Local conduction during acute myocardial infarction in rats: Interplay between central sympathetic activation and endothelin.

We investigated the effects of autonomic dysfunction and endothelin on local conduction and arrhythmogenesis during myocardial infarction. We recorded ventricular tachyarrhythmias, monophasic action potentials, and activation sequences in wild-type and ETB-deficient rats displaying high endothelin levels. Central sympathetic inputs were examined after clonidine administration. Clonidine mitigated early and delayed arrhythmogenesis in ETB-deficient and wild-type rats, respectively. The right ventricular activation delay increased in clonidine-treated ETB-deficient rats and slightly decreased in wild-type rats. The left ventricular voltage rise decreased in all groups, whereas the activation delay increased mainly in clonidine-treated ETB-deficient rats. Central sympathetic activation and endothelin modulate ischemia-induced arrhythmogenesis. Ischemia alters excitability, whereas endothelin impairs local conduction, an action partly counterbalanced by central sympathetic activity.

ULnar Artery Transient Compression Facilitating Radial Artery Patent Hemostasis (ULTRA): A Novel Technique to Reduce Radial Artery Occlusion After Transradial Coronary Catheterization.

AIMS: To evaluate the safety and efficacy of a novel technique with simultaneous compression of the ulnar artery in order to reduce the incidence of radial artery occlusion (RAO) after transradial cardiac catheterizations. METHODS AND RESULTS: Ipsilateral ulnar artery transient compression for 1 hour facilitating radial artery patent hemostasis (ULTRA) was performed in all patients treated transradially in October 2015 and was compared with patients treated with conventional patent hemostasis in September 2015. The primary endpoint of the study was to evaluate the incidence of RAO within 1 hour after removing the closure device, confirmed by the absence of palpation and the consecutive absence of flow signal with Doppler examination. A total of 119 patients were treated with the ULTRA method and 121 patients with conventional patent hemostasis. None of the patients treated with ULTRA had RAO compared with 6 patients (5%) of those treated with conventional patent hemostasis (P=.01). No hematomas EASY class ≥3, nerve injury, or ischemic pain complications were recorded in either group. CONCLUSION: The ULTRA technique may reduce the incidence of RAO in patients treated with the radial approach compared with conventional patent hemostasis.

Effects of central sympathetic activation on repolarization-dispersion during short-term myocardial ischemia in anesthetized rats.

AIMS: Sympathetic activation during myocardial ischemia enhances arrhythmogenesis, but the underlying pathophysiologic mechanisms remain unclear. We investigated the central sympathetic effects on ventricular repolarization during the early-period post-coronary artery occlusion. MAIN METHODS: We studied 12 Wistar rats (254±2 g) for 30 min following left coronary artery ligation, with (n=6) or without (n=6) pretreatment with the central sympatholytic agent clonidine. Mapping of left and right ventricular epicardial electrograms was performed with a 32-electrode array. As an index of sympathetic activation, heart rate variability in the frequency domain was calculated. Heart rate and repolarization duration were measured with a custom-made recording and analysis software, followed by calculation of intra- and inter-ventricular dispersion of repolarization. KEY FINDINGS: Heart rate and heart rate variability indicated lower sympathetic activation in clonidine-treated rats during ischemia. Repolarization duration in the left ventricle prolonged after clonidine at baseline, independently of heart rate, but no differences were present 30 min post-ligation. Dispersion of repolarization in the right ventricle remained stable during ischemia, whereas it increased in the left ventricle, equally in both groups. A similar trend was observed for inter-ventricular dispersion, without differences between groups. SIGNIFICANCE: In addition to intra-ventricular repolarization-dispersion, anterior-wall myocardial ischemia may also increase inter-ventricular repolarization-dispersion. Progressive central sympathetic activation occurs during myocardial ischemia, but it does not affect intra- or inter-ventricular dispersion of ventricular repolarization during the early phase. Further research is warranted on the potential effects during subsequent time-periods.

Central Sympathetic Activation and Arrhythmogenesis during Acute Myocardial Infarction: Modulating Effects of Endothelin-B Receptors.

