Intracerebroventricular endothelin receptor-A blockade in rats decreases phase-II ventricular tachyarrhythmias during acute myocardial infarction.

Endothelin alters central sympathetic responses, but the resultant effects on arrhythmogenesis are unknown. We examined ventricular tachyarrhythmias after endothelin receptor-A blockade in the brain of Wistar rats with acute myocardial infarction. For this aim, BQ-123 (n=6) or phosphate-buffered saline (n=6) were injected intracerebroventricularly. After 10 min, the left coronary artery was ligated, followed by implantation of telemetry transmitters. Electrocardiography and voluntary activity (as a surrogate of acute left ventricular failure) were continuously monitored for 24 h. Infarct-size was similar in the two groups. There were fewer episodes of ventricular tachyarrhythmias of shorter average duration in treated rats, leading to markedly shorter total duration (12.3+/-8.9 s), when compared to controls (546.2+/-130.3 s). Voluntary activity increased in treated rats during the last hours of recording, but bradyarrhythmic episodes were comparable between the two groups. Endothelin receptor-A blockade in the brain of rats decreases the incidence of ventricular tachyarrhythmias post-ligation, without affecting bradyarrhythmic episodes. These findings call for further research on the pathophysiologic role of endothelin during acute myocardial infarction.

Tissue engineering for post-myocardial infarction ventricular remodeling.

Myocardial tissue engineering involves the design of biomaterial scaffolds, aiming at regenerating necrotic myocardium after myocardial infarction. Biomaterials provide mechanical support to the infarct area and they can be used as vehicles for sustained and controlled local administration of cells and growth factors. Although promising results have been reported in experimental studies, many issues need to be addressed before human use.

Amiodarone attenuates apoptosis, but induces phospholipidosis in rat alveolar epithelial cells.

Amiodarone-induced pulmonary toxicity is a serious side-effect, but the underlying molecular mechanisms remain unclear. We examined phospholipidosis and apoptosis in rat alveolar epithelial cells after medium-term oral amiodarone treatment. Amiodarone (30 mg/kg daily, a dosage corresponding to that used clinically) or vehicle was administered by gavage in 33 Wistar rats for two weeks. Apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labelling (TUNEL) and the expression of apoptosis- and phospholipidosis-related proteins was measured by immunohistochemistry. Amiodarone decreased phospholipase-C-γ1 and increased phosphatidylinositol-(4,5)-bisphosphate, resulting in phospholipidosis, evidenced by the appearance of intracellular inclusion bodies with a multi-lamellated interior. Amiodarone exerted two opposite effects on apoptosis; compared to controls, the expression of activated-caspase-8 was higher in treated rats, while the expression of apoptosis inhibitors survivin, Bcl-2 and c-Flip was lower. On the other hand, the expression of activated-caspase-3 was lower after treatment. Overall, amiodarone attenuated apoptosis, evidenced by fewer TUNEL-positive cells. Medium-term oral amiodarone administration induced phospholipidosis in rat alveolar epithelial cells. Although such treatment decreased anti-apoptotic proteins, apoptosis was attenuated via a decrease in the caspase-3 pathway. These findings improve current understanding on the mechanisms underlying amiodarone-induced pulmonary toxicity.

Effects of clenbuterol on contractility and Ca2+ homeostasis of isolated rat ventricular myocytes.

Clenbuterol, a compound classified as a beta2-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of clenbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca2+ transients, and L-type Ca2+ current and compared these effects to two other clinically used beta2-AR agonists: fenoterol and salbutamol. Clenbuterol (30 microM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca2+ transient amplitude and L-type Ca2+ current. Selective beta1-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol (P < 0.05). Incubation with 2 microg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 microM clenbuterol. In addition, overexpression of inhibitory G protein (Gi) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the Gi protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through Gi, and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs.

Randomised comparison of growth hormone versus IGF-1 on early post-myocardial infarction ventricular remodelling in rats.

