Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure.

BACKGROUND: Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-ß1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-ß1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFß family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFß coreceptor that promotes TGF-ß1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity. METHODS: We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction-induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. RESULTS: BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9-/- mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction-induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3. CONCLUSIONS: Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.

Acute Hemodynamic Effects of Intra-aortic Balloon Counterpulsation Pumps in Advanced Heart Failure.

BACKGROUND: The utility of intra-aortic balloon counterpulsation pumps (IABPs) in low cardiac output states is unknown and no studies have explored the impact of IABP therapy on ventricular workload in patients with advanced heart failure (HF). For these reasons, we explored the acute hemodynamic effects of IABP therapy in patients with advanced HF. METHODS: We prospectively studied 10 consecutive patients with stage D HF referred for IABP placement before left ventricular assist device (LVAD) surgery and compared with 5 control patients with preserved left ventricular (LV) ejection fraction (EF) who did not receive IABP therapy. Hemodynamics were recorded using LV conductance and pulmonary artery catheters. Cardiac index (CI)-responder and CI-nonresponder status was assigned a priori as being "equal to or above" or below the median of the IABP effect on CI, respectively, within 24 hours after IABP activation. RESULTS: Compared with controls, patients with advanced HF had lower LVEF, lower LV end-systolic pressure, lower LV stroke work, and higher LV end-diastolic pressures and volumes before IABP activation. IABP activation reduced LV stroke work primarily by reducing end-systolic pressure. IABP therapy increased CI by a median of 20% as well as increased diastolic pressure time index and the myocardial oxygen supply:demand ratio. Compared with CI-nonresponders, CI-responders had higher systemic vascular resistance, lower right heart filling pressures, and a trend toward lower left heart filling pressures with improved indices of right heart function. Compared with CI-nonresponders, the diastolic pressure time index was increased among CI-responders. CONCLUSIONS: IABP therapy may be effective at reducing LV stroke work, increasing CI, and favorably altering the myocardial oxygen supply:demand ratio in patients with advanced HF, especially among patients with low right heart filling pressures and high systemic vascular resistance.

Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling.

Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFß) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles. Tamoxifen treated wild-type (WT-TAM; n = 5) and vehicle treated AlK-1-cKO mice (cKO-CON; n = 5) served as controls for tamoxifen treated AlK-1-cKO mice (cKO-TAM; n = 15). AlK-1 cKO-TAM mice demonstrated reduced 14-day survival compared to cKO-CON controls (13 vs 100%, respectively, p < 0.01). Seven days after treatment, cKO-TAM mice exhibited reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-TAM not cKO-CON mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume were increased in cKO-TAM, not cKO-CON mice. LV AlK-1 mRNA levels were reduced in cKO-TAM, not cKO-CON mice. LV levels of other TGFß-family ligands and receptors (AlK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFß1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-TAM mice, but LV levels of ß-MHC and SERCA were unchanged. No increase in markers of cardiac fibrosis, Type I collagen, CTGF, or PAI-1, were observed between groups. No differences were observed for any variable studied between cKO-CON and WT-TAM mice. Global deletion of AlK-1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of AlK-1 in cardiac remodeling independent of systemic AVMs are required.

Pulmonary Artery Pulsatility Index Is Associated With Right Ventricular Failure After Left Ventricular Assist Device Surgery.

BACKGROUND: Right ventricular failure (RVF) is a major cause of morbidity and mortality after CF-LVAD implantation. We explored the association of pulmonary artery compliance (PAC), pulmonary artery elastance (PAE), and pulmonary artery pulsatility index (PAPi) in addition to established parameters as preoperative determinants of postoperative RVF after CF-LVAD surgery. METHODS AND RESULTS: We retrospectively reviewed 132 consecutive CF-LVAD implantations at Tufts Medical Center from 2008 to 2013. Clinical, hemodynamic, and echocardiographic data were studied. RVF was defined as the unplanned need for a right ventricular assist device or inotrope dependence for ≥14 days. Univariate analysis was performed. RVF occurred in 32 of 132 patients (24%). PAC and PAE were not changed, whereas the PAPi was lower among patients with versus without postoperative RVF (1.32 ± 0.46 vs 2.77 ± 1.16; P < .001). RA pressure, RA to pulmonary capillary wedge pressure ratio (RA:PCWP), and RV stroke work index (RVSWI) were also associated with RVF. Using receiver operating characteristic curve-derived cut-points, PAPi < 1.85 provided 94% sensitivity and 81% specificity (C-statistic = 0.942) for identifying RVF and exceeded the predictive value of RA:PCWP, RVSWI, or RA pressure alone. CONCLUSIONS: PAPi is a simple hemodynamic variable that may help to identify patients at high risk of developing RVF after LVAD implantation.