Sympathetic activation during acute myocardial infarction (MI) is an important arrhythmogenic mechanism, but the role of central autonomic inputs and their modulating factors remain unclear. Using the in vivo rat-model, we examined the effects of clonidine, a centrally acting sympatholytic agent, in the presence or absence of myocardial endothelin-B (ETB) receptors. We studied wild-type (n = 20) and ETB-deficient rats (n = 20) after permanent coronary ligation, with or without pretreatment with clonidine. Cardiac rhythm was continuously recorded for 24 h by implantable telemetry devices, coupled by the assessment of autonomic and heart failure indices. Sympathetic activation and arrhythmogenesis were more prominent in ETB-deficient rats during the early phase post-ligation. Clonidine improved these outcomes throughout the observation period in ETB-deficient rats, but only during the delayed phase in wild-type rats. However, this benefit was counterbalanced by atrioventricular conduction abnormalities and by higher incidence of heart failure, the latter particularly evident in ETB-deficient rats. Myocardial ETB-receptors attenuate the arrhythmogenic effects of central sympathetic activation during acute MI. ETB-receptor deficiency potentiates the sympatholytic effects of clonidine and aggravates heart failure. The interaction between endothelin and sympathetic responses during myocardial ischemia/infarction and its impact on arrhythmogenesis and left ventricular dysfunction merits further investigation.

Transradial Approach for Cardiac Catheterization in Patients With Negative Allen's Test.

AIMS: To assess the efficacy and safety of transradial approach regardless of the Allen's test results for coronary angiography and angioplasty. METHODS AND RESULTS: Prospective data collection of 1035 consecutive patients who underwent coronary angiography with or without ad hoc angioplasty through the radial approach was conducted. Baseline demographic and procedural data were recorded. Allen's test was evaluated in all subjects before the procedure and catheterization was performed from the radial approach irrespective of the results. Radial artery patency was evaluated at discharge clinically, or by Doppler examination if pulse was not palpable. A total of 256 patients (24.7%) were found to have a negative Allen's test and 779 patients (75.3%) had a positive test. The baseline and procedural characteristics were similar in both groups. No significant differences in complications were reported. Radial artery thrombosis was observed in 6.2% of the negative Allen's test group and 4.8% of the positive Allen's test group (P=.85), but this was clinically silent even in the negative Allen's test group. CONCLUSION: Transradial approach for coronary angiography and ad hoc angioplasty can be performed with similar efficacy and safety regardless of the Allen's test results before the procedure.

Endothelin B-receptors and sympathetic activation: impact on ventricular arrhythmogenesis during acute myocardial infarction.

AIMS: We investigated the role of endothelin-B receptors on sympathetic activation originating from the adrenal gland or from the myocardium and its impact on arrhythmogenesis during acute myocardial infarction. MAIN METHODS: We studied two groups of rats (n=120, 284±2 g), namely wild-type and ETB-deficient. Myocardial infarction was induced by permanent ligation of the left coronary artery and ventricular tachyarrhythmias were evaluated from continuous electrocardiographic recordings. Sympathetic activation, measured by indices of heart rate variability, was evaluated after adrenalectomy or catecholamine depletion induced by reserpine. Acute left ventricular failure was assessed by total animal activity. KEY FINDINGS: Adrenalectomy decreased the total duration of tachyarrhythmias in ETB-deficient rats, but their incidence remained higher, compared to wild-type rats. After reserpine, heart rate variability indices and tachyarrhythmias were similar in the two groups during the initial, ischaemic phase. During evolving infarction, tachyarrhythmia duration was longer in ETB-deficient rats, despite lower sympathetic activation. Heart rate was lower in ETB-deficient rats throughout the 24-hour observation period, whereas activity was comparable in the two groups. SIGNIFICANCE: Endothelin-B receptors modulate sympathetic activation during acute myocardial infarction not only in the ventricular myocardium, but also in the adrenal gland. Sympathetic activation markedly increases early-phase ventricular tachyarrhythmias, but other mechanisms involving the endothelin system underlie delayed arrhythmogenesis.

Arrhythmogenesis after acute myocardial necrosis with and without preceding ischemia in rats.

