Eyal Porat

Outcomes of Medical Management of Acute Type B Aortic Dissection

Background— Currently, the optimal treatment of acute type B aortic dissection remains controversial. The purpose of this study was to report early clinical outcomes of medical management for acute type B aortic dissection. Methods and Results— Between January 2001 and March 2005, 129 consecutive patients with the confirmed diagnosis of acute type B aortic dissection were studied. Mean age was 61 years (range, 29 to 94), with 33.3% (43/129) female. Acute type B aortic dissection protocol was instituted with the intent to manage all patients medically. Indications for surgical intervention included rupture, aortic expansion, malperfusion, and intractable pain. All patients were followed-up after discharge. Hospital mortality was 10.1% (13/129), 19% (4/21) when vascular intervention was required, and 8.3% (9/108) when medical management was maintained. Early intervention was required in 21 cases (16.2%), 19 (14.7%) open vascular/aortic cases and 2 cases (1.6%) of percutaneous aortic interventions. Morbidity included rupture (4.7%), stroke (4.7%), paraplegia (8.5%), bowel ischemia (7%), acute renal failure (21%), dialysis requirement (13%), and peripheral ischemia (4.7%). Late vascular-related procedures were performed in 5.2% (6/116) of cases. Univariate risk factors for early mortality were rupture (P<0.0001), need for laparotomy (P<0.008), acute renal failure (P<0.0001), need for dialysis (P<0.0001), and lower extremity ischemia (P<0.0004). The only independent risk factors for hospital mortality by multiple logistic regression was rupture (P<0.0009), and independent risk factors for midterm death were history of chronic obstructive pulmonary disease (P<0.002) and low glomerular filtration rate (<57 mL/min; P<0.0001). Conclusions— Medical management for acute type B aortic dissection is associated acceptable outcomes. Outcomes of other management strategies, eg, endovascular stenting, for acute type B aortic dissection need to be compared with these results.

Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia

Toll-like receptors are expressed in immune cells and cardiac muscle. We examined whether the cardiac Toll-like receptor 4 (TLR4) is involved in the acute myocardial dysfunction caused by septic shock and myocardial ischemia (MI). We used wild type mice (WT), TLR4 deficient (TLR4-ko) mice and chimeras that underwent myeloablative bone marrow transplantation to dissociate between TLR4 expression in the heart (TLR4-ko/WT) and the immunohematopoietic system (WT/TLR4-ko). Mice were injected with lipopolysaccharide (LPS) (septic shock model) or subjected to coronary artery ligation (MI model) and tested in vivo and ex vivo, for function, histopathology proinflammatory cytokine and TLR4 expression. WT mice challenged with LPS or MI displayed reduced cardiac function, increased myocardial levels of IL-1 beta and TNF-alpha and upregulation of mRNA encoding TLR4 prior to myocardial leukocyte infiltration. TLR4 deficient mice sustained significantly smaller infarctions as compared to control mice at comparable areas at risk. The cardiac function of TLR4-ko mice was not affected by LPS and demonstrated reduced suppression by MI compared to WT. Chimeras deficient in myocardial TLR4 were resistant to suppression induced by LPS and the heart function was less depressed, compared to the TLR4-ko, following MI in the acute phase (4h). In contrast, hearts of chimeras deficient in immunohematopoietic TLR4 expression were suppressed both by LPS and MI, exhibiting increased myocardial cytokine levels, similar to WT mice. We concluded that cardiac function of TLR4-ko mice and chimeric mice expressing TLR4 in the immunohematopoietic system, but not in the heart, revealed resistance to LPS and reduced cardiac depression following MI, suggesting that TLR4 expressed by the cardiomyocytes themselves plays a key role in this acute phenomenon.

The effect of cardiac angiography timing, contrast media dose, and preoperative renal function on acute renal failure after coronary artery bypass grafting.

