Validation of the vitronectin knockout mouse as a model for studying myocardial infarction: Vitronectin appears to influence left ventricular remodelling following myocardial infarction.

BACKGROUND: Vitronectin (VN) is an abundant acute-phase plasma protein that regulates cell adhesion and migration as well as interactions with components of the plasminogen activator/plasmin system, specifically plasminogen activator inhibitor type 1. This system plays a major role in tissue remodelling regulating wound healing after myocardial infarction. OBJECTIVES: To investigate the feasibility of using VN knockout mice (VN(-/-)) to study the role of VN on ventricular remodelling following myocardial infarction. METHODS: Specifically bred VN(-/-) mice and normal wild-type (VN(+/+)) mice underwent coronary artery ligation and were assessed 28 days postligation using echocardiography and morphometric histology. RESULTS: No difference was observed between VN(-/-) mice and VN(+/+) mice with respect to gross phenotype, weight, coronary anatomy or echocardiographically measured ejection fraction (56%). Following myocardial infarction, VN(-/-) mice exhibited less ventricular dilation and less impairment in echocardiographic ejection fraction compared with VN(+/+) mice (48% versus 41%; P=0.01). VN(-/-) mice also exhibited smaller infarcts on morphometric analysis. CONCLUSIONS: The results of the present study confirmed the feasibility of using coronary artery ligation in VN knockout mice to investigate the role of VN in post-myocardial infarction remodelling. The absence of VN appears to result in favourable effects on wound healing. These data suggest that this model may offer novel insights into the role of VN in the regulation of myocardial remodelling.

Two-stage percutaneous closure of mitral periprosthetic valvular leak.

Periprosthetic valve leak can develop as a complication of valve replacement surgery and may manifest as symptomatic valvular regurgitation, heart failure, or haemolysis. We report a case of severe mitral periprosthetic valve leak requiring a two-stage percutaneous closure technique with multiple Amplatzer® III vascular plugs.

Changing outcomes of coronary revascularization in British Columbia, 1995-2001.

OBJECTIVES: To examine outcomes following all first coronary revascularization procedures, isolated coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) on British Columbia (BC) resident adults from 1995 to 2001. METHODS: CABG and PCI data were obtained from the BC Cardiac Registry, and mortality data were obtained from the BC Vital Statistics Agency. Analysis was performed by annual cohorts, and the rates reported are unadjusted. RESULTS: An increasing percentage of revascularization procedures was performed with PCI (62% in 1995 to 73% in 2001; P<0.001) due to the increased use of PCI procedures. Except in emergent cases, 30-day mortality improved after PCI (1.8% to 1.1%; P=0.02) and CABG (1.8% to 1.2%; P=0.01). Emergent cases accounted for 9.0% of PCIs and 2.7% of CABGs, the percentage treated by CABG decreasing from 14.5% in 1995 to 7.5% by 2001 (P<0.001). Mortality rates among emergent cases was higher at 30 days, with no trend in PCI mortality (12%) but a substantial reduction in 30-day mortality after CABG (28% to 10%; P=0.003). One-year survival free from repeat revascularization following PCI increased from 73% in 1995 to 83% in 2001 (P<0.001) and from 94% to 95% (P<0.005) following CABG. CONCLUSIONS: Improvements in procedure-related mortality observed in trials have extended to clinical practice. With respect to emergent cases, an increasing proportion were treated by PCI with no change in PCI mortality but associated with a drop in surgical mortality. There has been a consistent and substantial drop in the need for repeat procedures within one year for patients selected for PCI.

Characterizing the spectrum of in-stent restenosis: implications for contemporary treatment.

