Vasoactive role for angiotensin II type 2 receptors in human radial artery.

Angotensin II type 2 receptors are believed to counter the effects of the angiotensin type 1 receptors and there is no data relating to the co-localisation of either receptor in human diseased arteries. We sought to determine whether AT2R counter the effects of AT1R and immunolocalise both receptors to cells in human diseased arteries. Human radial arteries (RA, n=11) were placed in organ bath chambers and preincubated with the AT2R antagonist PD123319 for twenty minutes before an angiotensin II dose response curve. Immunohistochemistry was performed to identify receptors and pathology was quantified by image analysis software. We observed both receptors in human arteries. Angiogenic blood vessels within occluded arteries expressed both receptors. PD123319 impaired angiotensin II mediated vasoconstriction by 20 percent (n=5, p less than 0.05), however in other arteries, PD123319 exacerbated angiotensin II-mediated vasoconstriction by 60 percent (n=6, p less than 0.01), respectively. We conclude that inhibition of AT2R can enhance or reduce angiotensin II-mediated vasoconstriction. These data indicate that the role of AT2R in human diseased arteries is divergent although the AT2R-mediated vasorelaxation prevails.

Progression of aortic stenosis in elderly patients over long-term follow up.

BACKGROUND: The natural history of aortic stenosis (AS) in elderly patients remains poorly defined. In an elderly cohort over long-term follow-up, we assessed: 1) rates and predictors of hemodynamic progression and 2) composite aortic valve replacement (AVR) or death endpoint. METHODS: Consecutive Department of Veterans' Affairs patients with AS (>60 years) were prospectively enrolled between 1988 and 1994 (n=239) and followed until 2008. Patients with ≥ 2 trans-thoracic echocardiograms >6 months apart were included in the progression analysis (n=147). Baseline demographics, comorbidities and echocardiography parameters were recorded. Follow-up was censored at AVR/death. RESULTS: The age of patients was 73 ± 6 years; 82% were male. Baseline AS severity was mild (67%), moderate (23%) and severe (10%). Follow-up was 6.5 ± 4 years (range: 1-17 years). Annualized mean aortic valve gradient progression rates were: mild AS 4 ± 4 mmHg/year; moderate AS 6 ± 5 mmHg/year and severe AS 10 ± 8 mmHg/year (p<0.001). Five-year event-free survival was 66 ± 5%, 23 ± 7% and 20 ± 10% for mild, moderate and severe AS respectively. Progression to severe AS occurred in 35% and 74% of patients with mild and moderate AS respectively. Independent predictors of rapid progression were: baseline AS severity (per grade) (OR 2.6, p=0.001), aortic valve calcification (per grade) (OR 2.1, p=0.01), severe renal impairment (OR 4.0, p=0.04) and anemia (OR 2.3, p=0.05). CONCLUSIONS: In elderly patients, hemodynamic progression of AS is predicted by AS severity, renal function, aortic valve calcification and history of anemia. These factors identify patients at high risk of rapid hemodynamic progression, for whom more frequent clinical and echocardiographic surveillance is advisable.

Total arterial coronary artery bypass grafting in patients with diabetes: an 8-year experience.