BACKGROUND: The relative role of acute myocardial ischemia and infarction in ventricular arrhythmogenesis is incompletely understood. We compared the arrhythmia pattern after ischemia/infarction to that observed after direct myocardial necrosis without preceding ischemia in rats. METHODS: Coagulation necrosis was induced in Wistar rats (n=20, 280±3 g) by radiofrequency current application (for 15 s) from a 4-mm-tip ablation catheter. Myocardial infarction was induced by coronary artery ligation with (n=10) or without (n=10) reperfusion. Using 24-h telemetry recording, we examined ventricular arrhythmias, voluntary motor activity and indices of sympathetic activation. RESULTS: The coagulation-necrosis volume was 24.4%±0.6%, comparable to the infarct size in the absence of reperfusion. Acute left ventricular failure and sympathetic activation were similar in the three groups. Coagulation necrosis induced ventricular fibrillation immediately, followed by a second peak after ∼1 h. Reperfusion decreased ventricular arrhythmias, whereas a second arrhythmogenic period (between the third and the eight hour) was noted in non-reperfused infarcts (mainly monomorphic ventricular tachycardia). CONCLUSIONS: Distinct arrhythmia patterns occur after myocardial infarction (with or without reperfusion) and after direct necrosis. They are not produced by differences in sympathetic activation and are likely related to the evolution of myocardial injury. The necrosis rat model may be useful in studies of arrhythmogenesis.

Myocardial protection provided by chronic skeletal muscle ischemia is not further enhanced by ischemic pre- or postconditioning: comparative effects on intracellular signaling.

Chronic skeletal muscle ischemia protects the ischemic heart by preserving coronary flow and inducing arterioangiogenesis. We sought to determine the effect and the underlying molecular mechanisms of preconditioning (PreC) and postconditioning (PostC), applied in a model of chronic skeletal muscle ischemia. Male rabbits were divided into 3 series. In each series, the animals were subjected either to severe hind limb (HL) ischemia, by excision of the femoral artery, or to sham operation (SHO). After 4 weeks, all the animals underwent 30 minutes of regional heart ischemia and 3 hours reperfusion. The animals of the first series received no further intervention (HL and SHO groups), those of the second series underwent PreC (HL + PreC and SHO + PreC), and of the third series PostC (HL + PostC and SHO + PostC). Infarct size (I) and risk zones (R) were determined, and their ratio was calculated in percentage. Three additional series of experiments were performed with respective interventions up to the 10th minute of reperfusion, where sample tissue was obtained for assessment of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), glycogen synthase kinase 3ß (GSK3ß), p44/42, signal transducer and activator of transcription (STAT) 3, and STAT5. All groups demonstrated significantly smaller percentage of I/R compared with the SHO group (HL: 14.4% ± 3.7%, HL + PreC: 13.1% ± 1.0%, SHO + PreC: 21.3% ± 1.6%, HL + PostC: 18.0% ± 1.1%, and SHO + PostC: 24.3% ± 1.7%, P < .05 vs 35.7% ± 4.4% in SHO). The PreC and PostC did not further reduce the infarct size in HL groups. The Akt, eNOS, GSK3ß, p44/42, and STAT3 were activated in all PreC or PostC groups regardless of the infarct size reduction. The STAT5 was activated only in the HL groups compared with the SHO groups. In conclusion, chronic skeletal muscle ischemia results in effective cardioprotection, which is not further enhanced with application of PreC or PostC. The Akt, eNOS, GSK3ß, p44/42, and STAT3 may only be considered as indicators of the intracellular changes taking place during protection. Activation of STAT5 is possibly the end effector, which is responsible for infarct size reduction provided by chronic skeletal muscle ischemia.

Endothelin-B Receptors and Left Ventricular Dysfunction after Regional versus Global Ischaemia-Reperfusion in Rat Hearts.

