MR by multivariate regression (R(2) = 0.7). Conventional IMLC area did not uniquely distinguish patients with or without MR and correlated more weakly with MR (R(2) = 0.30 vs 0.73). Mitral leaflet concavity in the LAX view provides rapid and reliable recognition of functional MR, with greater reliability than IMLC area. This shape, consistent with tethering by intermediate chords, may have implications for potential intervention.

Aged↗
PubMed2002

Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model.

BACKGROUND: Current epidemiological data suggest that dental infections affecting tooth-supporting tissues (periodontitis) can disseminate into the systemic circulation and thereby contribute to atherosclerosis progression. To test this hypothesis, we investigated the effect of repeated systemic inoculations with Porphyromonas gingivalis (Pg), a putative periodontal pathogen, on the progression of atherosclerosis in heterozygous apolipoprotein E-deficient (ApoE(+/-)) mice. METHODS AND RESULTS: Ten-week-old, male ApoE(+/-) mice fed either a high-fat diet or regular chow were inoculated intravenously with live Pg (10(7) CFU) or vehicle once per week for 10, 14, or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, Pg 16S ribosomal DNA amplification with polymerase chain reaction, ELISA for systemic proinflammatory mediators, and immunolocalization of macrophages in the proximal aorta were performed. Atherosclerotic lesions of the proximal aortas and aortic trees were more advanced in Pg-challenged animals than in vehicle control animals and occurred earlier (at 10 weeks) when no lesions were apparent in control animals. At 24 weeks after inoculation, proximal aortic lesion size quantified by histomorphometry was 9-fold greater in chow-fed mice inoculated with Pg than in noninoculated mice (P<0.001) and was 2-fold greater in Pg-inoculated versus noninoculated high-fat diet-fed mice (P<0.001); all atherosclerotic lesions were macrophage-rich. Pg ribosomal DNA was found in the aortas, livers, and hearts 24 weeks after inoculation. CONCLUSIONS: These results provide evidence that long-term systemic challenge with Porphyromonas gingivalis, an oral pathogen, can accelerate atherogenic plaque progression.

Animals↗
PubMed2002

Mechanistic insights into functional mitral regurgitation.

Effective valve repair in patients with mitral regurgitation (MR) demands an understanding of its mechanism. In patients with ischemic heart disease and functional MR, which doubles late mortality, normal leaflets are apically displaced. This reflects an altered balance of forces acting on the leaflets: increased tethering forces restricting closure, resulting from an altered geometry of leaflet attachments, and decreased ventricular forces acting to close the leaflets. Extensive evidence confirms a central and predominant role of tethering as the final common pathway inducing functional MR; left ventricular (LV) pressure dynamically modulates the orifice area. Because ischemic MR is a disease of the entire mitral complex, including the remodeling LV, reducing annular size alone is often ineffective. Undersizing rings attempts to compensate for tethering; new and potentially more effective strategies directly address tethering by infarct plication, papillary muscle repositioning with a localized patch, or basal chordal cutting to increase coaptational surface area without prolapse. A comprehensive understanding of the valve in its ventricular context, therefore, provides new opportunities for successful valve repair in patients.

Humans↗
PubMedDate not supplied

Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study.

BACKGROUND: Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model. METHODS: We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation. FINDINGS: Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9.9% (range -20 to 0.3) relative to baseline (p=0.011) whereas in the treated group it improved by 6.6% (-5.7 to 50.8; comparison between groups p=0.002). INTERPRETATION: These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.

Animals↗