OBJECTIVE: Coronary artery bypass grafting using arterial conduits may improve survival and minimise harvest site complications. However, in diabetes, the outcomes of coronary artery bypass grafting performed exclusively using arterial conduits are uncertain. We reviewed our experience with this approach. METHODS: From 1996 to 2008, 400 patients with diabetes (managed with oral hypoglycaemics, insulin or both) underwent primary isolated coronary artery bypass grafting for triple vessel coronary disease. In 246 (61.5%), total arterial revascularisation was achieved using single or bilateral internal thoracic arteries supplemented by one or more radial arteries (arterial group), while in the remaining 154 (38.5%), at least one venous conduit was used (mixed conduits group: mean 1.5 veins per patient). Propensity-score matching was used to adjust for bias. RESULTS: Total arterial revascularisation patients were more likely to be younger (arterial: 63 ± 10 years vs mixed: 67 ± 10 years, P < 0.0001), of elective priority (85% vs 75%, P = 0.018) and less likely to have moderate-severe left ventricular dysfunction (23% vs 36%, P = 0.024). Use of bilateral internal thoracic arteries was similar between groups (16% vs 11%, P = 0.19). There was a comparable in-hospital mortality (1.9% vs 2.0%, P > 0.99) and major morbidities, except the arterial group who experienced less stroke (0.4% vs 3.2% vs P = 0.04) and harvest site infections (0.4% vs 4%, P = 0.016). Mean follow was 7.8 ± 3.7 years. Estimated survival at 12-year survival in the arterial group was 80% ± 3.2% vs 54% ± 5.5% (P < 0.0001). Subsequently, 103 propensity-score-matched patient pairs were created between the two groups. After matching, in-hospital mortality (1% vs 2%, P > 0.99) and major morbidities were similar, as was an estimated 12-year survival (69% ± 6.1% vs 59% ± 6.5%, P > 0.99). CONCLUSIONS: The use of veins to supplement arterial conduits did not deleteriously affect survival. However, the significant number of patients receiving arterial grafts in both groups may have masked any potential difference. Greater numbers and longer follow-up will reveal the potential of this approach.

ACE2 and AT4R are present in diseased human blood vessels.

A growing body of evidence suggests that the angiotensin II fragments, Ang(1-7) and Ang(3-8), have a vasoactive role, however ACE2, the enzyme that produces Ang(1-7), or AT4R, the receptor that binds Ang (3-8), have yet been simultaneously localised in both normal and diseased human conduit blood vessels. We sought to determine the immunohistochemical distribution of ACE2 and the AT4R in human internal mammary and radial arteries from patients undergoing coronary artery bypass surgery. We found that ACE2 positive cells were abundant in both normal and diseased vessels, being present in neo-intima and in media. ACE2 positive immunoreactivity was not present in the endothelial layer of the conduit vessels, but was clearly evident in small newly formed angiogenic vessels as well as the vaso vasorum. Endothelial AT4R immunoreactivity were rarely observed in either normal and diseased arteries, but AT4R positive cells were observed adjacent to the internal elastic lamine in the internal mammary artery, in the neo-intima of radial arteries, as well as in the media of both internal mammary artery and radial artery. AT4R was abundant in vaso vasorum and within small angiogenic vessels. Both AT4R and ACE2 co-localised with smooth muscle cell alpha actin. This study identifies smooth muscle cell alpha actin positive ACE2 and AT4R in human blood vessels as well as in angiogenic vessels, indicating a possible role for these enzymes in pathological disease.

Calcitonin receptor immunoreactivity associated with specific cell types in diseased radial and internal mammary arteries.

AIMS: To determine and quantify calcitonin receptor (CTR) immunoreactivity associated with specific cell types within, and associated with, the endothelial layers, neo-intima, media and vasa vasorum of diseased radial and internal mammary arteries. METHODS AND RESULTS: Immunohistochemistry and anti-CTR antibodies were used to identify positive cells within remnants of diseased human radial (n = 3) and internal mammary arteries (n = 4) that remained after bypass surgery. Three cell types expressed CTR, including endothelial cells, fibroblast-like cells within the neo-intima, and cellular structures aligned with the smooth muscle cells of the media. Other smaller cells within the surrounding parenchyma of the vasa vasorum of diseased vessels and blood-borne cells were also immunoreactive. Immunoquantification of CTR expression (Intensity x Proportional Area) in the endothelium (P < 0.05), neo-intima (P < 0.02) and media (P < 0.03) established a significant statistical correlation (Students' two-tailed t-test) with the ratio of intimal/media thickness. CONCLUSIONS: Increased immunoreactivity developed using anti-CTR antibodies was associated with specific cell types in the endothelial layers, neo-intima, media and vasa vasorum of diseased regions of radial and internal mammary arteries, in which there was an increased intimal/media ratio. Furthermore, CTR+, blood-borne cells present in the vessels of diseased regions suggest recruitment into these surrounding tissues.

What factors influence the results of coronary artery bypass grafting in aged patients?