OBJECTIVE: Growth hormone and insulin-like growth factor-1 participate in post-myocardial infarction healing, but their relative importance is unclear. We compared the treatment effects of these agents on left ventricular remodelling. DESIGN: Wistar rats were randomised into a single dose of either growth hormone (0.5microg, n=29), or insulin-like growth factor-1 (0.5microg, n=27), delivered by direct intramyocardial punctures, and were compared with controls (n=30). Five minutes after treatment, myocardial infarction was generated by permanent ligation of the left coronary artery. Twenty-four hours post-ligation, serum levels of catecholamines were measured using radioimmunoassay and infarct size as well as infarct expansion index were calculated. The expression of genes related to extracellular matrix and angiogenesis was measured using polymerase chain reaction. RESULTS: Infarct expansion index was lower in growth hormone-treated rats (0.28+/-0.03, p=0.007) and in insulin-like growth factor-1-treated rats (0.35+/-0.03, p=0.044) compared to controls (0.51+/-0.06). Infarct size was significantly (p=0.0076) lower in growth hormone-treated rats (32.2+/-2.0%) and marginally (p=0.094) lower in insulin-like growth factor-1-treated rats (36.2+/-2.3%) compared to controls (42.0+/-2.7%). Survival rates were comparable in the three groups. Epinephrine was lower in the growth hormone group (2.8+/-0.2microg/l) compared to either controls (5.0+/-0.6microg/l, p=0.007), or to insulin-like growth factor-1-treated rats (6.3+/-0.6microg/l, p=0.0001). Collagen I and III expression in the infarct zone was higher in the growth hormone group compared to either the insulin-like growth factor-1 group or to controls. CONCLUSIONS: Both growth hormone and insulin-like-growth factor-1 decrease early infarct expansion, but growth hormone results in more favourable extracellular matrix remodelling and sympathetic activation.

Microscopic papillary thyroid cancer as an incidental finding in patients treated surgically for presumably benign thyroid disease.

BACKGROUND: Papillary thyroid microcarcinoma (PTMC) is a relatively common entity in the general population. AIM: To present our experience with papillary thyroid microcarcinoma of the thyroid as an incidental finding in patients treated surgically for presumably benign thyroid disease. SETTINGS AND DESIGN: Histology reports of patients treated surgically with a preoperative diagnosis of benign thyroid disease were reviewed to identify patients with PTMC. Patients with a preoperative diagnosis of thyroid cancer were excluded from this study. MATERIALS AND METHODS: The files of 380 patients who underwent surgery for presumably benign thyroid disease in our hospital from 1990 to 2002 were reviewed. Data regarding patient's demographics, pathology findings, management and outcomes, were retrieved. STATISTICAL ANALYSIS USED: The findings are expressed as absolute numbers and as percentages (with reference to the total number of patients of this study). RESULTS: Twenty-seven patients with PTMC diagnosed incidentally following thyroid surgery for presumably benign thyroid disease (27/380 or 7.1%) (multinodular goiter = 20 patients, follicular adenoma = 6 patients, diffuse hyperplasia of the thyroid = 1 patient) are presented. Mean diameter of PTMC was 4.4 mm. In 11 patients (40.7%) the tumor was multifocal and in about half of them tumor foci were found in both thyroid lobes. In two patients the tumor infiltrated the thyroid capsule. Total/near-total thyroidectomy was performed in all these patients (in three as completion thyroidectomy). All patients received suppression therapy and 20 of them underwent adjuvant radioiodine therapy. Follow-up (mean 4.56 years, range 1-12 years) was completed in 25 patients; all these patients were alive and disease-free. CONCLUSIONS: PTMC is not an uncommon incidental finding after surgery for presumably benign thyroid disease (7.1% in our series). The possibility of an underlying PTMC should be taken into account in the management of patients with nodular thyroid disease; total/near total thyroidectomy should be considered, at least in selected patients with presumably benign nodular thyroid disease.

Early, intracoronary growth hormone administration attenuates ventricular remodeling in a porcine model of myocardial infarction.

OBJECTIVE: Ventricular remodeling is a common corollary of myocardial infarction. We hypothesized that this process may be attenuated by growth hormone, administered as a single high-dose, selectively in the infarct zone, early postmyocardial infarction. DESIGN: In 35 pigs (29+/-4 kg), myocardial infarction was generated by inflation of an over-the-wire angioplasty balloon in the circumflex artery for 60 min and 5 further pigs were sham-operated. Ten minutes after reperfusion, the pigs were randomized (2:1) to either growth hormone (1 IU/kg) (n=23) or normal saline (n=12), delivered via the balloon catheter. All survivors were treated with captopril and were sacrificed 4 weeks after myocardial infarction. RESULTS: Compared to controls, growth hormone-treated animals displayed lower heart weight (4.1+/-0.5 g/kg body weight, versus 3.4+/-0.4 g/kg, respectively, p=0.003) and dimensions (left ventricular short axis diameter 46+/-7 mm versus 37+/-6 mm, p=0.01; right ventricular short axis diameter 38+/-7 mm versus 30+/-5 mm p=0.001). Growth hormone increased wall thickness in the infarct (6.0+/-1.8 in controls versus 9.9+/-3.7 in treated animals, p=0.004) and non-infarct zones (10.6+/-1.8 in controls versus 15.5+/-3.8 in treated animals, p=0.0006) and produced higher (p<0.05) microvascular density in both zones. CONCLUSION: Intracoronary administration of growth hormone attenuates left and right ventricular remodeling by inducing hypertrophy and by enhancing angiogenesis.

Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation.

OBJECTIVE: To assess the effectiveness and safety of pharmacological conversion of persistent atrial fibrillation (AF) with a combined propafenone plus ibutilide regimen. METHODS AND RESULTS: 100 consecutive patients (66 men, mean (SD) age 65 (10) years) with persistent AF (mean (SD) duration 99 (92) days) admitted for elective pharmacological cardioversion were randomly assigned to treatment with either intravenous ibutilide (1 mg plus an additional 1 mg, if required; n = 51) or oral propafenone (600 mg) plus intravenous ibutilide at the same dose (n = 49). Success rates were 41.1% (21 of 51 patients) for ibutilide alone and 71.4% (35 of 49 patients) for propafenone plus ibutilide (p = 0.0044). However, cardioversion occurred earlier in the ibutilide alone group (55 (20) minutes) compared with the combination group (81 (32) minutes, p = 0.0019). A comparable increase in the QTc interval was observed in both groups but one case of sustained torsade de pointes, requiring electrical cardioversion, was observed in the propafenone plus ibutilide group. No other complications were noted during the hospitalisation period. CONCLUSION: Concurrent administration of propafenone plus ibutilide for pharmacological cardioversion of persistent AF is safe and more effective than ibutilide alone.

Variation of inflammatory indexes after electrical cardioversion of persistent atrial fibrillation. Is there an association with early recurrence rates?

Inflammation has been recently implicated in the pathophysiology of atrial fibrillation (AF). The aim of this study was to examine the variation of inflammatory indexes during the first week after successful electrical cardioversion of persistent AF. Successive measurements of white blood cell (WBC) count, C-reactive protein (CRP) and fibrinogen levels were performed in 30 cardioverted patients. At the end of the 7-day follow-up period, AF had recurred in 30% of patients. A significant variance was found in serial measurements of fibrinogen levels in the two groups (non-relapse and relapse, p = 0.005). Fibrinogen levels increased significantly in patients who relapsed into AF, but remained stable in patients who remained in sinus rhythm. In the latter patients, CRP values tended to decrease post-cardioversion, but WBC count was significantly lower (p < 0.001) on the 7th day (6083 +/- 1335), compared with baseline values (6648 +/- 1395). The variation of inflammatory indices post-cardioversion might have prognostic implications with regard to sinus rhythm maintenance.

Early, selective growth hormone administration may ameliorate left ventricular remodeling after myocardial infarction.

Left ventricular (LV) remodeling after myocardial infarction (MI) may lead to congestive heart failure, disability and death. It consists of expansion of the infarct zone and dilatation of the non-infarcted myocardium, causing shape distortion and ventricular enlargement. Experimental studies have shown that treatment with growth hormone (GH) stimulates cardiac repair, resulting in increased infarct zone collagen scar formation and possibly enhanced proteinosynthesis. These actions may ameliorate the process of LV remodeling. We hypothesize that these beneficial effects may be more prominent, if GH is delivered selectively in the infarct area, during the early phase of acute MI. Experimental and clinical studies are necessary to validate this hypothesis.

Treatment of acute lower limb ischemia following the use of the Duett sealing device: report of three cases and review of the literature.

Three cases of local thrombolysis in the treatment of acute lower limb ischemia complicating the utilization of the Duett sealing device are presented. Routine usage of several vascular closure devices after cardiac catheterization and percutaneous coronary intervention (PCI) has been adopted in our institution during the last 3 years (September 1999 to April 2003). The Duett closure device has been used in 420 patients (post-coronary angiography, 359; post-PCI, 61). Three patients (0.7%) demonstrated acute leg ischemia used by inadvertent intravascular administration of the sealing material related to this device. All three were treated successfully by catheter-directed local thromolysis (tissue plasminogen activator 5 mg bolus followed initially by 1 mg/hr and consequently by 0.5-1.0 mg/hr depending upon the development of significant hematoma and lasting for 24 hr). In conclusion, interventional treatment using local thrombolysis should be the first-line treatment in acute lower limb ischemia complicating the utilization of the Duett sealing device.

