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Background: Because of the wide variation in the course of Takayasu arteritis (TA), predicting outcome is challenging. We assess long-term outcome and prognosis factors for vascular complications in patients with TA., Methods: A retrospective multicenter study of characteristics and outcomes of 318 patients with TA fulfilling American College of Rheumatology and Ishikawa criteria was analyzed. Factors associated with event-free survival, relapse-free survival, and incidences of vascular complications were assessed. Risk factors for vascular complications were identified in a multivariable model., Results: The median age at TA diagnosis was 36 [25-47] years, and 276 patients (86.8%) were women. After a median follow-up of 6.1 years, relapses were observed in 43%, vascular complications in 38%, and death in 5%. Progressive clinical course was observed in 45%, carotidodynia in 10%, and retinopathy in 4%. The 5- and 10-year event-free survival, relapse-free survival, and complication-free survival were 48.2% (42.2; 54.9) and 36.4% (30.3; 43.9), 58.6% (52.7; 65.1) and 47.7% (41.2; 55.1), and 69.9% (64.3; 76.0) and 53.7% (46.8; 61.7), respectively. Progressive disease course ( P =0.018) and carotidynia ( P =0.036) were independently associated with event-free survival. Male sex ( P =0.048), elevated C-reactive protein ( P =0.013), and carotidynia ( P =0.003) were associated with relapse-free survival. Progressive disease course ( P =0.017), thoracic aorta involvement ( P =0.009), and retinopathy ( P =0.002) were associated with complication-free survival., Conclusions: This nationwide study shows that 50% of patients with TA will relapse and experience a vascular complication ≤10 years from diagnosis. We identified specific characteristics that identified those at highest risk for subsequent vascular complications., (© 2017 American Heart Association, Inc.)

Lower extremity peripheral artery disease (PAD) is one manifestation of atherosclerosis. Patients with PAD have an increased rate of mortality due to concurrent coronary artery disease and hypertension. Betablockers (BB) may, therefore, be prescribed, especially in case of heart failure. However, BB safety in PAD is controversial, because of presumed peripheral hemodynamic consequences of BB that could lead to worsening of symptoms in patients with PAD. In this context, we aimed to determine the impact of BB on all-cause and cardiovascular mortality and amputation rate at 1 year after hospitalization for PAD from the COPART Registry population. This is a prospective multicenter observational study collecting data from consecutive patients hospitalized for PAD in vascular medicine departments of 4 academic hospitals in France. Patients with, either claudication, critical limb ischemia or acute lower limb ischemia related to a documented PAD were included. We compared the outcomes of patients with BB versus those without BB in their prescription list at hospital discharge. The mean age of the study population was 70.9 years, predominantly composed of males (71%). Among the 1267 patients at admission, 28% were treated by BB for hypertension, prior myocardial infarction or heart failure. During their hospital stay, 40% underwent revascularization (including bypass surgery 29% and angioplasty 74%), 17% required an amputation, and 5% died. In a multivariate analysis, only prior myocardial infarction was found associated with BB prescription with an odds ratio (OR) of 3.11, P < 0.001. Conversely, chronic obstructive pulmonary disease or PAD with ulcer impeded BB prescription (OR: 0.57 and 0.64, P = 0.007; P = 0.001, respectively). One-year overall mortality of patients with BB did not differ from those without (23% vs. 23%, P = 0.95). The 1-year amputation rate did not differ either (4% vs. 6%, P = 0.14). Patients hospitalized for PAD with a BB in their prescription did not worsen their outcome at 1 year compared to patients without BB. Based on these safety data, prospective study could be conducted to assess the effect of BB on long-term mortality and amputation rate in patients with mild, moderate, and severe PAD., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background: The goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-α antagonists and tocilizumab) in patients with Takayasu arteritis., Methods and Results: This was a retrospective, multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years [20-55 years] treated by tumor necrosis factor-α antagonists [80%] or tocilizumab [20%]) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 [1-5]). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L [10-46 mg/L] versus 58 mg/L [26-76 mg/L]; P=0.006) and a trend toward fewer immunosuppressants drugs used before biologics (P=0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L [P<0.05] and 15 versus 7.5 mg [P<0.05] at baseline and 12 months, respectively). The 3-year relapse-free survival was 90.9% (83.5%-99%) over the biological treatment period compared with 58.7% (43.3%-79.7%; P=0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-α antagonists and tocilizumab. After a median follow-up of 24 months (2-95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases., Conclusion: This nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile., (© 2015 American Heart Association, Inc.)

Background: Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and >30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering., Methods and Results: Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n=7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6±0.1 mm; MR regurgitation fraction, 24.2±2.9%) and mitral annulus dilatation (P<0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9±1.1 mm in controls, 0.5±0.08 with both, 1.0±0.3 with chordal cutting alone, 2.0±0.4 with ring alone; P<0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P<0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r(2)=0.82, P<0.01)., Conclusions: Comprehensive annular and subvalvular repair improves long-term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up.

