Regulation of the isozymes of protein kinase C in the surviving rat myocardium after myocardial infarction: distinct modulation for PKC-alpha and for PKC-delta

Objective The goal of this study was to clarify the regulation of the isozymes of protein kinase C (PKC) in the process of remodeling after myocardial infarction. Methods An in vivo model of regional myocardial infarction induced by ligation of the left anterior coronary artery in rats was used. Hemodynamic parameters and the heart and lung weights were determined 1 week and 1, 2 and 3 months after operation. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, PKC activity (ELISA) and the expression of its major isozymes, PKC-α, PKC-δ and PKC-ε (Westernblot analysis) were determined. Results As early as one week after myocardial infarction, heart weight and left ventricular enddiastolic pressures were significantly increased. Lung weights increased after 2 – 3 months, indicating progressive pulmonary congestion. The activity of PKC was significantly increased about 1.8-fold after 1 week, decreasing progressively in the later time course. Whereas the expression of PKC-ε did not change, PKC-α was increased after 1 month (157 %) and then returned to baseline values. In contrast, PKC-δ expression was significantly augmented after 2 and 3 months of myocardial infarction (187 %). Conclusions These data demonstrate for the first time that in the remodeling heart after myocardial infarction, a subtype-selective regulation of the PKC isozymes occurs: The upregulation of PKC-α coincides with the development of hypertrophy, whereas the extensive upregulation of PKC-δ outlasts the process of developing hypertrophy and persists in the failing heart. The trigger mechanisms for this newly characterized process remains to be elucidated. Received: 25 October 2001, Returned for revision: 3 December 2001, Revision received: 19 December 2001, Accepted: 20 December 2001     

Progressive heart failure after myocardial infarction in mice

We tested the hypotheses that myocardial infarction in mice would lead to progressively worsening heart failure 12–18 weeks later and that exercise testing would provide a suitable means to evaluate left ventricular function sequentially. C57BL/6 mice (n = 69) underwent left coronary artery ligation (n = 50) or thoracotomy without ligation (n = 19). Sixteen animals (32 %) died within 24 h of coronary ligation. Twenty additional animals (40 %) died between days 3 and 14, and these mice showed infarct sizes of > 50 % of the left ventricle. Fourteen animals (28 %) that survived two weeks underwent echocardiography and treadmill testing 12 and 18 weeks after infarction, with no further mortality. Mice were then killed, morphometric assessment made, infarct size evaluated, and myocardial norepinephrine content and expression of BNP and ANF measured. Mice with infarcts >30 % of the left ventricle (n = 6; 12 % of original cohort) had left ventricular dilation (p < 0.0001) and hypertrophy (p < 0.001), impaired left ventricular systolic function (p < 0.0001) and reduced exercise duration (p = 0.03) and total work (p = 0.03) 12–18 weeks after infarction. Mice with infarcts < 30 % of the left ventricle (n = 8; 16 % of original cohort) had no significant functional changes or left ventricular remodeling. Hearts from mice with infarcts > 30 % had reduced myocardial norepinephrine levels (MI < 30 %: 177 ± 54 pg/mg, n = 6; MI > 30 %: 66 ± 14 pg/mg wet weight, n = 4; p = 0.005) and increased mRNA content of BNP (p < 0.03) and ANF (p = 0.023). Coronary artery occlusion in mice provides a relevant model of clinical heart failure that is progressive and can be assessed by sequential exercise testing, providing a means to study the development of heart failure and its treatment. Received: 3 October 2001, Returned for revision: 22 October 2001, Revision received: 3 December 2001, Accepted: 12 December 2001     

Acute myocardial infarction and congestive heart failure following a blunt chest trauma

 A 42-year-old man experienced chest discomfort after being struck by a low-speed flying object. Two weeks after the accident, the patient complained of severe shortness of breath accompanied by ankle edema. Chest X-ray indicated acute pulmonary edema and left ventricular enlargement. There were Q waves and flat T waves in the precordial ECG leads. Echocardiography revealed dyskinesis in the interventricular septum, hypokinesis in the anterior left ventricular wall, and severe impairment of left ventricular function. A coronary angiogram showed 90% stenosis of the proximal left descending coronary artery. Subsequent medical therapy with diuretics and enalapril led to significant improvement in ventricular function and the patient's symptoms. We conclude that a mild blunt chest trauma can cause myocardial infarction and severe congestive heart failure. Careful investigations into myocardial ischemia or infarction and a close follow-up should be conducted in all patients presenting with a blunt chest trauma. Received: April 22, 2002 / Accepted: August 2, 2002 Correspondence to L. Wang     

C-reactive protein and heart failure after myocardial infarction in the community

Background

There is a paucity of data on the prognostic role of C-reactive protein (CRP) measured after myocardial infarction. We prospectively examined the association of CRP with heart failure and death among patients with myocardial infarction in the community.