Background. Endothelin-1 (ET-1) is implicated in left ventricular dysfunction after ischaemia-reperfusion. ETA and ETB receptors mediate diverse actions, but it is unknown whether these actions depend on ischaemia type and duration. We investigated the role of ETB receptors after four ischaemia-reperfusion protocols in isolated rat hearts. Methods. Left ventricular haemodynamic variables were measured in the Langendorff-perfused model after 40- and 20-minute regional or global ischaemia, followed by 30-minute reperfusion. Wild-type (n = 39) and ETB-deficient (n = 41) rats were compared. Infarct size was measured using fluorescent microspheres after regional ischaemia-reperfusion. Results. Left ventricular dysfunction was more prominent in ETB-deficient rats, particularly after regional ischaemia. Infarct size was smaller (P = 0.006) in wild-type (31.5 ± 4.4%) than ETB-deficient (45.0 ± 7.3%) rats after 40 minutes of regional ischaemia-reperfusion. Although the recovery of left ventricular function was poorer after 40-minute ischaemia-reperfusion, end-diastolic pressure in ETB-deficient rats was higher after 20 than after 40 minutes of regional ischaemia-reperfusion. Conclusion. ETB receptors exert cytoprotective effects in the rat heart, mainly after regional ischaemia-reperfusion. Longer periods of ischaemia suppress the recovery of left ventricular function after reperfusion, but the role of ETB receptors may be more important during the early phases.

Likelihood of Brugada ECG pattern confirmed after propafenone administration for atrial fibrillation cardioversion.

It has been reported that Brugada syndrome is responsible for about half of the sudden cardiac death events with no evidence of structural heart disease. We report a case of hidden ECG Brugada pattern, revealed after oral propafenone administration in the setting of pharmaceutical atrial fibrillation cardioversion.

Chronic skeletal muscle ischemia preserves coronary flow in the ischemic rat heart.

Chronic skeletal muscle ischemia confers cytoprotection to the ventricular myocardium during infarction, but the underlying mechanisms remain unclear. Although neovascularization in the left ventricular myocardium has been proposed as a possible mechanism, the functional capacity of such vessels has not been studied. We examined the effects of chronic limb ischemia on infarct size, coronary blood flow, and left ventricular function after ischemia-reperfusion. Hindlimb ischemia was induced in 65 Wistar rats by excision of the left femoral artery, whereas 65 rats were sham operated. After 4 wk, myocardial infarction was generated by permanent coronary artery ligation. Infarct size was measured 24 h postligation. Left ventricular function was evaluated in isolated hearts after ischemia-reperfusion, 4 wk after limb ischemia. Neovascularization was assessed by immunohistochemistry, and coronary flow was measured under maximum vasodilatation at different perfusion pressures before and after coronary ligation. Infarct size was smaller after limb ischemia compared with controls (24.4 ± 8.1% vs. 46.2 ± 9.5% of the ventricle and 47.6 ± 8.7% vs. 80.1 ± 9.3% of the ischemic area, respectively). Indexes of left ventricular function at the end of reperfusion (divided by baseline values) were improved after limb ischemia (developed pressure: 0.68 ± 0.06 vs. 0.59 ± 0.05, P = 0.008; maximum +dP/dt: 0.70 ± 0.08 vs. 0.59 ± 0.04, P = 0.004; and maximum -dP/dt: 0.86 ± 0.14 vs. 0.72 ± 0.10, P = 0.041). Coronary vessel density was markedly higher (P = 0.00021) in limb ischemic rats. In contrast to controls (F = 5.65, P = 0.00182), where coronary flow decreased, it remained unchanged (F = 1.36, P = 0.28) after ligation in limb ischemic rats. In conclusion, chronic hindlimb ischemia decreases infarct size and attenuates left ventricular dysfunction by increasing coronary collateral vessel density and blood flow.

Chronic skeletal muscle ischemia in rats decreases the inducibility of ventricular tachyarrhythmias after myocardial infarction.

BACKGROUND: Chronic hind-limb ischemia confers cytoprotection after coronary occlusion, but it is unclear whether it ameliorates substrate formation for ventricular tachyarrhythmias (VTs). MATERIALS AND METHODS: Chronic hind-limb ischemia was generated by femoral artery excision in 50 rats, while 25 animals were sham-operated. Left coronary artery ligation was performed after 3 weeks and infarct size was measured 24 hours thereafter. The inducibility of VTs was assessed by programmed electrical stimulation (PES) 4 weeks post-ligation. A score was assigned, based on protocol stage and tachyarrhythmia duration. Monophasic action potentials (MAP) were recorded prior to and 4 weeks after ligation. RESULTS: The infarct size was smaller (p=0.000079) in the ischemic rats (25.7±2.1%) than in the controls (41.7±2.2%), accompanied by a lower (p=0.029) arrhythmia score (1.05±0.38 versus 2.70±0.68, respectively). The action potential duration (APD) was shorter (p<0.05) in the ischemic rats prior to ligation and remained stable after 4 weeks. CONCLUSION: Chronic hind limb ischemia limits infarct size and decreases inducible ventricular tachyarrhythmias.