Background: one of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling that exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing 2 second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting., Methods and Results: a posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, 6 sheep were randomized to sham surgery (control group) and 12 to second-order chordal cutting (6 each to anterior leaflet [AntL] and bileaflet [BiL] chordal cutting, techniques that are in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-myocardial infarction (MI) (euthanasia), we measured LV end-diastolic (EDV) and end-systolic volume (ESV), ejection fraction, wall motion score index, and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echocardiography. All measurements were comparable among groups at baseline and chronic MI. At euthanasia, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls versus 30.5±6.1% with chordal cutting (P<0.01) (LVESV in controls, 82.5±2.6 mL; in AntL, 60.6±5.1 mL; in BiL, 61.8±4.1 mL). LVEDV increased by 63±2.0% in controls versus 26±5.5% and 22±3.4% with chordal cutting (P<0.01). LV ejection fraction and wall motion score index were not significantly different at follow-up among the chordal cutting and control groups. MR progressively increased to moderate in controls but decreased to trace-mild with AntL and BiL chordal cutting (MR vena contracta in controls, 5.9±1.1 mm; in AntL, 2.6±0.1 mm; in BiL, 1.7±0.1 mm; P<0.01). BiL chordal cutting provided greater PL mobility (decreased PL restriction angle to 54.2±5.0° versus 83±3.2° with AntL chordal cutting; P<0.01)., Conclusions: reduced leaflet tethering by chordal cutting in the chronic post-MI setting substantially decreases the progression of LV remodeling with sustained reduction of MR over a chronic follow-up. These benefits have the potential to improve clinical outcomes.

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.

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.

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.

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.

The objective of this study was to evaluate, using echocardiography, the involvement of the renin-angiotensin system (RAS) in left ventricular (LV) hypertrophy development in experimental hyperthyroidism. Thyrotoxicosis was produced by a daily intraperitoneal injection of L-thyroxine (T4), 0.1 mg/kg per day for 15 days in Wistar rats. Control (euthyroid) rats received intraperitoneal daily injection of the thyroxine solvent. Two series of experiments were performed. In the first series, euthyroid (n = 10) and hyperthyroid (n = 14) rats were surgically prepared with a femoral artery catheter. After a 3-day recovery period, blood pressure and heart rate were measured and blood samples were collected in conscious and unrestrained rats. In the second series of experiment, measurement of LV geometry was realized with two-dimensional time-movement echocardiography on the 15th day of treatment in control conditions and after long-term treatment with the angiotensin II type I receptor antagonist valsartan (10 mg/kg per day for 15 days) in both euthyroid and hyperthyroid rats. The dose and duration of T4 treatment was sufficient to induce a significant degree of hyperthyroidism with characteristic features including tachycardia, systolic hypertension, myocardial hypertrophy, hyperthermia, and weight loss. In addition, we measured an increase in free fractions of thyroid hormones, and a threefold increase in plasma renin activity. Echocardiographic examinations in rats revealed a strong correlation between LV weight and echocardiographic LV mass. Hyperthyroid rats exhibited an increased LV mass with a marked increase in the LV end-diastolic posterior wall and septal thickness. Chronic treatment with valsartan prevented this concentric LV hypertrophy (p < 0.01), with full prevention of the LV posterior wall hypertrophy (p < 0.001) and decreased LV septal hypertrophy (p < 0.05). In conclusion, the cardiovascular alterations of hyperthyroidism were reproduced with thyroid hormone injections in rats. Activation of the RAS in hyperthyroid rats was accompanied by increased LV mass. Using valsartan, we demonstrated that the RAS impinged on the LV remodelling in our experimental hyperthyroidism model. A chronic treatment with an angiotensin II type I receptor antagonist prevented the development of the concentric LV hypertrophy associated with thyrotoxicosis.

Background: Autologous skeletal myoblast (SM) transplantation improves function of infarcted myocardium, but pretransplantation cultures remain a complex process. This study assessed whether it could be optimized by muscle preconditioning with the local anesthetic bupivacaine or even bypassed with the use of the so-called mince technique., Methods and Results: Muscle preconditioning consisted of intramuscular injections of the tibialis anterior of rats, 2 days before harvest. After 7 days of culture, the number of available myoblasts was significantly increased compared with nonconditioned controls (1 683 147 versus 85 300, P:=0.0013). The mince technique was then assessed. A myocardial infarction was created in 66 rats by coronary artery ligation. One week later, rats were reoperated on and intramyocardially injected with culture medium alone (controls, n=23), autologous cultured SM (3.5 x 10(6), n=21), or autologous muscle minced into a fine slurry, which was immediately transplanted (n=22). All muscles had been preconditioned. Left ventricular function was assessed by 2D echocardiography. Whereas end-diastolic volumes expanded over time in all groups, left ventricular ejection fraction (%, mean+/-SEM) was increased only in the cultured SM-transplanted group at 1 (P:=0. 0006) and 2 months (P:=0.0008) versus baseline (37.52+/-1.92 and 40. 92+/-2.17 versus 30.34+/-1.74), with a significant additional benefit between 1 and 2 months (P:=0.0069)., Conclusions: Cell culture remains mandatory for SM transplantation to be successful but, in a clinical perspective, this process can be made more expeditious by preharvest muscle conditioning with bupivacaine, which greatly enhances the baseline cell yield.