OBJECTIVE Our objective was to assess the effect of the timing of cardiac angiography, contrast media dose, and preoperative renal function on the prevalence of acute renal failure after cardiac surgery. METHODS Data on 395 consecutive patients who underwent coronary artery bypass grafting were prospectively collected. Creatinine clearance was estimated by the Cockcroft-Gault equation. Patients were divided into 3 groups according to the time between cardiac angiography and surgery (group A, < or = 1 day; group B, > 1 day and < or = 5 days; group C, > 5 days). Patients who underwent a salvage operation or were receiving dialysis before surgery were excluded. Acute renal failure was defined as 25% decrease from baseline of estimated creatinine clearance and estimated creatinine clearance of 60 mL/min or less on postoperative day 3. Owing to differences in preoperative characteristics between groups, propensity score analysis was used to adjust those differences. RESULTS Acute renal failure developed in 13.6% of patients. Hospital mortality was 3.3% and was higher in patients in whom acute renal failure developed (22%) versus those in whom it did not (0.3%; P < .001). Multivariable analysis identified preoperative estimated creatinine clearance of 60 mL/min or less (odds ratio [OR], 7.1), operation within 24 hours of catheterization (OR = 3.7), use of more than 1.4 mL/kg of contrast media (OR = 3.4), lower hemoglobin level (OR = 1.3), older age (OR = 1.1), and lower weight (OR = 0.95) as independent predictors of postoperative acute renal failure. Analysis of interaction between contrast dose and time of surgery revealed that high contrast dose (>1.4 mL/kg) predicted acute renal failure if surgery was performed up to 5 days after angiography. CONCLUSIONS Whenever possible, coronary bypass grafting should be delayed for at least 5 days in patients who received a high contrast dose, especially if they also have preoperative reduced renal function.

Endothelial Progenitor Cell Function Inversely Correlates With Long-term Glucose Control in Diabetic Patients: Association With the Attenuation of the Heme Oxygenase-Adiponectin Axis

BACKGROUND Endothelial progenitor cells (EPCs) are attenuated, both in number and functionality, in animal models of chronic cardiovascular and metabolic disorders. This effect has subsequently been linked to the aggravation of long-term morbidity and mortality associated with such disorders. The objective was to examine EPC number and survival in chronic diabetic vs nondiabetic patients in conjunction with the examination of their redox, inflammatory, and antioxidant defense system (Nrf2 genes) status in serum and visceral fat. METHODS Visceral adipose tissue from diabetic and nondiabetic patients undergoing coronary artery bypass graft surgery was analyzed for Nrf2-dependent genes. Oxidative stress was evaluated using thiobarbituric acid-reactive substance assay (TBARS). Peripheral blood, collected 1 day prior to surgery, was evaluated for inflammatory cytokines and EPCs. RESULTS When compared with controls (P < 0.05), results of the thiobarbituric acid-reactive substance assay were higher in diabetic patients. Although Nrf2-dependent antioxidant proteins (thioredoxin-1 [Trx-1], nicotinamide adenine dinucleotide phosphate [NAD(P)H] quinone oxidoreductase [NQO1], glutathione S-transferase [GST]) were upregulated, heme oxygenase (HO-1) and adiponectin protein expression were lower in the diabetic group (P < 0.05). Serum levels of bilirubin were lower (P < 0.005) while the levels of inflammatory cytokines were higher in diabetic patients (P < 0.05). EPC levels and their colony forming units were significantly lower (P < 0.05) with reduced viability in diabetic patients as compared with nondiabetic patients. CONCLUSIONS These results demonstrate for the first time that in diabetic patients, there is an inadequate heme oxygenase-adiponectin axis response, which could compromise the compensatory antioxidant and anti-inflammatory effects consequently contributing toward EPC dysfunction in these patients.

Cardiac surgery in patients on chronic hemodialysis: short and long-term survival.