BACKGROUND: Reports addressing treatment of in-stent restenosis (ISR) are principally derived from clinical trials. OBJECTIVES: To characterize the spectrum of ISR in an unselected population, and to explore clinical and angiographic factors determining management. METHODS: During a prespecified six-month period before the introduction of drug-eluting stents, consecutive cases of ISR that were identified during clinically driven cardiac catheterization at five hospitals offering all approved treatment modalities for ISR were prospectively registered. RESULTS: ISR was identified in 363 patients; 301 (84%) had one ISR lesion and 62 (16%) had multiple lesions. Unstable clinical presentations accounted for 51%, including 15% with ST-elevation myocardial infarction. The median interval (25th, 75th percentiles) from stent insertion to angiographic diagnosis of ISR was eight months (Q1,Q3: 4,15), with a median stented length of 18 mm (Q1,Q3: 15,28). The majority of lesions (60%) displayed a diffuse ISR pattern (Mehran types 2 and 3). ISR type was independent of time to re-presentation, diabetes, arterial territory and total stent length. Treatment included percutaneous coronary intervention (PCI) alone (n=139 [38%]), PCI with brachytherapy (n=105 [29%]), medical therapy (n=60 [17%]) and coronary artery bypass graft surgery (n=59 [16%]). Medical therapy was associated with small vessel size and recurrent ISR, and coronary artery bypass graft surgery was associated with multiple lesions, as well as diffuse, occlusive and recurrent ISR. For patients treated percutaneously, PCI treatment alone was more common for focal restenosis and after ST-elevation myocardial infarction, and brachytherapy was the more common treatment for diffuse and recurrent ISR, and stable angina. CONCLUSIONS: These data provide a benchmark description of the spectrum of ISR with which the impact of drug-eluting stents may be compared and better understood.

Catheter thrombosis during primary percutaneous coronary intervention for acute ST elevation myocardial infarction despite subcutaneous low-molecular-weight heparin, acetylsalicylic acid, clopidogrel and abciximab pretreatment.

BACKGROUND: Subcutaneous enoxaparin is increasingly employed as the antithrombin of choice in non-ST elevation myocardial infarction and in conjunction with various fibrinolytic regimens in acute ST elevation myocardial infarction (STEMI). Few data exist describing the use of subcutaneous or intravenous enoxaparin as an anticoagulant in the highly thrombotic setting of primary percutaneous coronary intervention (PCI) for STEMI. METHODS: The Which Early ST Elevation Therapy (WEST) study compared fibrinolysis (with and without early cardiac catheterization) with primary PCI in a setting that expedited both strategies on first medical contact. Patients assigned primary PCI are administered acetylsalicylic acid 325 mg, clopidogrel 300 mg and subcutaneous enoxaparin 1 mg/kg before transport to a PCI centre. Of 36 initial patients treated with primary PCI, three patients had procedures that were complicated by extensive thrombosis within coronary catheters and on PCI equipment. RESULTS: Index cases were men aged 43 to 68 years who presented with confirmed STEMI and angiographically proven acute total or subtotal occlusion of a major epicardial coronary segment. During PCI, performed 76 min to 102 min following enoxaparin administration, a clot developed within the guide catheter or on the coronary guidewires and balloon catheter shafts, thus necessitating the replacement of all PCI equipment. In one case, there was evidence of continued intracoronary clot propagation and embolization. CONCLUSION: A single, conventional, weight-adjusted dose of subcutaneous enoxaparin before expedited primary PCI for STEMI may not provide a reliable antithrombotic effect. Supplementary intravenous enoxaparin is now strongly recommended within the WEST study, and a substudy evaluating pre- and postprocedural antifactor Xa activity has been initiated.

N-acetylcysteine for prevention of radiographic contrast material-induced nephropathy: is the intravenous route best?