Methods and Results

All Olmsted County residents who had a myocardial infarction meeting standardized criteria were prospectively enrolled to measure CRP on admission and followed for heart failure and death. A total of 329 consecutive patients (mean age 69 ± 16 years, 52% men) were enrolled. At 1 year, 28% of patients experienced heart failure and 20% died. There was a strong positive graded association between CRP and the risk of developing heart failure, as well as dying over the period of follow-up (P < .001). Compared with patients in the first tertile, patients in the third tertile of the CRP distribution had a markedly increased risk of heart failure and death independently of age, sex, troponin T, Q wave, comorbidity, previous myocardial infarction, and recurrent ischemic events (adjusted hazard ratio 2.47 [95% confidence interval, 1.27-4.82] for heart failure and 3.96 [95% confidence interval, 1.78-8.83] for death).

Conclusions

These prospective data indicate that among contemporary community subjects with myocardial infarction, heart failure and death remain frequent complications. CRP is associated with a large increase in the risk of heart failure and death, independently of age, sex, myocardial infarction severity, comorbidity, previous myocardial infarction, and recurrent ischemic events. These data suggest that inflammatory processes may play a role in the development of heart failure and death after myocardial infarction independently of other conventional prognostic indicators.     

Early rather than delayed administration of lisinopril protects the heart after myocardial infarction in rats

Background:ACE inhibitors have shown beneficial results in several studies after myocardial infarction (MI). However, this studies have shown conflicting results about the ideal starting time of the ACE inhibitors administration after MI and the importance of infarct size. Objectives: This study was designed to assess the long-term effects of lisinopril on mortality, cardiac function, and ventricular fibrosis after MI, in rats. Methods: Lisinopril (20 mg/kg/day) was given on day 1 or 21 days after coronary occlusion in small or large infarctions. Results: The mortality rate was reduced by 39% in early treatment and 30% in delayed treatment in comparison to the untreated rats. Early treatment reduced cardiac dysfunction in small MIs; however, delayed treatment did not. No statistical difference was observed among the groups for large MIs. No statistical difference was observed among the groups with large or small MIs on myocardial hydroxyproline concentration. Conclusions: Both early and delayed treatments with lisinopril increased survival. Treatment exerts no marked effects on fibrosis; early treatment has exerted beneficial influences on cardiac function whereas delayed treatment had no consistent effects. The protective effect of lisinopril is detectable only in small (< 40% of LV) MIs. Received: 6 May 1999, Returned for 1. revision: 28 May 1999, 1. Revision received: 20 July 1999, Returned for 2. revision: 26 August 1999, 2. Revision received: 28 September 1999, Accepted: 29 September 1999     

Angiogenesis and microvascularization after cryothermia-induced myocardial infarction: A quantitative fluorescence microscopic study in rats

Microvascularization of infarcted myocardial tissue may be a prerequisite for successful therapeutic interventions, including cardiomyoblast or satellite cell transplantation. Because little is known on microvascular restitution within infarcted tissue, we studied angiogenesis and microvascularization after cryothermia-induced myocardial infarction using intravital fluorescence microscopic techniques. Methods: In anesthetized, orally intubated and ventilated Sprague-Dawley rats (n = 20), a sternotomy was performed and a standardized cryolesion was induced to the right ventricle by freezing for 5 min to −160°C. Myocardial angiogenesis and microvascularization were analyzed quantitatively after rethoracotomy on days 7 (n = 6) or 28 (n = 8). Sham-operated animals (n = 6) served as controls. Results: Seven days after cryothermia, the central tissue area of the injured myocardium (28.4 ± 9.2 mm²) was characterized by complete lack of capillary perfusion, while the periphery of the cryolesion (27.6 ± 5.7 mm²) revealed a heterogeneous capillary perfusion pattern with a density of 300.9 ± 38.9 cm⁻¹. Adjacent myocardial tissue showed intact capillary perfusion (density: 563.0 ± 44.4 cm⁻¹) comparable with that of sham-operated controls. After 28 d the area with lack of capillary perfusion was found significantly reduced to 7.3 ± 3.7 mm² (P < 0.05); however, it was still surrounded by a heterogeneously perfused area of myocardial tissue of 57.7 ± 19.2 mm² (density: 271.1 ± 52.7 cm⁻¹), indicating partial restitution of capillary perfusion. Although at day 7 within the central zone of the cryolesions, capillary perfusion was completely shut down, perfusion of microvessels larger than capillaries, i.e., arterioles and venules, were found maintained, however, with a density markedly lower (1.96 ± 1.04 mm⁻¹) when compared with that of sham-controls (4.28 ± 1.52 mm⁻¹). After 28 d the number of these larger-sized microvessels increased significantly with values of density even higher compared with those observed in controls (6.89 ± 1.71 mm⁻¹, P < 0.05), indicating new vessel formation. Conclusions: Our study indicates partial restitution and function of the microvascular network within infarcted myocardial tissue, which may serve as an appropriate prerequisite for successful application of novel therapeutic strategies to improve myocardial function. Received: 6 May 1998, Returned for revision: 2 June 1998, Revision received: 9 November 1998, Accepted: 3 December 1998     