AIM: Early and late results were studied in order to improve the indication for coronary artery bypass grafting (CABG) and to enhance METHODS: A total of 1 973 patients aged 70 years and older who had undergone isolated CABG were studied. Elective operations (EL) were performed in 1 716 patients and 257 patients underwent urgent or emergency operations (UR/EM). Patients were divided into two groups; 104 patients aged 80 years and older (Oct. Group) and 1 869 patients of septuagenarians (Sept. Group). There were no differences between the groups in the number of diseased vessels. RESULTS: Total operative mortality rates in the Oct. and the Sept. groups were 7% and 4%, respectively. The operative mortality of elective surgery was 4% in both groups. The operative mortality of UR/EM CABG was significantly higher in the Oct. group than in the Sept. group (21% vs 6%). Operative mortality was significantly higher in patients with preoperative poor (<49%) left ventricular ejection fraction (LVEF) than in patients with higher (>50%) LVEF (6% vs 3%). Among preoperative risk factors, diabetes mellitus and peripheral vascular disease were significant contributory factors to operative death. In the follow-up study, 70% patients of the Oct. group and 72% patients of the Sept. group survived. Preoperative number of diseased vessels and number of CABG grafts did not influence the early and late CONCLUSION: Preoperative poor LVEF, diabetes mellitus and peripheral vascular disease were significant contributory factors to operative death. When feasible, CABG in octogenarians should be performed electively.

The radial artery in reoperative coronary bypass surgery:.

BACKGROUND: Failure of saphenous vein grafts (SVG) is a significant cause for coronary reoperation (redo CABG). The radial artery (RA) because of its availability, and versatility is well suited to use (together with internal thoracic arteries (ITA) in redo CABG, especially to replace failed SVG. We evaluated our experience where the RA was a major conduit in redo CABG over the past 5 years. METHODS: From July 1996 to June 2002, 590 consecutive patients underwent redo CABG where one or both RA(s) were used, together with LITA or RITA. The mean age was 67.3 years, 82% were male, and 19% diabetic, 419 (71%) had Class III or IV angina, 135 (23%) had left main stenosis, and 210 (36%) had an LVEF < 0.50. There were a total of 877 RA conduits (303 single, 287 bilateral), 518 new LITA or RITA. A mean of 2.8 new distal anastomoses constructed 92% (2.6 per patient)of the arterial grafts. Follow-up was at 1 month, 3 months, and then yearly. The results were compared with 6466 primary CABG performed in the same time frame, and with a prior cohort of 741 consecutive patients having redo CABG without an RA in which identical operative techniques had otherwise been used. RESULTS: The 30-day mortality was 3.9% (23 patients). Morbidity was low. Perioperative myocardial infarction occurred in 16 (2.7%) patients, stroke in 10 (1.7%), sternal infection in 10 (1.7%), donor site infection in 2 (0.3%), and IABP use in 23 patients (3.9%)-including 10 preoperatively. The results were better when compared to a prior cohort of 741 patients with redo CABG (1991 to 1996) without use of the RA. The results were inferior to that of the contemporary primary CABG. Operative mortality was 3.9% versus 0.9%, p = 0.002, myocardial infarction 2.7% versus 0.8%, p = 0.03. CONCLUSION: The use of the RA (together with ITA) in redo CABG achieved total arterial revascularization in 92% of cases and is associated with excellent results, at least equal to or superior to those achieved previously.

Prediction and functional analysis of native disorder in proteins from the three kingdoms of life.

An automatic method for recognizing natively disordered regions from amino acid sequence is described and benchmarked against predictors that were assessed at the latest critical assessment of techniques for protein structure prediction (CASP) experiment. The method attains a Wilcoxon score of 90.0, which represents a statistically significant improvement on the methods evaluated on the same targets at CASP. The classifier, DISOPRED2, was used to estimate the frequency of native disorder in several representative genomes from the three kingdoms of life. Putative, long (>30 residue) disordered segments are found to occur in 2.0% of archaean, 4.2% of eubacterial and 33.0% of eukaryotic proteins. The function of proteins with long predicted regions of disorder was investigated using the gene ontology annotations supplied with the Saccharomyces genome database. The analysis of the yeast proteome suggests that proteins containing disorder are often located in the cell nucleus and are involved in the regulation of transcription and cell signalling. The results also indicate that native disorder is associated with the molecular functions of kinase activity and nucleic acid binding.