Use of oral N-acetylcysteine for preventing radiographic contrast material-induced nephropathy (RCIN) has become widespread, despite conflicting results from clinical trials and meta-analyses. The variability in study results may reflect differences in baseline risks in study patients, hydration regimens, choice of contrast agent, definition of RCIN, and the oral dosage formulation of N-acetylcysteine used. Injectable N-acetylcysteine recently has become available in the United States. Although oral N-acetylcysteine regimens are typically administered during a 48-hour period, more rapid intravenous administration could offer an important advantage for urgent procedures such as coronary angiography. However, the three published studies in which intravenous N-acetylcysteine protocols were used have produced divergent results, likely because of substantially different dosage regimens. With few intravenous studies available, clinicians may look to more broadly studied oral regimens to estimate equivalent intravenous dosages. In the oral studies, however, a wide range of formulations were used, and the bioavailability of each product was uncertain. In addition, the intravenous route circumvents first-pass metabolism, resulting in less glutathione production, perhaps compromising the antioxidant effects of N-acetylcysteine administration. Overall, little evidence exists that any studied N-acetylcysteine protocol improves clinical outcomes in terms of reducing length of hospital stay, need for dialysis, or mortality. Furthermore, N-acetylcysteine may directly affect serum creatinine level, which all clinical trials to date have used as a primary outcome measure. If oral or intravenous N-acetylcysteine is used with the intention of preventing RCIN, more established preventive measures should not be overlooked, including adequate hydration with isotonic saline, avoidance of potentially nephrotoxic drugs, and use of iso-osmolar radiographic contrast media.

A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: lack of effect.

BACKGROUND: Contrast-induced nephropathy (CIN) after cardiac catheterization is common in patients with preexisting renal dysfunction. Studies of oral acetylcysteine to prevent CIN have produced conflicting results. Intravenous N-acetylcysteine (NAC) has logistic advantages in this setting. The objective of this study was to evaluate, in a blinded, randomized, placebo-controlled fashion, whether intravenous NAC reduced CIN in the setting of cardiac catheterization in patients with preexisting renal insufficiency. METHODS: Patients with renal dysfunction undergoing cardiac catheterization were randomly assigned to intravenous NAC 500 mg immediately before the procedure or placebo. All patients received isotonic saline (200 mL) beforehand, followed by 1.5 mL/kg per hour for 6 hours, unless contraindicated. Exclusion criteria included acute renal failure, creatinine >400 micromol/L, concurrent dialysis, unstable clinical status, and prior NAC use. Baseline creatinine was obtained immediately before the procedure and repeated 2 to 8 days later. The primary end point was the occurrence of CIN defined as a reduction in creatinine clearance from baseline of >5 mL/min (Cockcroft-Gault formula). RESULTS: The study was terminated early because of a determination of futility by the Data Safety Monitoring Committee after enrollment of 487 patients. The median baseline creatinine clearance was 44 mL/min (interquartile range, 33, 55). Median contrast received was 120 mL (interquartile range, 80, 175). Baseline characteristics were similar in the two groups. Altogether, 98 (22.0%) subjects had the primary end point: 23.3% in the NAC group and 20.7% in the placebo arm (P =.57). CONCLUSIONS: In this large, randomized trial, enrolling a high-risk group of patients with impaired renal function, intravenous NAC was ineffective in preventing CIN.

Association between aortic stenosis and hypertension.

BACKGROUND AND AIM OF THE STUDY: Hypertension causes increased shear stress across the aortic valve. Shear stress across endothelial cells in vitro induces inflammation, which has been demonstrated on stenosed valve leaflets in vivo. In theory, longstanding hypertension could result in aortic stenosis. The study aim was to identify a possible clinical association between these two conditions. METHODS: Data relating to patients with a primary or secondary discharge diagnosis of hypertension or aortic stenosis in the Republic of Ireland were obtained from the Hospital In-Patient Enquiry National File for 1995 to 1999 inclusive. Proportions were compared using chi-squared testing. RESULTS: A total of 3.39 million discharges occurred during this period. Hypertension was the primary or secondary diagnosis in 6.2%, and aortic stenosis in 0.33%. Both conditions were present in 0.07%. Hypertension was present in 21.0% of those with aortic stenosis, and aortic stenosis in 1.1% of those with hypertension. Hypertension was associated with aortic stenosis with an odds ratio of 4.0 (95% confidence interval 3.9 to 4.2, p = 0.0001). CONCLUSION: Aortic stenosis and hypertension were significantly associated in patients discharged from hospital. If hypertension is shown to be contributing to aortic valve disease then, potentially, better blood pressure control might prevent the progression of stenosis.