Circulating multimarker profile of patients with symptomatic heart failure supports enhanced fibrotic degradation and decreased angiogenesis.

BACKGROUND: Heart failure (HF) involves myocardial fibrosis and dysregulated angiogenesis. OBJECTIVE: We explored whether biomarkers of fibrosis and angiogenesis correlate with HF severity. METHODS: Biomarkers of fibrosis [procollagen types I and III (PIP and P3NP), carboxyterminal-telopeptide of type I collagen (ICTP), matrix metalloproteases (MMP2 and MMP9), tissue inhibitor of MMP1 (TIMP1)]; and angiogenesis [placental growth factor (PGF), vascular endothelial growth factor (VEGF), soluble Fms-like tyrosine kinase-1 (sFlt1)] were measured in 52 HF patients and 19 controls. RESULTS: P3NP, ICTP, MMP2, TIMP1, PGF, and sFlt1 levels were elevated in HF, while PIP/ICTP, PGF/sFlt1, and VEGF/sFlt1 ratios were reduced. PIP/ICTP, MMP-9/TIMP1, and VEGF/sFlt1 ratios were lowest among patients with severe HF. CONCLUSIONS: Severe HF is associated with collagen breakdown and reduced angiogenesis. A multimarker approach may guide therapeutic targeting of fibrosis and angiogenesis in HF.

Mechanically unloading the left ventricle before coronary reperfusion reduces left ventricular wall stress and myocardial infarct size.

BACKGROUND: Ischemia/reperfusion injury worsens infarct size, a major determinant of morbidity and mortality after acute myocardial infarction (MI). We tested the hypothesis that reducing left ventricular wall stress with a percutaneous left atrial-to-femoral artery centrifugal bypass system while delaying coronary reperfusion limits myocardial injury in a model of acute MI. METHODS AND RESULTS: MI was induced by balloon occlusion of the left anterior descending artery in adult male swine. In the MI group (n=4), 120 minutes of left anterior descending artery occlusion was followed by 120 minutes of reperfusion without mechanical support. In the mechanically supported group (MI+unload; n=4), percutaneous left atrial-to-femoral artery bypass was initiated after 120 minutes of ischemia, and left anterior descending artery occlusion was prolonged for an additional 30 minutes, followed by 120 minutes of reperfusion with device support. All animals were euthanized after reperfusion, and infarct size was quantified by triphenyltetrazolium chloride staining. Compared with baseline, mean left ventricular wall stress and stroke work were not changed at any point in the MI group but were decreased after reperfusion in the MI+unload group (mean left ventricular wall stress, 44 658 versus 22 963 dynes/cm(2); stroke work, 2823 versus 655 mm Hg·mL, MI versus MI+unload). Phosphorylation of reperfusion injury salvage kinase pathway proteins from noninfarcted left ventricular tissue was unchanged in the MI group but was increased in the MI+unload group. Compared with the MI group, total infarct size was reduced in the MI+unload group (49% versus 28%, MI versus MI+unload). CONCLUSIONS: These data support that first unloading the left ventricle despite delaying coronary reperfusion during an acute MI reduces myocardial injury.

Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure.

BACKGROUND: Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine transforming growth factor-ß1 (TGFß1) promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a coreceptor for TGFß1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced endoglin expression may limit cardiac fibrosis in heart failure. METHODS AND RESULTS: We first report that endoglin expression is increased in the left ventricle of human subjects with heart failure and determined that endoglin is required for TGFß1 signaling in human cardiac fibroblasts using neutralizing antibodies and an siRNA approach. We further identified that reduced endoglin expression attenuates cardiac fibrosis, preserves left ventricular function, and improves survival in a mouse model of pressure-overload-induced heart failure. Prior studies have shown that the extracellular domain of endoglin can be cleaved and released into the circulation as soluble endoglin, which disrupts TGFß1 signaling in endothelium. We now demonstrate that soluble endoglin limits TGFß1 signaling and type I collagen synthesis in cardiac fibroblasts and further show that soluble endoglin treatment attenuates cardiac fibrosis in an in vivo model of heart failure. CONCLUSION: Our results identify endoglin as a critical component of TGFß1 signaling in the cardiac fibroblast and show that targeting endoglin attenuates cardiac fibrosis, thereby providing a potentially novel therapeutic approach for individuals with heart failure.