Hemofiltration during cardiopulmonary bypass for high risk adult cardiac surgery.

AIMS: The role of hemofiltration (HF) during cardiopulmonary bypass (CPB) in adult cardiac surgery is controversial. It may be beneficial during prolonged CPB in high-risk surgery. Accordingly, we sought to compare two groups of patients undergoing high-risk cardiac surgery with or without HF. METHODS: One hundred and eighteen patients who underwent complex cardiac surgical procedures during a 12-month period were divided into two groups. Group I (n=61) comprised patients who were treated with hemofiltration during CPB. Group II (n=57) were not filtered. Estimated risk of death, standard demographic, clinical and surgical features were obtained and predetermined outcomes were studied. Statistical comparisons were made. RESULTS: Age, procedure times and mortality rates were similar in both groups. The mean volume of fluid removed in group I was 3.4 L. The preoperative mean Parsonnet score was 24.8 in group I and 22.5 in group II (ns). Postoperative serum hemoglobin, hematocrit, platelet, and albumin levels were all significantly higher in group I patients (p=0.0015) indicating hemoconcentration. Post-operative chest drainage showed a trend toward decreased post-operative bleeding in group I (p=0.065). Postoperative pleural effusions requiring chest tube drainage were significantly less in group I (9.8% vs. 29.8% 6; p = 0.0062). The incidence of lung infection was also decreased from 26.3% to 13.1% (p=0.05). Operative mortality was similar in both groups (11.4% in group 1, 10.5% in group II, ns). CONCLUSION: Hemofiltration during CPB attenuates postoperative anemia, thrombocytopenia and hypoalbuminemia, may reduce post-operative bleeding and appears to decrease post-operative pulmonary complications.

Secondary structure prediction with support vector machines.

MOTIVATION: A new method that uses support vector machines (SVMs) to predict protein secondary structure is described and evaluated. The study is designed to develop a reliable prediction method using an alternative technique and to investigate the applicability of SVMs to this type of bioinformatics problem. METHODS: Binary SVMs are trained to discriminate between two structural classes. The binary classifiers are combined in several ways to predict multi-class secondary structure. RESULTS: The average three-state prediction accuracy per protein (Q(3)) is estimated by cross-validation to be 77.07 +/- 0.26% with a segment overlap (Sov) score of 73.32 +/- 0.39%. The SVM performs similarly to the 'state-of-the-art' PSIPRED prediction method on a non-homologous test set of 121 proteins despite being trained on substantially fewer examples. A simple consensus of the SVM, PSIPRED and PROFsec achieves significantly higher prediction accuracy than the individual methods.

The mid-term results of ventricular containment (ACORN WRAP) for end-stage ischemic cardiomyopathy.

The acorn cardiac support device (ACSD) is a device designed to treat heart failure by containing the heart to prevent further dilation. Six patients with symptomatic heart failure due to ischemic cardiomyopathy were treated surgically with ACSD. All patients simultaneously underwent coronary artery bypass grafting. Ventricular reconstruction was also performed in 5 of the 6 patients. We followed up the patients for 12 months postoperatively, monitoring the left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), mitral regurgitation, and NYHA classification. Both the LVEDD and LVESD were significantly improved one month postoperatively (from 63.2 to 50.6 mm, p=0.004, and from 51.6 to 39.5 mm, p=0.025, respectively). These dimensions did not change significantly over the next 11 months. NYHA functional class improved significantly from a mean of 3 to 1.4 at 12 months (p=0.012). Mitral regurgitation improved from a mean of 2.7 preoperatively to 1.4 at 12 months and the average LVEF also improved from 27% preoperatively to 35.9% at 12 months after surgery. However these latter two results were not statistically significant. There were no late deaths and no readmissions for heart failure. Repeat coronary angiography at 6 months revealed patent grafts in all patients. The mid-term results of ACSD for patients with symptomatic heart failure suggest that ventricular containment may be useful for preventing further cardiac dilation in patients with ischemic cardiomyopathy. Randomized, long-term studies are needed to assess the efficacy and possible role of ASCD in the future management of heart failure.