OBJECTIVE Open-heart surgery carries a high risk for hemodialysis patients. This study focuses on the short and long-term outcomes of hemodialysis patients undergoing heart surgery. DESIGN The study was carried out as a retrospective analysis in the Department of Cardiothoracic Surgery in a large university-affiliated hospital. PATIENTS 115 hemodialysis patients underwent cardiac surgery in our department between 1 July 1996 and 31 July 2006. 67.5 % (77 patients) underwent isolated coronary artery bypass grafting (CABG), 13.2 % (15 patients) underwent isolated aortic valve replacement (AVR) and 20.2 % (23 patients) underwent mitral valve surgery or combined valve and coronary artery bypass grafting or multiple valve surgery. METHODS The relationship between several variables (age, sex, hypertension, diabetes, and previous myocardial infarction, type of disease, preoperative ejection fraction, and congestive heart failure) and operative (30 days) mortality and late survival was analyzed. RESULTS The overall 30-day mortality was 18.3 % (21 patients). It was 13 % (10/77 patients) for the isolated CABG group and 13.3 % (2/15) for the isolated AVR group. Patients undergoing combined valve and coronary surgery or multiple valve surgery had a higher perioperative mortality of 39.1 % (9/23) compared to the isolated CABG and isolated AVR patients. Perioperative death was also higher in patients with moderate and severe LV dysfunction, and in patients with diabetes. The duration of dialysis periods was not related to perioperative death. Mean follow-up was 26.4 +/- 29.7 months (0.1 to 104 months). Actuarial survival at 1 year and 5 years was 76 % and 55 % for isolated CABG, 59 % and 21 % for isolated AVR, and 44 % and 33 % for all other cases, respectively (log rank P = 0.001). CONCLUSION Patients on dialysis have a high risk of perioperative mortality and poor long-term survival rates. Mortality is higher and survival is worse after combined CABG and valve-related procedures or multiple valve surgery than after isolated CABG and AVR.

Elevated level of pro-inflammatory eicosanoids and EPC dysfunction in diabetic patients with cardiac ischemia

BACKGROUND Circulating endothelial progenitor cells (EPCs) are recruited from the blood system to sites of ischemia and endothelial damage, where they contribute to the repair and development of blood vessels. Since numerous eicosanoids including leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) have been shown to exert potent pro-inflammatory activities, we examined their levels in chronic diabetic patients with severe cardiac ischemia in conjunction with the level and function of EPCs. RESULTS Lipidomic analysis revealed a diabetes-specific increase (p<0.05) in inflammatory and angiogenic eicosanoids including the 5-lipoxygenase-derived LTB (4.11±1.17 vs. 0.96±0.27 ng/ml), the lipoxygenase/CYP-derived 12-HETE (117.08±35.05 vs. 24.34±10.03 ng/ml), 12-HETrE (17.56±4.43 vs. 4.15±2.07 ng/ml), and the CYP-derived 20-HETE (0.32±0.04 vs. 0.06±0.05 ng/ml) the level of which correlated with BMI (p=0.0027). In contrast, levels of the CYP-derived EETs were not significantly (p=0.36) different between these two groups. EPC levels and their colony-forming units were lower (p<0.05) with a reduced viability in diabetic patients compared with non-diabetics. EPC function (colony-forming units (CFUs) and MTT assay) also negatively correlated with the circulating levels of HgA1C. CONCLUSION This study demonstrates a close association between elevated levels of highly pro-inflammatory eicosonoids, diabetes and EPC dysfunction in patients with cardiac ischemia, indicating that chronic inflammation impact negatively on EPC function and angiogenic capacity in diabetes.

Is gender an independent risk factor for coronary bypass grafting

BACKGROUND Postoperative mortality after coronary artery bypass grafting (CABG) surgery is traditionally considered to be influenced by gender. However, the data are conflicting and it is not clear whether gender is a true independent risk factor for death in this setting. We analyzed our database to determine whether gender is an independent risk factor for death after CABG. PATIENTS AND DESIGN A retrospective analysis of 1 758 isolated first-time coronary artery bypass graft patients treated between 2003 and 2005 was conducted in the Department of Cardiothoracic Surgery of Rabin Medical Center, a major tertiary facility in Israel. RESULTS The female patients had a distinctly different pre- and intraoperative profile compared with the male patients, and significantly higher postoperative mortality (p < 0.05). On a propensity scoring of 359 matched pairs, the risk factors for death were found to be severe left ventricular dysfunction, chronic obstructive pulmonary disease, and use of an intra-aortic balloon pump (p < 0.05). The addition of intraoperative data to the model yielded only cardiopulmonary bypass time and use of an intra-aortic balloon pump as risk factors for death (p < 0.05). Validation with the bootstrap technique revealed that strong predictors of death (> 50 % of the sample) were cardiopulmonary bypass time, use of an intra-aortic balloon pump, and, to a lesser extent, chronic obstructive pulmonary disease. Female gender was not found to be an independent risk factor for death after coronary artery bypass graft. CONCLUSIONS Female gender is apparently not an independent risk factor for coronary artery bypass graft mortality in this patient group.