The pulmonary artery pulsatility index identifies severe right ventricular dysfunction in acute inferior myocardial infarction.

BACKGROUND: Right ventricular dysfunction (RVD) is a major cause of morbidity and mortality in the setting of acute inferior wall myocardial infarction (IWMI), and early detection may improve clinical outcomes. We defined a novel hemodynamic index, the pulmonary artery pulsatility index (PAPi), and explored whether the PAPi correlates with severe RVD in acute IWMI. METHODS: From 2008 to 2010, we identified 20 patients presenting with angiographically confirmed proximal right coronary artery occlusion and suspected RVD (sRVD) as defined by hemodynamic instability, profound bradycardia, or ST-elevation in lead V4R. Two controls groups were studied (1) 50 patients with nonobstructive coronary artery disease (Non-CAD) and (2) 14 patients presenting with acute coronary syndrome requiring left coronary stenting (ACS). Hemodynamic indices analyzed at the time of catheterization included: (1) the right atrial to pulmonary capillary wedge pressure ratio (RA:PCWP), (2) right ventricular stroke work (RVSW), and (3) the PAPi. Qualitative echocardiographic scores of RV systolic function were determined by two blinded investigators within 24 hr of catheterization. RESULTS: Among subjects with sRVD, 7 (35%) received a percutaneous RV support device (pRVSD) for medically refractory RV failure and 4 (20%) died prior to hospital discharge. Compared to Non-CAD and ACS controls, subjects with sRVD had a significantly lower PAPi (4.32 ± 3.04 vs. 5.52 ± 4.40 vs. 1.11 ± 0.57, respectively, P < 0.01) and a higher RA:PCWP ratio (0.48 ± 0.24 vs. 0.51 ± 0.26 vs. 0.81 ± 0.30, respectively, P < 0.05). Both the PAPi and RA:PCWP ratios correlated significantly with RVSW and qualitative echocardiographic grading. The PAPi demonstrated the highest sensitivity (88.9%) and specificity (98.3%) for predicting in-hospital mortality and/or requirement of a pRVSD. Using ROC curve derived cut-points, a PAPi ≤ 0.9 provided 100.0% sensitivity and 98.3% specificity (C-statistic: 0.998) for predicting these outcomes, exceeding the predictive value of the RA:PCWP ratio or RVSW. CONCLUSIONS: The PAPi is a simple, invasive hemodynamic measure that may help identify high-risk patients with acute IWMI with severe RVD. Earlier identification of this high-risk population may improve clinical outcomes.

Effect of chronic dissection on early and late outcomes after descending thoracic and thoracoabdominal aneurysm repair.

OBJECTIVE: Although chronic aortic dissection (CD) has traditionally been considered a predictor of perioperative morbidity and mortality after descending thoracic/thoracoabdominal aneurysm repair (thoracoabdominal aortic aneurysm [TAA]), recent reports have rejected this assertion. Still, few contemporary studies document late outcomes after TAA for CD, which is the goal of this study. METHODS: From August 1987 to December 2005, 480 patients underwent TAA; 73 (15%) CD and 407 (85%) degenerative aneurysms (DA). Operative management consisted of a clamp-and-sew technique with adjuncts in 53 (78%) CD and 355 (93%) DA patients (P < .001). Epidural cooling was used to prevent spinal cord injury (SCI) in 51 (70%) CD and 214 (53%) DA patients (P = .007). Study end points included perioperative SCI/mortality, freedom from reintervention, and long-term survival. RESULTS: CD patients were younger (mean age 64.5 years CD vs 72.5 years DA, P < .001) and more frequently had a family history of aneurysmal disease (23% CD vs 6% DA, P < .001). Forty-three (59%) CD patients had elective TAA (vs 322 (79%) DA, P = .001). Eleven (15%) CD patients had Marfan's syndrome (vs 0% DA, P < .001), and 17 (23%) CD patients had a prior arch or ascending aortic repair (vs 16 [4%] DA, P < .001). CD patients were more likely to have Crawford type I & II thoracoabdominal aneurysms (44 [60%] vs 120 [29%] DA, P < .001), while only two (3%) CD patients had type IV aneurysms (vs 99 [24%] DA). There was no difference in perioperative mortality between the two groups (11% CD vs 8.6% DA, P = .52), nor was there a difference in flaccid paralysis, which occurred in five (7%) CD and 22 (5%) DA patients (P = .92). At 5 years, 70% of CD patients were free from reintervention versus 74% of DA (P = .36). The actuarial survival was 53% and 32% at 5 and 10 years for CD versus 47% and 17% for DA (P = .07). CONCLUSIONS: Despite increased operative complexity, CD does not appear to increase perioperative SCI or mortality after TAA when compared with DA. Long-term freedom from aneurysm-related reintervention is similar for both groups as is survival, despite patients with CD being of younger age at presentation.