A case of gallstone ileus with an unusual impaction site and spontaneous evacuation.

Gallstone ileus is an unusual cause of colonic obstruction. The formation of a fistula between the gall bladder and the bowel wall may allow a gallstone to enter the intestinal tract. Plain abdominal films, abdominal ultrasound and abdominal computed tomography aid in the diagnosis. Although surgery is the treatment of choice in cases of colonic gallstone ileus, colonoscopic removal of the impacted stone should be attempted. We describe the case of an 85-year-old man who presented with symptoms and signs of large bowel obstruction. Diagnostic evaluation revealed a large gallstone impacted in the sigmoid colon, which is a rather unusual impaction site. Despite our efforts we could not extract the stone endoscopically, mainly due to its large size. Yet, despite its large size, the stone was spontaneously evacuated a few hours later.

Winter swimming: healthy or hazardous?. Evidence and hypotheses.

Swimming in cold water during the winter season is an extreme sport, with fans all over the world. However, its effects on health have been debated. This article examines the hypothesis that the effects of winter swimming may depend on previous exposure to cold stimuli. Immersion in cold water in unaccustomed persons may lead to detrimental consequences, while, in regular winter swimmers, adaptive physiologic mechanisms increase tolerance to cold. Furthermore, these mechanisms may prevent the occurrence of a wide variety of diseases. Prospective studies and epidemiological data are needed to test this hypothesis.

Haemodynamic and catecholamine response to simulated ventricular tachycardia in man: effect of baseline left ventricular function.

OBJECTIVE: To examine the effects of baseline left ventricular function on the haemodynamic and catecholamine responses to ventricular tachycardia. DESIGN: Experimental cohort study. SETTING: Cardiac catheterisation laboratory in tertiary referral centre. SUBJECTS: 24 patients (19 male, 5 female; mean (SD) age, 59 (10) years) without coronary artery disease, divided into two groups with normal or impaired left ventricular function: group A, ejection fraction > 65% (n = 10); group B, ejection fraction < 45% (n = 14). Other medical and demographic factors were similar in the two groups. INTERVENTIONS: Ventricular tachycardia was simulated with rapid pacing at 150 beats/min for 10 minutes. MAIN OUTCOME MEASURES: Arterial blood pressure; venous plasma catecholamine concentrations. RESULTS: During rapid pacing, blood pressure was lower in group B (with impaired left ventricular function) than in group A: systolic blood pressure, 102 (11) v 115 (9) mm Hg (p = 0.005); mean blood pressure, 79 (6) v 85 (6) mm Hg (p = 0.02). The ejection fraction correlated with the lowest systolic blood pressure (r = 0.64, p = 0.0006). Although the rise in adrenaline was comparable between the two groups, the rise in noradrenaline was more pronounced (p < 0.05) in patients in group B. CONCLUSION: At low rates and in selected patients, the underlying state of left ventricular function affects haemodynamic tolerance of ventricular tachycardia. Patients with impaired left ventricular function have a lower blood pressure during ventricular tachycardia, despite an exaggerated noradrenaline release.

Platelet hyperaggregability to platelet activating factor (PAF) in non-ST elevation acute coronary syndromes.

It is known that myocardial ischaemia increases platelet aggregatory response to various agonists, ex vivo. We investigated the platelet aggregatory response to platelet activating factor (PAF), ex vivo, in patients with non-ST elevation acute coronary syndromes and determined the specificity and sensitivity of this response. Thirty-two consecutive patients with non-ST elevation acute coronary syndromes and 20 healthy volunteers were studied. Platelet aggregation in platelet-rich plasma was studied on the day of admission. The maximal aggregation achieved within 2 min after the addition of PAF (100 nM) was expressed as a percentage of 100% light transmission. PAF EC50 values were defined as the concentration that induces 50% of maximal aggregation. The PAF EC50 values of the non-ST elevation acute coronary syndromes patients were significantly lower compared to those of the controls (p < 0.0001). The maximal percentage of aggregation was also significantly higher (p < 0.0005). Ninety-one per cent of the patients were correctly classified using PAF EC50 values (specificity 90.0% and sensitivity 91.2%); the corresponding results using the maximal percentage of aggregation were 80% (specificity 70.0% and sensitivity 87.5%). The estimated values used as thresholds were 22.47 nM and 17.97 for the PAF EC50 and the maximal percentage of aggregation, respectively. The results of the present study suggest that platelet hyperaggregability to PAF, ex vivo, in non-ST elevation acute coronary syndromes is characterised by a high specificity and sensitivity, and thus it may represent a mechanism contributing to the pathophysiology of acute coronary syndromes.