Ras inhibition attenuates myocardial ischemia-reperfusion injury

Myocardial injury, developed after a period of ischemia/reperfusion (I/R) results in the destruction of functional heart tissue, this being replaced by scar tissue. Intracellular signaling pathways mediating cardiomyocyte death are partially understood and involve the activation of Ras. p38-MAPK, JNK and Mst-1 are downstream effectors of Ras protein. We hypothesized that S-farnesylthiosalicylic acid (FTS), a synthetic small molecule that detaches Ras from the inner cell membrane, consequently inhibiting Ras activity, reduces I/R myocardial injury in vitro and in vivo. Wistar rat hearts were isolated, mounted on the Langendorff apparatus and subjected to ischemia (30 min, 37 degrees C) and reperfusion. During the reperfusion period, the hearts were perfused with FTS (1 microM) solution or control buffer. Left anterior descending (LAD) ligation and subsequent reperfusion was performed in two groups of Wistar rats. Rats received 5mg/kg FTS or PBS according to two protocols: (A) FTS or PBS were administered daily 7 days prior, immediately before and 14 days (every other day) after LAD occlusion or (B) every other day for 14 days post-I/R. Hearts from FTS-treated rats (Langendorff) and FTS-treated rats (protocol A) showed a significant improvement in myocardial performance and smaller scar tissue compared with the PBS group. Infarct size in the FTS-treated group was 12.7+/-2% vs. 23.7+/-4% in the PBS-treated (in vitro) group and 17.3+/-2.5% vs. 36+/-7% compared with control I/R rats (in vivo) p<0.05. These effects may be associated with the down regulation of JNK as a short-term effector and with Mst-1 in the long-term remodeling process.

Clinical profile and outcome of patients with severe aortic stenosis at high surgical risk: single-center prospective evaluation according to treatment assignment.

The study sought to assess the clinical profile, outcome, and predictors for mortality of “real‐world” high‐risk severe aortic stenosis patients according to the mode of treatment assigned.

TLR4 Expression Is Associated with Left Ventricular Dysfunction in Patients Undergoing Coronary Artery Bypass Surgery

Introduction Toll-like receptor 4 (TLR4) is an innate immune receptor expressed in immune cells and the heart. Activation of the immune system following myocardial ischemia causes the release of proinflammatory mediators that may negatively influence heart function. Aim The aim of this study is to determine whether TLR4 is activated in peripheral monocytes and heart tissue taken from patients with varying degrees of myocardial dysfunction caused by coronary artery diseases and scheduled for coronary artery bypass graft (CABG) surgery before 12 months following operation. Methods and Results Patients (n = 44) undergoing CABG surgery having left ventricular ejection fraction ≤ 45% (‘reduced EF’, n = 20) were compared to patients with preserved EF >45% (‘preserved EF’ group, n = 24). ‘Reduced EF’ patients exhibited increased TLR4 expression in monocytes (2.78±0.49 vs. 1.76±0.07 rMFI, p = 0.03). Plasma levels of C-reactive protein, microRNA miR-320a, brain natriuretic peptide (pro BNP) and NADPH oxidase (NOX4) were also significantly different between the ‘preserved EF’ and ‘reduced EF’groups. Elevated TLR4 gene expression levels in the right auricle correlated with those of EF (p<0.008), NOX4 (p<0.008) and miR320, (p<0.04). In contrast, no differences were observed in peripheral monocyte TLR2 expression. After CABG surgery, monocyte TLR4 expression decreased in all patients, reaching statistical significance in the ‘reduced EF’ group. Conclusion TLR4 is activated in peripheral monocytes and heart tissue obtained from patients with ischemic heart disease and reduced left ventricular function. Coronary revascularization decreases TLR4 expression. We therefore propose that TLR4 plays a pathogenic role and may serve as an additional marker of ischemic myocardial dysfunction.