Metabolic changes and myocardial injury during cardioplegia: a pilot study.

BACKGROUND: The timing, nature, and severity of both increased cardiac troponin I (cTn-I) levels and myocardial injury during ischemic arrest with cardioplegia are unknown. To define them more accurately, we studied myocardial metabolic activity and the release of markers of myocardial cell injury into the coronary sinus before, during, and after cardioplegia. METHODS: We simultaneously measured creatine kinase, creatine kinase-MB, cTn-I, lactate, phosphate, and blood gases in coronary sinus and systemic arterial blood from 12 patients before cardiopulmonary bypass, after removal of the aortic cross-clamp, and after discontinuation of cardiopulmonary bypass. We also measured coronary sinus flow and transmyocardial fluxes of all analytes and calculated myocardial oxygen consumption, myocardial carbon dioxide production, and myocardial energy expenditure. RESULTS: Myocardial lactate release increased 10-fold after removal of the aortic cross-clamp (p = 0.012) and was accompanied by a surge in myocardial phosphate uptake (p = 0.056). These events were associated with only partial cardioplegia-induced suppression of myocardial oxygen consumption (p = 0.0047), myocardial carbon dioxide production (p = 0.0022), and myocardial energy expenditure (p = 0.0029). Simultaneously, coronary sinus cTn-I levels increased from a mean of 0.76 to 2.43 ng/mL after removal of the aortic cross-clamp, and 2.51 ng/mL after cardiopulmonary bypass (p = 0.014), leading to an increase in arterial cTn-I concentration from 0.18 to 0.98 and 3.01 ng/mL (p = 0.0002). Thus, cTn-I release across the myocardium was absent at baseline, became detectable (p = 0.012) after removal of the aortic cross-clamp, and correlated with cross-clamp and pump times. Similar changes occurred with creatine kinase-MB. CONCLUSIONS: Metabolic myocardial stress occurs during ischemic arrest with cardioplegia and is associated with inadequate suppression of metabolism and with a surge in cTn-I and creatine kinase-MB release, which is maximal after removal of the aortic cross-clamp. These changes are likely to represent structural myocardial cell injury.

Surgical implications of variations in hand collateral circulation: anatomy revisited.

OBJECTIVES: One of the risks associated with harvesting the radial artery is hand ischemia. Accordingly, this study investigated the variations of the hand collateral circulation. METHODS: Fifty hands of cadavers were examined. Variations of the palmar arches were recorded. A classic superficial palmar arch was defined as direct continuity between the ulnar artery and the superficial palmar branch of the radial artery. A classic complete deep palmar arch was defined as direct continuity between the radial artery and the deep branch of the ulnar artery. RESULTS: A classic superficial palmar arch was found in 10% (5/50) of hands, and a classic complete deep palmar arch was found in 90% (45/50) of hands. The superficial palmar branch of the ulnar artery supplied blood to all fingers in 66% (33/50) of hands. Although the superficial palmar branch of the ulnar artery was continuous with the radial artery in only 34% (17/50) of hands (including the classic type of superficial palmar arch), every hand had at least one major branch connecting the radial and ulnar arteries. CONCLUSIONS: Variations in the terminations of the radial and ulnar arteries are common. Although the classic type of superficial palmar arch occurs relatively infrequently, there is always a significant anastomosis between the radial and the ulnar artery in the hand. This anatomic study confirms the presence of a collateral supply in the hand. In the absence of vascular disease, harvesting the radial artery should be regarded as a safe procedure.

Geometric endo-ventricular patch repair of inferior left ventricular scars improves mitral regurgitation and clinical outcome.