Endovascular management of patients with critical limb ischemia.

BACKGROUND: Although percutaneous intervention (PTA) is considered first-line therapy for peripheral vascular disease in many scenarios, its role in critical limb ischemia (CLI), wherein anatomic disease is more extensive, remains unclear. In the present study, late (5-year) clinical and patency data for PTA in CLI are defined. METHODS: From January 2002 to December 2007, 409 patients underwent infrainguinal PTA ± stent for CLI (Rutherford IV-VI) of 447 limbs. Primary patency, assisted patency, limb salvage, and survival were assessed using Kaplan-Meier. Predictors of patency, limb salvage, and death were determined using multivariate models. RESULTS: Demographics included age (70 ± 12 years old), diabetes (65.8%), and dialysis dependence (13%). The superficial femoral artery was treated in 58% of the patients, 16% were limited to the crural vessels, 38% had multilevel treatment, and stents were placed in 26%. Eighty percent of patients received postprocedure clopidogrel. Mean follow-up was 28 months (0-83). Five-year primary and assisted patency were 31% ± 0.04 and 75% ± 0.04, respectively. Limb salvage at 5 years was 74% ± 0.038. Sixty-three patients had major amputations. Survival at 5 years was 39% ± 0.03. Multivariate analysis identified dialysis dependence (P = .0005; 2.7 [1.6-4.8]), ≤1 vessel runoff (P = .02; 1.5 [1.1-2.0]), and warfarin use (P = .001; 1.7 [1.25-2.3]) as negative predictors of primary patency, but none of these were negative predictors of assisted patency. Dialysis dependence (P = .006; 2.5 [1.3-4.8]), female gender (P = .02; 2.0 [1.1-3.7]), and ≤1 vessel run-off (P = .04; 1.8 [1.0-3.2]) predicted limb loss. Dialysis dependence (P = .0003; 2.3 [1.5-3.5]), diabetes (P = .04; 1.5 [0.5-2.1]), and poor run-off (P = .04; 1.6 [1.2-2.1]) were predictors of mortality. CONCLUSION: Although primary patency is low, excellent limb salvage rates can be achieved in patients with CLI through close follow-up and secondary interventions. These data, and the 12% annual death rate, validate PTA as first-line therapy in patients with CLI.

Right Atrial Pressure Is Associated With Outcomes in Patient With Cardiogenic Shock Receiving Acute Mechanical Circulatory Support.

Background: We describe the association between longitudinal hemodynamic changes and clinical outcomes in patients with cardiogenic shock (CS) receiving acute mechanical circulatory support devices (AMCS) at a single center. We hypothesized that improved right atrial pressure is associated with better survival in CS. Methods: Retrospective analysis of patients from Tufts Medical Center that received AMCS for CS. Baseline characteristics and invasive hemodynamics were collected, analyzed, and correlated against outcomes. Hemodynamics were recorded at different time intervals during index admission [pre-AMCS, 24 h after AMCS (post AMCS), and last available set of hemodynamics (final-AMCS)]. Logistic regression was performed to determine variables associated with in-hospital mortality. Results: A total of 76 patients had longitudinal hemodynamics available. In hospital mortality occurred in 46% of the cohort. Mean baseline right atrial pressure (RAP) was significantly higher among non-survivors vs. survivors (19.5+6.6 vs. 16.4+5.3 mmHg). Change in right atrial pressure from baseline to before device removal (ΔRA:final AMCS-pre AMCS) was significantly different between survivors and non survivors (-6.5 ± 6.9 mmHg vs. -2.5 ± 6.2 mmHg p = 0.03). Unadjusted logistic regression revealed baseline RAP (OR: 1.1 95% CI: 1.0-1.2), 24 h post device implant RAP (OR: 1.3 95% CI: 1.1-1.4), and final RAP (OR: 1.3 95% CI: 1.1-1.5) to be significant predictors of in-hospital mortality. In a multivariate logistic regression baseline RAP was no longer significantly associated with mortality in the overall cohort, while 24 h (OR: 1.26 95% CI: 1.1-1.5) and final RAP (OR: 1.3 95% CI: 1.1-1.6) remained statistically significant. Conclusion: We report a novel retrospective analysis of hemodynamic changes in patients with CS receiving AMCS. Our findings identify the potential importance of venous congestion as a prognostic marker of mortality. Furthermore, early decongestion or reduced RA pressure is associated with better survival in these critically ill CS patients. These observations suggest the need for further study in larger retrospective and prospective cohorts of patients with varying degrees of CS severity.