Dose-dependent effects of sildenafil on post-ischaemic left ventricular function in the rat isolated heart.

OBJECTIVES: Sildenafil may be beneficial during myocardial ischaemia/reperfusion, but this effect may be dose-dependent, accounting for previous conflicting results. We have explored the effects of two acute and one chronic administration regimen on left ventricular function. METHODS: The study was conducted on 36 Wistar rats (290 +/- 7 g). Sildenafil was administered 30 min before ischaemia at a low (0.7 mg/kg, n= 8) or high (1.4 mg/kg, n= 8)dosage. The chronic treatment arm (n= 8) consisted of two daily injections of sildenafil (0.7 mg/kg) for three weeks. The control group was formed by 12 rats. Ischaemic contracture, post-ischaemic recovery and hypercontracture were measured in isolated, Langendorff-perfused preparations. KEY FINDINGS: Ischaemic contracture tended to be lower after high-dose sildenafil, while remaining unchanged after low-dose or chronic sildenafil administration. Compared with controls (62.9 +/- 2.0% of baseline developed pressure), post-ischaemic recovery was higher (P= 0.0069) after low dose (75.1 +/- 2.4%), unchanged (P= 0.13) after high dose (69.1 +/- 2.1%), but lower (P < 0.001) after chronic (42.9 +/- 4.5%) sildenafil administration. Compared with controls (71.8 +/- 3.9 mmHg), hypercontracture was higher (P= 0.0052) after chronic sildenafil administration (89.5 +/- 4.1 mmHg), but similar after acute low dose (65.7 +/- 3.3 mmHg, P= 0.33) or high dose (67.1 +/- 4.7 mmHg, P= 0.43). CONCLUSIONS: The effects of sildenafil after ischaemia/reperfusion were strongly dose-dependent. Beneficial actions on left ventricular function were evident after acute pretreatment with a low dosage, but were lost after doubling the dose. Chronic sildenafil administration deteriorated left ventricular function during ischaemia and reperfusion.

Chronic hind limb ischemia reduces myocardial ischemia-reperfusion injury in the rabbit heart by promoting coronary angiogenesis/arteriogenesis.

BACKGROUND/AIM: Application of ischemic injury in a remote organ may provide protection of other tissues against ischemia. We hypothesized that ischemia in the rabbit hind limb protects against myocardial ischemia by increasing angiogenesis/arteriogenesis. MATERIALS AND METHODS: In the first experiment, severe limb ischemia (LI) was induced in 26 New Zealand White rabbits by excision of the femoral artery while another 26 served as controls (no ischemia; sham operation [SHO]). Four weeks later, the blood vessels of the subendocardial and intramyocardial areas of the excised hearts were counted. In the second experiment, 14 LI rabbits and 14 SHO controls were subjected to 30 min of regional heart ischemia and 3 h reperfusion. Infarct size and the areas-at-risk were determined. RESULTS: Compared with controls, LI rabbits showed more subendocardial (103+/-14 vs. 113+/-13 capillaries/mm2, respectively; p=0.01) and intramyocardial blood vessels (102+/-12 vs. 114+/-16 capillaries/mm(2), respectively; p=0.009). LI rabbits had significantly smaller infarct size compared with the SHO animals (infarct areas/areas-at-risk: 14.37+/-11.23% vs. 31.31+/-13.73%, respectively; p=0.003). CONCLUSION: Chronic hind LI reduces myocardial infarct size by promoting coronary angiogenesis/arteriogenesis in an experimental model.

Endothelin-B receptors and ventricular arrhythmogenesis in the rat model of acute myocardial infarction.

