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.

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.

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.

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.

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.

Cardiac pacing and coronary hemodynamics.

This article reviews the current knowledge on the effects of pacing on coronary hemodynamics. In particular, the possible effects of heart rate, atrioventricular delay, ventricular depolarization sequence, and ventricular pacing site on the coronary circulation are examined.

Importance of the site of ventricular tachycardia origin on left ventricular hemodynamics in humans.

Experimental animal data have indicated that the site of ventricular tachycardia origin and, hence, the degree of asynchronous contraction, may influence the hemodynamic tolerance during sustained ventricular tachycardia. However, data in man are scarce. We studied patients with preserved left ventricular function and absence of significant coronary artery disease. Ventricular tachycardia was simulated with rapid pacing (at 120 and 150 beats/min), performed randomly, from the right ventricular apex or the right ventricular outflow tract. Following pacing from one site, it was repeated from the alternate site. Compared to outflow tract pacing, QRS duration was significantly longer during rapid pacing from the apex. Left ventricular pressure was recorded using a micromanometer-tipped catheter. During sinus rhythm, peak systolic pressure was 142 +/- 14 mmHg; at 120 beats/min, it decreased to 109 +/- 12 mmHg during pacing from the apex and to 127 +/- 21 mmHg during pacing from the outflow tract (P = 0.008). This difference diminished at 150 beats/min (101 +/- 16 mmHg vs 112 +/- 16 mmHg, respectively, P = 0.21). During sinus rhythm end-diastolic pressure was 13 +/- 1 mmHg, which did not change significantly during pacing at 120 beats/min. During pacing at 150 beats/min, end-diastolic pressure increased to 21 +/- 3 mmHg during pacing from the apex and to 16 +/- 2 mmHg during pacing from the outflow tract (P = 0.005). Changes in first derivative of pressure and in isovolumic relaxation time constant were comparable during pacing from the two sites. Thus, it seems that tachycardias originating from the right ventricular outflow tract result in more favorable left ventricular hemodynamics, compared to those from the right ventricular apex.

Coronary blood flow changes during atrioventricular sequential pacing with different atrioventricular delays in normal individuals.

This study examined the effects of different atrioventricular (AV) intervals, during AV sequential pacing, on hemodynamics and coronary blood flow in individuals with normal hearts. Left anterior descending artery blood flow velocity was measured, using intracoronary Doppler, in 17 normal individuals. Five pacing tests were applied in random order for 5 min, at 15 beats/min above the sinus rate. Four tests using AV sequential pacing with AV intervals of 175, 150, 100, and 50 ms, and one using atrial pacing were applied. Mean flow velocity was 21 +/- 9 cm/s, 20 +/- 9 cm/s, 17 +/- 7 cm/s, 17 +/- 7 cm/s, and 22 +/- 10 cm/s, respectively (F = 8.87, p = .00001). The hemodynamic effects of these 5 pacing tests were assessed in 8 different normal subjects. Isovolumic relaxation time constant and left ventricular systolic pressure decreased, whereas right atrial pressure increased during AV sequential pacing with short AV intervals. Thus, during short-term AV sequential pacing at rest, coronary blood flow in a normal left anterior descending artery decreases with short AV intervals.

Prospective randomized trial of external versus internal transcatheter cardioversion in patients with chronic atrial fibrillation.

To evaluate the safety and long-term efficacy of internal transcatheter cardioversion, forty patients with chronic, lone atrial fibrillation were studied. The patients were randomised to internal transcatheter cardioversion or to conventional external cardioversion. In cases where the procedure was unsuccessful, cross-over to the alternate method was performed. Oral anticoagulation therapy was started three weeks prior to the procedure and was maintained for another three weeks following successful cardioversion. Sinus rhythm was restored in 16/18 patients (88%) in the internal cardioversion group, versus 9/22 patients (40%) in the external cardioversion group (p < 0.01). In addition, 8/13 (61%) patients who were crossed-over to internal cardioversion were successfully cardioverted to sinus rhythm. In contrast, both patients who were crossed-over to external cardioversion remained in atrial fibrillation. During a mean follow-up period of 23 months, 13 (39.3%) patients maintained sinus rhythm. Using the intention to treat principle, the recurrence rate was not statistically different between the two methods. It is concluded that internal cardioversion is more effective in acutely restoring sinus rhythm compared to external cardioversion. However, both methods have similar long-term recurrence rates.

Coronary blood flow velocity during apical versus septal pacing.

Previous studies have indicated that ventricular asynchrony may significantly affect resting coronary blood flow velocity. Our study argues against this hypothesis, as comparable left anterior descending blood flow velocities were found during three pacing modalities, associated with varying degrees of asynchrony: (a) atrial pacing, (b) atrioventricular (AV) sequential pacing from the right ventricular apex and (c) AV sequential pacing from the proximal right ventricular septum.

Short-term atrioventricular sequential pacing does not adversely affect collateral blood flow: a study during angioplasty.

Altered sequence of ventricular activation sequence results in marked derangements in mechanical events. In the present study, we investigated the comparative effects of atrial and AV sequential pacing on collateral blood flow during angioplasty. Twenty-eight patients with stable angina and left anterior descending artery disease undergoing balloon angioplasty were studied. Collateral flow was determined during balloon inflation from the distal flow velocity of the ipsilateral artery (17 patients) or from the increase of the maximal diastolic blood flow velocity (Vc) of the contralateral artery (11 patients). Flow measurements were made using the Doppler flow guidewire. The relative resistance in the collateral vascular bed (RR) also was estimated in the latter group of patients. After the first balloon inflation, two similar consecutive balloon inflations were done under atrial and AV sequential pacing, at a rate of 15 beats/min higher than the sinus rate, in the absence of vasoactive medication. One minute after the initiation of pacing, the second and third balloon inflations were begun and the pacing continued until the balloon inflations were completed. In the ipsilateral group, average peak velocity was 84.6 +/- 24.2 mm/2 during atrial pacing and 82.7 +/- 29.7 mm/s during AV sequential pacing (P = NS). In the contralateral group, Vc was 18% +/- 12% during atrial pacing and 17% +/- 14% during AV sequential pacing, and the RR was 4.5 +/- 4.7 and 4.9 +/- 6.4, respectively (both P = NS). The coronary wedge/mean blood pressure was similar during the two tested balloon inflations. Short-term AV sequential pacing at rest does not adversely affect collateral blood flow and resistance in patients with left anterior descending artery disease.