Management of diseases of the descending thoracic aorta in the endovascular era: a Medicare population study.

OBJECTIVE: Prospective trials have shown improved perioperative outcomes with endovascular repair of thoracic aortic (TEVAR) pathologies compared with conventional surgery (OPEN). There are no long-term population data detailing the impact of TEVAR on practice patterns and results of treatment of descending thoracic aortic pathology (DTA), which are the goal of this study. METHODS: All procedures performed on the DTA captured in the Medicare database from 2004 to 2007 were identified by ICD-9 codes and stratified into OPEN and TEVAR cohorts. Outcomes included perioperative mortality (χ(2)) and 5-year actuarial survival. RESULTS: There were 11,166 patients identified (4838 [43%] TEVAR vs. 6328 [57%] OPEN) with 7247 (65%) nonruptured, degenerative thoracic aortic aneurysms (TAA), 2701 (24%) descending aortic dissections, 1033 (9%) thoracic aortic ruptures, and 185 (2%) traumatic aortic tears. The distribution of cases changed significantly during the study period (P < 0.0001) with an increase in TEVAR, decrease in OPEN, and increase in total cases over time (). The perioperative mortality was lower in the TEVAR group for the entire population (360 [7.4%] TEVAR vs. 1175 [18.5%] OPEN, P < 0.0001), and for the individual pathologies: TAA (182/3529 [5%] TEVAR vs. 451/3718 [12%] OPEN, P < 0.001), dissections (76/833 [9%] TEVAR vs. 399/1868 [21%] OPEN, P < 0.001) and ruptures (87/368 [24%] TEVAR vs. 298/665 [45%] OPEN, P < 0.0001). The Kaplan-Meier curve significantly favored TEVAR for the entire cohort because of the early mortality of the OPEN cohort but the curves converged by 5 years. The 5-year survival by indication was: entire population (53.4% TEVAR vs. 53.3% OPEN, P < 0.0001), TAA (55.8% TEVAR vs. 59.7% OPEN, P = 0.84), dissection (58.2% TEVAR vs. 50.6% OPEN, P < 0.0001), ruptures (23.3% TEVAR vs. 25.3% OPEN, P = 0.001), and trauma (62.9% TEVAR vs. 50.9% OPEN, P = 0.12). CONCLUSION: There has been a significant increase in the use of TEVAR for management of diseases of the DTA. TEVAR offers a significant perioperative survival advantage when compared with OPEN regardless of the indication for repair. However, in the Medicare population, the 5-year survival is similar between the 2 cohorts.

Balloon expandable stents facilitate right renal artery reconstruction during complex open aortic aneurysm repair.

OBJECTIVE: Patients undergoing repair of thoracoabdominal (TAA) or visceral aortic segment aneurysms typically require reconstruction of the renal arteries. The use of balloon expandable stents (BES) has been proposed as an alternative to endarterectomy or bypass for renal artery reconstruction (RAR) during open aortic aneurysm repair. We report technical aspects and long-term patency data for this method of right RAR during complex open aortic aneurysm repair. METHODS: During the interval July 1, 2005 to December 31, 2007, a total of 67 patients underwent right RAR using a BES during concomitant TAA (type I: n = 2 [2.9%], type II: n = 8 [11.9%], type III: n = 13 [19.4%], and type IV: n = 22 [32.8%]), juxtarenal (n = 9 [13.4%]) or suprarenal (n = 13 [19.4%]) AAA repair. Indications for RAR were orificial stenosis (n = 21 [31%]) and/or technical considerations referable to the proximal aortic suture line. Patency of the renal stent was evaluated in patients with computed tomography angiography using three-dimensional reconstruction or with abdominal duplex evaluation at follow-up. RESULTS: The mean patient age was 75.1 years, 54.4% were male, and 18% of operations were in nonelective circumstances. Twenty-seven (39%) out of 67 patients had a preoperative creatinine level > or = 1.4 mg/dL. Two patients (2.9%) developed permanent renal failure postoperatively (neither related to renal artery occlusion). Mean radiologic follow-up was 405 days (11-1281) with 98% stent patency noted. One patient had an early stent occlusion noted at 1 month. An additional patient was noted to have a nonflow-limiting dissection distal to the renal stent, and another was noted to have distal migration of the stent beyond the renal ostium; however, these findings were clinically silent. CONCLUSIONS: The use of BES during complex open aortic aneurysm repair affords a rapid and durable mode of RAR, obviating the need for endarterectomy and its associated technical complications.