An epidemiological study of Heyde's syndrome: an association between aortic stenosis and gastrointestinal bleeding.

BACKGROUND AND AIM OF THE STUDY: An association between aortic stenosis (AS) and gastrointestinal (GI) bleeding attributed to intestinal angiodysplasia has been termed Heyde's syndrome. Case-control studies of patients with AS or intestinal angiodysplasia assessing the degree of association have produced discrepant findings. METHODS: Data were examined for all patients discharged from public hospitals in the Republic of Ireland between 1997 and 2001 (3.8 million events) with a primary or secondary discharge diagnosis of AS (ICD-9-CM code 424.1), GI bleeding presumed due to intestinal angiodysplasia (ICD-9-CM codes 569.84, 569.85, 578.1, 578.9), or both. Proportions were compared using chi-squared testing. RESULTS: There was a significant (p <0.0001) association between AS and GI bleeding, with an odds ratio of 4.5 (95% confidence interval 3.0-6.8). Age was a significant confounding factor; patients with both conditions were significantly older than patients with one or none of the conditions (p <0.0001). The incidence of GI bleeding in patients with AS was 0.9%, and the incidence of AS in patients with GI bleeding was 1.5%. CONCLUSION: The results of this large retrospective analysis support the existence of an association between AS and GI bleeding presumed due to intestinal angiodysplasia. However, the percentage of patients with both conditions was low, and this may explain why some smaller studies have failed to demonstrate such an association.

Heyde's syndrome: a review.

Bleeding from gastrointestinal angiodysplasia in patients with aortic stenosis (AS), termed Heyde's syndrome, has been recognized for many years. Intestinal angiodysplasia (IA) and AS are chronic degenerative diseases that are often asymptomatic, with a higher prevalence in the population than is clinically apparent. The incidence of both conditions increases with age, and both are associated with traditional cardiovascular risk factors. Many studies suggest that there is an increased prevalence of IA in AS and vice versa, but there is wide variation between studies. Evidence is mounting that severe AS may cause Type 2 acquired von Willebrand's disease, also termed von Willebrand's syndrome. This involves loss of the large multimers, which are required to maintain hemostasis in high flow conditions, such as occur in angiodysplastic arteriovenous malformations. Heyde's syndrome appears to consist of bleeding from previously latent intestinal angiodysplasia as a result of this acquired hematological defect, which is associated with aortic stenosis. Treatment options include localization of angiodysplastic bleeding points with cauterization, but this is associated with a high recurrence rate. Aortic valve replacement has been shown to improve the hematological abnormalities, and this is paralleled by clinical improvements. Valve replacement appears to offer the best hope of long-term resolution of the bleeding, and should be considered in most cases, particularly in those in whom the AS is symptomatic. In those patients deemed unfit for surgery in whom no bleeding point can be identified, recurrent blood transfusions may offer some symptomatic relief.

Anti-inflammatory effects of statins in patients with aortic stenosis.