The arrhythmogenic effects of endothelin-1 (ET-1) are mediated via ETA-receptors, but the role of ETB-receptors is unclear. We examined the pathophysiologic role of ETB-receptors on ventricular tachyarrhythmias (VT/VF) during myocardial infarction (MI). MI was induced by coronary ligation in two animal groups, namely in wild-type (n = 63) and in ETB-receptor-deficient (n = 61) rats. Using a telemetry recorder, VT/VF episodes were evaluated during phase I (the 1st hour) and phase II (2-24 h) post-MI, with and without prior beta-blockade. Action potential duration at 90% repolarization (APD90) was measured from monophasic epicardial recordings and indices of sympathetic activation were assessed using fast-Fourier analysis of heart rate variability. Serum epinephrine and norepinephrine were measured with radioimmunoassay. MI size was similar in the two groups. There was a marked temporal variation in VT/VF duration; during phase I, it was higher (p = 0.0087) in ETB-deficient (1,519 +/- 421 s) than in wild-type (190 +/- 34 s) rats, but tended (p = 0.086) to be lower in ETB-deficient (4.2 +/- 2.0 s) than in wild-type (27.7 +/- 8.0 s) rats during phase II. Overall, the severity of VT/VF was greater in ETB-deficient rats, evidenced by higher (p = 0.0058) mortality (72.0% vs. 32.1%). There was a temporal variation in heart rate and in the ratio of low- to high-frequency spectra, being higher (<0.001) during phase I, but lower (p < 0.05) during phase II in ETB-deficient rats. Likewise, 1 h post-MI, serum epinephrine (p = 0.025) and norepinephrine (p < 0.0001) were higher in ETB-deficient (4.20 +/- 0.54, 14.24 +/- 1.39 ng/ml) than in wild-type (2.30 +/- 0.59, 5.26 +/- 0.67 ng/ml) rats, respectively. After beta-blockade, VT/VF episodes and mortality were similar in the two groups. The ETB-receptor decreases sympathetic activation and arrhythmogenesis during the early phase of MI, but these effects diminish during evolving MI.

Serum leptin levels in patients undergoing carotid endarterectomy: a pilot study.

INTRODUCTION: Elevated serum leptin levels are associated with cardiovascular events. We investigated the role of serum leptin in patients undergoing carotid endarterectomy (CEA). METHODS: A total of 74 patients (55 men; 38 symptomatic and 36 asymptomatic; mean age 66.9 +/- 8.2 years) undergoing CEA for >70% carotid artery stenosis were enrolled. RESULTS: Serum leptin levels were lower in symptomatic compared with asymptomatic patients (7.1 +/- 1.3 vs 14.4 +/- 4.7 ng/dL; P < .001). Interleukin-6 (IL-6) levels were higher in symptomatic compared with asymptomatic patients (4.3 +/- 1.7 vs 3.3 +/- 1.1 pg/dL; P = .017). Symptomatic patients had more intense macrophage accumulation (0.7% +/- 0.1% vs 0.3% +/- 0.1%; P < .001). Serum leptin and serum IL-6 levels were independently associated with the presence of symptoms in multivariate analysis. CONCLUSION: Serum leptin levels were decreased in symptomatic carotid artery disease. This finding requires further investigation in larger studies.

Systemic hypertension augments, whereas insulin-dependent diabetes down-regulates, endothelin A receptor expression in the mammary artery in coronary artery disease patients.

BACKGROUND: Endothelin (ET) A receptor antagonism causes decreased vasodilation in hypertensive coronary arteries and decreased effects on coronary artery compliance in diabetic patients. METHODS: We investigate the mRNA expression of ET-1, ET(A) and ET(B) receptors, using real time RT-PCR, in biopsies from the internal mammary artery obtained from 49 patients, 18 diabetics and 34 hypertensives, all undergoing coronary artery bypass grafting. RESULTS: Hypertensive patients had higher ET-1 mRNA expression (16438 [8417, 23917]), than normotensive patients (2974 [2283, 18055], p=0.008). Diabetic patients had significantly lower ET(A) receptor levels than non-diabetic patients (455 [167, 1496] vs. 1660 [700, 3190], respectively, p = 0.003). CONCLUSIONS: Multivariate analysis demonstrated that the presence of systemic hypertension was the only independent predictor of log ET(A) receptor expression and log ET-1 expression, while insulin-dependent diabetes was negatively correlated with ET(A) receptor expression. ETB receptor expression was not correlated with any predictor. Systemic hypertension is associated with increased ET-1 and ET(A) receptor mRNA expression, whereas insulin-dependent diabetes down-regulates ET(A) receptor mRNA expression in the internal mammary artery in patients with coronary artery disease undergoing bypass grafting.