Intermediate-term outcomes of endovascular treatment for symptomatic chronic mesenteric ischemia.

OBJECTIVE: Endovascular therapy for chronic mesenteric ischemia (CMI) has been increasingly utilized. Early outcomes compare favorably with open mesenteric bypass--the current gold standard. The goal of this study is documentation of intermediate-term anatomic and functional outcomes of endovascular mesenteric revascularization for symptomatic CMI. METHODS: This is a retrospective review of all patients undergoing endovascular treatment of symptomatic CMI from July 2002 to March 2008. Study endpoints included periprocedural mortality, major morbidity, patency, symptomatic recurrence, and survival. Endpoints were analyzed using actuarial methods. RESULTS: Sixty-six mesenteric arteries (78.8% stenotic/21.2% occluded) were treated in 49 patients. One or more vessels were treated in each case; however, four mesenteric artery total occlusions (3 SMAs/1 IMA) could not be crossed. Initial symptom relief was noted in 89.8% (n = 44) with no change in 5 patients. Single-vessel treatments were performed in 32 patients (65.3%) and two-vessel interventions in 17 (34.7%). The 30-day mortality rate was 2.0% (n = 1). Major complications occurred in 8 patients (16.3%). The mean follow-up duration was 37.4 +/- 2.98 months (range, 0-66). Restenosis on follow-up imaging occurred in 64.9% (n = 24) of the 37 patients who had radiographic surveillance at a mean follow-up interval of 8.5 +/- 1.9 months and was diagnosed most often by Duplex scan or computed tomographic angiography (CTA). Fourteen patients (28.6%) developed recurrent symptoms with 13 requiring a reintervention. Actuarial 36-month freedom from symptomatic recurrence was 60.9% +/- 9.4%. Two-vessel treatment was protective against symptom recurrence (P = .0014) and reintervention (P = .0060) by univariate analysis. A total of 19 reinterventions were required in 14 patients (28.6%) at a mean of 17 months from the original treatment. Primary patency at 36 months was 63.9 +/- 8.5%. Actuarial survival at 48 months was 81.1% +/- 6.1% with no CMI-related deaths in the study cohort. CONCLUSION: Intermediate (3-year) follow-up indicates that significant restenosis and symptom recurrence are common following the endovascular treatment of symptomatic CMI. Thirty percent of the cohort required a reintervention, one-third of which were conversions to surgical reconstruction. Similar to the surgical paradigm of two-vessel revascularization, endovascular treatment of multiple mesenteric arteries produced better outcomes. A first-line endovascular approach to patients with CMI is a reasonable clinical strategy, but close follow-up is mandatory.

Long-term outcomes of diabetic patients undergoing endovascular infrainguinal interventions.