BACKGROUND: The surgical reconstruction of inferior left ventricular (LV) aneurysms and scars has been considered a difficult procedure and there has been little material published about this treatment option. In this study we report on our experience with reconstruction of the inferior wall and compare it to the outcome of anterior LV reconstructions. METHODS: Seventeen patients (group 1) underwent geometric endo-ventricular patch repair (GER) of inferior LV aneurysms and dyskinetic scars between January 1998 and December 2000. In addition to poor LV function, 5 of these patients had severe mitral valve regurgitation (MR), 8 had moderate MR, and 4 had mild MR preoperatively. These patients also underwent coronary artery bypass graft surgery or valve surgery. The perioperative course, survival, and clinical status were evaluated in this group and was compared to those of 86 patients (group 2) undergoing anterior GER during the same period. RESULTS: There was 1 early death in group 1 (5.8%) and 6 in group 2 (7%) (p = ns). At the conclusion of the operative procedure, all patients in group 1 were weaned off cardiopulmonary bypass with trivial to mild MR. There was 1 late death in group 1 (6.2%) and 2 in group 2 (2.8%) (p = ns). Eleven patients (73%) in group 1 were in New York Heart Association class 1 compared to 60 in group 2 (77%) (p = ns). Follow-up echocardiography showed that 80% of patients in group 1 had trivial MR. CONCLUSIONS: The surgical reconstruction of inferior LV aneurysms and scars can be performed safely with the expectation of a reasonable early outcome similar to that achieved with anterior LV scars. When used in this setting GER improves MR, reducing the likelihood of heart failure decompensation.

High lactate predicts the failure of intraaortic balloon pumping after cardiac surgery.

BACKGROUND: Despite the use of intraaortic balloon pump (IABP) support in complex cardiac surgical patients, morbidity and mortality rates are high. More advanced mechanical cardiovascular support should be considered in those patients who are highly likely to die despite IABP support. We sought to identify early, readily available prognostic markers for patients receiving IABP support. METHODS: A retrospective analysis was performed on 39 patients requiring IABP support following cardiac surgery for more than 2 years. The accuracy and predictive ability of multiple potential markers of mortality were statistically assessed. RESULTS: Sixty-seven percent of the patients were successfully weaned from IABP support and 46% survived to hospital discharge. Serious complications occurred in 13% of patients. Serum lactate more than 10 mmol/L in the first 8 hours of IABP support predicted a 100% mortality. Base deficit more than 10 mmol/L, mean arterial pressure less than 60 mm Hg, urine output less than 30 mls/h for 2 hours, and dose of epinephrine or norepinephrine more than 10 microg/min were other highly predictive prognostic markers. CONCLUSIONS: Morbidity and mortality rates remain high despite IABP support following cardiac surgery. Mortality can be predicted by the presence of elevated serum lactate, elevated base deficit, hypotension, oliguria and large vasopressor doses, any of which should prompt appropriate consideration as to other mechanical cardiovascular support.

An extracorporeal membrane oxygenation-based approach to cardiogenic shock in an older population.

BACKGROUND: We investigated the efficacy of an integrated system of advanced supportive care based on extracorporeal membrane oxygenation (ECMO) in older patients with an estimated mortality of more than 90% to establish whether its use is justifiable. METHODS: Treatment was provided by cardiac surgeons and critical care physicians and included the following key elements: (1) ECMO, (2) early application of continuous venovenous hemofiltration, (3) inhaled nitric oxide, (4) maintenance of perfusion pressure with norepinephrine, (5) maintenance of pulmonary blood flow by ventricular filling with intravenous colloids, (6) avoidance of early postoperative anticoagulation, (7) frequent use of transesophageal echocardiography, and (8) low tidal volume ventilation. Demographic features, intraoperative details, postoperative course, ECMO weaning rate, morbidity, survival to hospital discharge, and the quality of life of survivors were recorded. RESULTS: Seventeen consecutive patients (median age, 69 years) with refractory cardiogenic shock were studied. The median duration of ECMO was 86 hours (20 to 201 hours). Eleven patients (65%) were successfully weaned from ECMO. Seven patients (41%) survived to discharge. The major causes of morbidity were bleeding and leg ischemia. All patients who survived to discharge were alive and well at follow-up (median, 21 months) and reported a satisfactory quality of life. CONCLUSIONS: An ECMO-based approach can be used with acceptable results in the treatment of refractory cardiogenic shock, even in older patients.