BACKGROUND: Aortic stenosis is an inflammatory process, as evidenced by increased tissue expression and serum levels of various endothelial cellular adhesion molecules. Aortic stenosis and atherosclerosis have many risk factors in common, including hypercholesterolemia. In atherosclerosis, statins lower cholesterol and display some anti-inflammatory activity. We hypothesized that statins might also have anti-inflammatory effects in patients with aortic stenosis. METHODS: This observational cross-sectional study measured levels of cellular adhesion molecules in 129 patients (88 male, mean age 68) with aortic stenosis (mean echo gradient 49 mm Hg, range 22 to 112) and compared levels in patients already on statin therapy for primary or secondary prevention of coronary artery disease, to those not on treatment. Concomitant conditions included hypertension (47%), diabetes (10%), and ischemic heart disease (54%). A comparison group consisted of 45 patients with stable ischemic heart disease. RESULTS: Patients on statins (35) were more likely to have hypertension (62% vs 42%, P =.05), but no significant differences existed in sex, age, concomitant ischemic heart disease, or diabetes. Statin-treated patients had a 20% lower vascular cellular adhesion molecule level than those without (484 +/- 143 ng/L vs 604 +/- 245 ng/L, P =.006). The reduction in cellular adhesion molecule levels was consistent in patients with aortic stenosis alone, aortic stenosis and ischemic heart disease, or ischemic heart disease alone. There were no differences in the levels of the other adhesion molecules between the three groups, or related to statin therapy. CONCLUSION: Statin therapy is associated with reduced serum levels of vascular cellular adhesion molecules in patients with aortic stenosis. Vascular cellular adhesion molecule levels are similar in patients who have aortic stenosis, ischemic heart disease, or both. A prospective study is required to confirm this finding and to determine whether this suppression of endothelial inflammation translates into a slowing of the progression of aortic stenosis.

Population rates of invasive cardiac procedures in British Columbia, 1995 to 2001.

BACKGROUND: This study examined the rates of coronary angiography (CA), percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) in British Columbia (BC) between 1995 and 2001. METHODS: Data sources were as follows: CABG--BC Cardiac Registries; CA and PCI--BC Medical Services Plan; acute coronary syndromes (ACS)--Hospital Separation database; population data--BC Statistics. All rates were age and sex standardized per 100,000 BC resident adults over 20 years of age. RESULTS: The rate of diagnostic CA increased from 352 per 100,000 in 1995 to 400 per 100,000 in 2001 (P<0.01). The rate of PCI increased from 101 per 100,000 in 1995 to 154 per 100,000 in 2001 (P<0.01). Single stage 'ad hoc' PCI increased from 38% in 1995 to 68% in 2001. The rate of CABG remained stable at between 70 and 79 per 100,000. There was a downward trend in the annual hospitalized incidence of ACS (477 to 430 per 100,000, P=0.04). The incidence of ACS and the rates of CA, PCI and CABG were higher for men in all age groups. PCI was more common than CABG in all groups. CONCLUSIONS: The incidence of ACS in BC is falling. The rates of diagnostic CA and PCI are increasing. The latter finding may reflect an appropriate evidence-based response to data supporting greater application of CA following ACS after publication of several studies supporting a routine invasive approach. The PCI rate is rising compared with the CABG rate, likely reflecting changes in patient selection and improved PCI technology, as well as a limited ability of the system to provide surgical procedures.

An unusual complication of coil embolization of a large coronary-pulmonary fistula.

A 58-year-old man with hemoptysis was found to have a large fistula from his circumflex artery to the pulmonary system. Coil embolization was performed. This resulted in occlusion of the fistula, including a small branch likely supplying the sinus node. Following the procedure he developed junctional bradycardia but remained hemodynamically stable. He had a brief period of atrial fibrillation which, after 48 hours, reverted to a rhythm from an ectopic focus in the low right atrium. This case highlights an unusual complication of fistula embolization and emphasizes the need for caution when occluding vessels which may supply the sinus node.

N-acetylcysteine reduces urinary albumin excretion following contrast administration: evidence of biological effect.