Acute endothelin-A receptor antagonism prevents normal reduction of myocardial ischemia on repeated balloon inflations during angioplasty.

BACKGROUND: Myocardial ischemia and reperfusion are associated with increased production of endothelin (ET)-1. METHODS AND RESULTS: We examined the effects of BQ-123, a selective ET(A) receptor antagonist, in 80 patients. All patients were randomly allocated to an intracoronary infusion of saline or BQ-123 (6 micromol/L over 20 minutes). The reference group consisted of 20 patients undergoing coronary angiography. BQ-123 produced a 10% (P:<0.005) increase in distal coronary artery diameter. The main study group consisted of 30 patients undergoing coronary angioplasty. All patients underwent a minimum of 3 balloon inflations (BIs). Surface and intracoronary electrocardiographic ST-segment shift as well as pain score were recorded at the end of each BI. BQ-123 or saline was given by intracoronary infusion between the second and the third BI in random allocation. In the saline group, intracoronary ST-elevation decreased from 1.26+/-0.55 mV during the first BI to 0.77+/-0.56 mV during the third BI (P:<0.05) and the surface ST elevation decreased from 0.20+/-0.15 to 0.10+/-0.07 mV (P:<0.05). In the BQ-123 group, the respective values were 1.22+/-0.48 mV and 1.13+/-0.62 mV (intracoronary) and 0.17+/-0.18 and 0.17+/-0.21 mV (surface) (both P:=NS). The decrease in pain score was significantly higher in the saline group (F:=5.97, P:=0.004). In 30 patients (collateral circulation group), the angioplasty protocol was repeated with the use of a pressure guide wire. BQ-123 produced a significant (F:=3.30, P:=0.04) decrease in coronary wedge pressure. CONCLUSIONS: Acute ET(A) receptor antagonism prevents the normal reduction of myocardial ischemia on repeated BIs during angioplasty. This may be explained by a "steal" effect through coronary collaterals.

Improved left ventricular relaxation during short-term right ventricular outflow tract compared to apical pacing.

STUDY OBJECTIVES: Pacing-induced asynchrony may deteriorate left ventricular function; however, limited data exists in humans. The aim of our study was to compare left ventricular hemodynamics during short-term atrioventricular sequential pacing from the right ventricular apex and from the outflow tract of the right ventricle. DESIGN: Three 5-min pacing intervals were applied in a random order, at a rate of 15 beats/min above the resting sinus rate. Atrioventricular sequential pacing from the two sites was compared with atrial pacing. During each pacing mode, left ventricular pressure was recorded, and cardiac output was calculated using Doppler echocardiography. SETTING: Cardiac catheterization laboratory. PATIENTS: Twenty patients (18 male, mean age 62 +/- 11 years) without structural heart disease were studied. RESULTS: During atrial pacing, maximum negative first derivative of pressure (dp/dt) was 1,535 +/- 228 mm Hg/s; during pacing from the apex it decreased to 1,221 +/- 294 mm Hg/s (p = 0.0001), but was not significantly different during pacing from the outflow tract (1,431 +/- 435 mm Hg/s, p > 0.05). Isovolumic relaxation time constant (tau) during atrial pacing was 39.7 +/- 11.9 ms; during pacing from the apex, it increased to 47.9 +/- 14.0 (p = 0.001), but was not significantly different during pacing from the outflow tract (42.5 +/- 11.2, p > 0.05). Peak systolic pressure decreased significantly during atrioventricular sequential pacing from either site; however, it did not differ between the two sites. No differences in end-diastolic pressure, maximum positive dp/dt, or cardiac output could be demonstrated. CONCLUSION: In patients with no structural heart disease, short-term right ventricular outflow tract pacing is associated with more favorable diastolic function, compared to right ventricular apical pacing.

Treatment of a coronary artery aneurysm with a novel stent.

We report a case of a prominent aneurysm of the right coronary artery secondary to atherosclerotic coronary artery disease. The aneurysm was complicated by recurrent myocardial infarction despite optimal medical treatment. It was successfully treated with coronary artery stenting, using a novel device, consisting two stents with a layer of expandable graft material placed between them. Follow-up angiography 6 months after the procedure showed a sustained excellent result.