OBJECTIVE: Diabetes mellitus (DM) has traditionally predicted poor outcomes after lower extremity revascularization for peripheral vascular disease (PVD). This study assessed the influence of DM on long-term outcomes of percutaneous transluminal angioplasty, with or without stenting (PTA/stent), in patients with PVD. METHODS: From January 2002 to December 2007, 920 patients underwent 1075 PTA/stent procedures. Patients were stratified into DM and non-DM cohorts. Study end points included primary patency (PP), assisted patency (AP), limb salvage, and survival and were evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: There were 533 DM and 542 non-DM limbs. Median follow-up was 34 months. Overall, the 5-year actuarial PP was 42% +/- 2.4%, AP was 81% +/- 2.0%, limb salvage was 89% +/- 1.6%, and survival was 60% +/- 2.4%. On univariate analysis, DM vs non-DM was associated with inferior 5-year PP (37% +/- 3.4% vs 46% +/- 3.3%; P = .009), limb salvage (84% +/- 2.6% vs 93% +/- 1.8%, P < .0001), and survival (52% +/- 3.5% vs 68% +/- 3.1%, P = .0001). AP did not differ between DM and non-DM patients (P = .18). In the entire cohort, DM (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.01-1.54; P = .04), single-vessel peroneal runoff (HR, 1.54; 95% CI, 1.16-2.08; P = .003), and dialysis (HR, 1.59; 95% CI, 1.10-2.33; P = .02) were associated with decreased PP on multivariate analysis. The only variables on multivariate analysis to predict limb loss and death were critical limb ischemia (HR, 9.09; 95% CI, 4.17-20.00; P < . 0001; HR, 2.99; 95% CI, 2.01-4.44; P < .0001, respectively) and dialysis (HR, 2.94; 95% CI, 1.39-5.00; P = .003; HR, 4.24; 95% CI 2.80-6.45; P < .0001, respectively). CONCLUSIONS: DM is an independent predictor of decreased long-term primary patency after PTA/stent. Although acceptable assisted patency rates can be achieved with close surveillance and reintervention, long-term limb salvage remains inferior in diabetic patients compared with non-diabetic patients due to a more severe clinical presentation and poor runoff.

Secondary intervention after endovascular abdominal aortic aneurysm repair.

OBJECTIVE: Endovascular Abdominal Aortic Aneurysm Repair (EVAR) has been criticized because of the need for frequent secondary interventions (2ndINT) to maintain effective abdominal aortic aneurysm (AAA) exclusion. The study goal is to detail such interventions and determine their effect on clinical outcomes. METHODS: From January 1997 to December 2007, 832 patients underwent EVAR. Those requiring 2ndINT were stratified according to the indications and specific nature of 2ndINT and treatment. Study endpoints included freedom from 2ndINT, aneurysm-related and overall survival. RESULTS: There were 91 (11%) patients who underwent 131 2ndINT (mean follow-up 35 months). No demographic features (age, gender, etc) predicted the need for 2ndINT. Actuarial 5-year freedom from 2ndINT was 80%. Indications for 2ndINT included: sac rupture 5 (4%), graft migration/ type I endoleak 37 (28%), persistent type II endoleak 40 (38%), endotension with sac growth 5 (4%), and limb occlusion/kinking 24 (18%). The majority of 2ndINT were accomplished with an endovascular approach (76%) with a >80% initial success rate for all indications except type II endoleak in which the initial intervention was successful only 34% of the time. Initial 2ndINT were successful in 62% and 35 (38%) patients underwent more than one 2ndINT. Multivariate predictors of 2ndINT were AAA sac size >5.5cm (OR = 2.1, P = 0.004), and preprocedure coil embolization (hypogastric or inferior mesenteric artery) (OR = 2.1, P = 0.008). The actuarial survival was 70% at 5 years and the aneurysm-related survival was 97.5% with no difference in either parameter in patients who underwent 2ndINT compared with those who did not. CONCLUSIONS: Although 2ndINT are common after EVAR, most were addressed through an endovascular approach; technical success thereof varies widely with the specific indication for 2ndINT. Secondary intervention did not adversely affect aneurysm-related or overall actuarial 5-year survival.

Thoracoabdominal aneurysm repair: hybrid versus open repair.

OBJECTIVE: Hybrid repair of thoracoabdominal aortic aneurysms (TAAA) may reduce morbidity and mortality in high-risk candidates for open repair. This study reviews the outcomes of hybrid TAAA repair for Crawford extent I-III TAAA in high-risk patients in comparison to patients who underwent concurrent open TAAA repair. METHODS: During the interval from June 2005 to December 2007, a total of 23 high-risk patients with TAAA (type I: 9 [39%], II: 5 [22%], and III: 9 [39%]) underwent renal and/or mesenteric debranching (11 [48%] with four vessel debranching) with subsequent placement of a thoracic stent graft; 77 patients underwent open TAAA repair (type I: 13 [17%], II: 11 [14%], III: 27 [35%], and IV: 26 [34%]) during the same interval. The primary high-risk criteria for hybrid TAAA included advanced age/poor functional status (n = 14), major pulmonary dysfunction (n = 8), and technical consideration (prior thoracic aortic aneurysm repair [n = 4] or prior thoracoabdominal aneurysm repair [n = 2] and obesity [n = 2]) with 6 patients having overlapping high-risk criteria. Composite (30-day) mortality and/or permanent paraplegia (PP) were the major study endpoints. RESULTS: The hybrid and open TAAA groups had (respectively) no statistical difference in mean age (76.6 vs 72.7 years), aneurysm size (6.51 vs 6.52 cm), and non-elective operation (30.4% vs 26.0%). The hybrid group had a higher mean Society for Vascular Surgery (SVS) risk score (9.1 vs 6.0; P