BACKGROUND: There are conflicting results regarding the effectiveness of N-acetylcysteine (NAC) in attenuating contrast-induced nephropathy (CIN). NAC administration independently reduces serum creatinine, potentially confounding studies utilizing creatinine-based endpoints. Albuminuria is a marker of renal injury and spot urine albumin: creatinine ratios (ACR) reflect 24-h urine albumin excretion. We performed a pre-specified secondary analysis from our published negative randomized control trial of NAC for prevention of CIN, to determine if NAC administration reduces albuminuria after contrast exposure following cardiac catheterization. METHODS: We included study patients who had paired urine specimens obtained pre- and post-cardiac catheterization. Baseline characteristics were compared using the chi square test or Mann-Whitney U-test, as appropriate. Changes in ACR were evaluated using binomial exact test. The effect of NAC on post-cardiac catheterization changes in ACR ratio was evaluated by ordinal logistic regression. RESULTS: A total of 125 patients met inclusion criteria (pre- and post-catheterization urinalysis within 7 days). Baseline characteristics neither differ between NAC and placebo groups, nor were they different from those who were excluded. Among the patients receiving NAC, 10.7% improved their ACR ratio and 7.1% worsened; in contrast, in patients on placebo only 4.3% improved, while 21.7% worsened (P=0.015). Change in ACR ratio was not associated with change in kidney function as measured by calculated creatinine clearance or GFR. CONCLUSIONS: The results of this analysis suggest NAC may attenuate contrast-induced glomerular or tubular injury, as defined by albumin excretion, and appears to be independent of any effect on creatinine-derived measures of kidney function. Larger studies are required to confirm this observation.

Techniques for percutaneous closure of prosthetic paravalvular leaks.

Percutaneous transcatheter closure techniques are now routinely applied in the management of atrial and ventricular septal defects, patent ductus arteriosus, and other pathological cardiac and vascular communications. Recently, these same techniques have been applied to paravalvular defects. Reports are few; success variable and techniques vary widely. We review the current considerations and techniques of percutaneous transcatheter closure of paravalvular leaks.

Percutaneous closure of prosthetic paravalvular leaks: case series and review.

BACKGROUND: Paravalvular leaks (PVLs) are a well-recognized complication of prosthetic valve replacement. Most are asymptomatic and benign, but some may cause symptoms due to a large regurgitant volume or hemolysis. Medical therapy is palliative, while reoperation carries significant morbidity and mortality. Percutaneous transcatheter closure techniques, now routinely applied in the management of pathological cardiac and vascular communications, may be adaptable to PVL closure, potentially offer symptomatic relief. METHODS: We reviewed our experience with attempted percutaneous closure of PVLs, using data from medical and procedural records. RESULTS: Between 2001 and 2004, 14 procedures were performed in 10 patients, all under general anesthesia, with transesophageal and radiographic guidance. Mitral (9) and aortic (1) valve replacements were involved, both mechanical and bioprosthetic. A variety of devices were used, including atrial septal occluders, patent ductus arteriosus occluders, and coils (all of label use). Six had a single procedure, which was technically successful in four: in two, the PVL could not be crossed. Four underwent a second procedure, which was technically successful in three; in one the previously deployed device was dislodged necessitating urgent, but ultimately uneventful, surgical removal and leak repair. One patient had transient severe hemolysis, which resolved after 1 week. At 1-year follow-up (9/10 pts) three had died, five had sustained symptomatic improvement while 1 patient with a residual leak still required regular blood transfusions. CONCLUSIONS: Percutaneous closure of PVLs is time-consuming but feasible in selected patients, with a reasonable degree of technical and clinical success. A second procedure may be necessary and a variety of complications can occur.

Percutaneous occlusion of a pulmonary aneurysm causing hemoptysis in a patient with pulmonary atresia and aortopulmonary collaterals.

A 28-year-old male was referred for cardiac catheterization because of recurrent severe hemoptysis necessitating resuscitation and subsequently preventing weaning from ventilation. He had a history of pulmonary atresia, ventricular septal defect, overriding aorta with right-sided aortic arch diagnosed at birth. Eisenmenger's syndrome ensued and he was not felt to be suitable for corrective cardiac surgery. He had multiple major aortopulmonary collateral vessels to both lungs with a large aneurysm in an artery to the right lower lobe, which was suspected to be the source of his bleeding. Occlusion of this aneurysm was achieved percutaneously using an Amplatzer septal occluder device. He had no further bleeding and was successfully weaned from ventilation. Six months later, he has recovered to his functional baseline and has not had any further episodes of hemoptysis.