Left Ventricular Unloading Before Reperfusion Promotes Functional Recovery After Acute Myocardial Infarction.

BACKGROUND: Heart failure after an acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. We recently reported that activation of a transvalvular axial-flow pump in the left ventricle and delaying myocardial reperfusion, known as primary unloading, limits infarct size after AMI. The mechanisms underlying the cardioprotective benefit of primary unloading and whether the acute decrease in infarct size results in a durable reduction in LV scar and improves cardiac function remain unknown. OBJECTIVES: This study tested the importance of LV unloading before reperfusion, explored cardioprotective mechanisms, and determined the late-term impact of primary unloading on myocardial function. METHODS: Adult male swine were subjected to primary reperfusion or primary unloading after 90 min of percutaneous left anterior descending artery occlusion. RESULTS: Compared with primary reperfusion, 30 min of LV unloading was necessary and sufficient before reperfusion to limit infarct size 28 days after AMI. Compared with primary reperfusion, primary unloading increased expression of genes associated with cellular respiration and mitochondrial integrity within the infarct zone. Primary unloading for 30 min further reduced activity levels of proteases known to degrade the cardioprotective cytokine, stromal-derived factor (SDF)-1α, thereby increasing SDF-1α signaling via reperfusion injury salvage kinases, which limits apoptosis within the infarct zone. Inhibiting SDF-1α activity attenuated the cardioprotective effect of primary unloading. Twenty-eight days after AMI, primary unloading reduced LV scar size, improved cardiac function, and limited expression of biomarkers associated with heart failure and maladaptive remodeling. CONCLUSIONS: The authors report for the first time that first mechanically reducing LV work before coronary reperfusion with a transvalvular pump is necessary and sufficient to reduce infarct size and to activate a cardioprotective program that includes enhanced SDF-1α activity. Primary unloading further improved LV scar size and cardiac function 28 days after AMI.

Introduction of a quality improvement curriculum in the Department of Internal Medicine, Lincoln Medical Center.

Community hospitals with limited resources struggle to engage physicians in Quality improvement initiatives. We introduced Quality Improvement (QI) curriculum for residents in response to ACGME requirements and surveyed the residents understanding of QI and their involvement in QI projects before and after the introduction of the curriculum. The current article describes our experiences with the process, the challenges and possible solutions to have a successful resident led QI initiative in a community hospital. Methods: A formal QI curriculum was introduced in the Department of Internal Medicine from September to October 2015 using the Model for Improvement from Institute for Health care Improvement (IHI). Learners were expected to read the online modules, discuss in small group sessions and later encouraged to draft their QI projects using the Charter form and PDSA form available on the HI website. Online surveys were conducted a week prior and 3 months after completion of the curriculum Results: 80% (100/117) of residents completed the pre-curriculum survey and 52% (61/117) completed the survey post curriculum. 96.7% of residents report that physicians should lead QI projects and training rather than the hospital administrators. Residents had 20% increase in understanding and confidence in leading quality improvement projects post curriculum once initiated. Most Residents (72%) feel QI should be taught during residency. Active involvement of residents with interest was seen after the initiation of Open School Institute of health improvement (IHI) curriculum as compared to Institutional led QI's. The resident interventions, pitfalls with change processes with an example of PDSA cycle are discussed. Conclusion: A Dedicated QI curriculum is necessary to prepare the physicians deliver quality care in an increasing complex health care delivery system. The strength of the curriculum is the ease of understanding the material, easily available to all, and can be easily replicated in a Community Hospital program with limited resources. Participation in QI by residents may promote constructive competitiveness among related hospitals in public system to improve delivery of safe care. Abbreviations: ACGME: Accreditation Council for Graduate Medical Education; IHI: Institute of Healthcare Improvement; PDSA: Plan-Do-Study-Act; PGY: QI: Quality improvement.