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca²⁺ transport protein, such as sarcoplasmic reticulum Ca²⁺(SR-Ca²⁺)-ATPase, Na⁺-Ca²⁺ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca ²⁺ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ration of E wave to A wave velocity. Expression of myocardial α-skeletal actin, β-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca²⁺-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na⁺-Ca²⁺ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling. Received: 9 August 1999, Returned for revision: 16 September 1999, Revision received: 5 January 2000, Accepted: 26 January 2000     

Electrophysiological characterization of murine myocardial ischemia and infarction

Background Genetically altered mice will provide important insights into a wide variety of processes in cardiovascular physiology underlying myocardial infarction (MI). Comprehensive and accurate analyses of cardiac function in murine models require implementation of the most appropriate techniques and experimental protocols. Objective In this study we present in vivo, whole-animal techniques and experimental protocols for detailed electrophysiological characterization in a mouse model of myocardial ischemia and infarction. Methods FVB mice underwent open-chest surgery for ligation of the left anterior descending coronary artery or sham-operation. By means of echocardiographic imaging, electrocardiography, intracardiac electrophysiology study, and conscious telemetric ECG recording for heart rate variability (HRV) analysis, we evaluated ischemic and post-infarct cardiovascular morphology and function in mice. Results Coronary artery ligation resulted in antero-apical infarction of the left ventricular wall. MI mice showed decreased cardiac function by echocardiography, infarct-typical pattern on ECG, and increased arrhythmia vulnerability during electrophysiological study. Electrophysiological properties were determined comprehensively, but were not altered significantly as a consequence of MI. Autonomic nervous system function, measured by indices of HRV, did not appear altered in mice during ischemia or infarction. Conclusions Cardiac conduction, refractoriness, and heart rate variability appear to remain preserved in a murine model of myocardial ischemia and infarction. Myocardial infarction may increase vulnerability to inducible ventricular tachycardia and atrial fibrillation, similarly to EPS findings in humans. These data may be of value as a reference for comparison with mutant murine models necessitating ischemia or scar to elicit an identifiable phenotype. The limitations of directly extrapolating murine cardiac electrophysiology data to conditions in humans need to be considered. Received: 5 October 2000, Returned for 1. revision: 2 November 2000, 1. Revision received: 24 November 2000, Returned for 2. revision: 28 November 2000, 2. Revision received: 13 December 2000, Accepted: 14 December 2000     

ST2与心肌梗死和心力衰竭的关系

<正>白介素1(interleukin-1,IL-1)受体家族包括IL-1R、IL-18R及其辅助蛋白IL-1RAcP、IL-18RAcP等[1]。1989年,ST2作为IL-1受体家族的新成员被发现,之后证实其参与多种病理生理过程,在炎症和变态反应性疾病中发挥重要作用,     

Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, iv) or enalaprilat (1 mg/kg, iv) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 ± 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 ± 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure. Received: 22 September 1998, Returned for revision: 14 October 1998, Revision received: 23 November 1998, Accepted: 8 December 1998     

Skeletal muscle abnormalities in rats with experimentally induced heart hypertrophy and failure

Background: In congestive heart failure (CHF), function and metabolism of skeletal muscles are abnormal. Aim: To evaluate whether the reduced oxidative capacity of skeletal muscles in CHF is due to impaired O₂ utilisation. Methods: CHF was induced in rats by injecting 50 mg/Kg monocrotaline. Several animals received the same dose of monocrotaline but only compensated right ventricular hypertrophy and no sign of congestion resulted. Two age- and diet-matched groups of control animals were also studied. In soleus and extensor digitorum longus (EDL) muscles, we studied skeletal muscle blood flow, oxidative capacity and respiratory function of skinned muscle fibres. Results: In CHF, we observed a decrease of muscle blood flow (statistically significant in the soleus, p < 0.05 vs. controls). In compensated rats, a similar trend in blood flow was observed. In both soleus and EDL, a significant reduction of high energy phosphate and a shift of the redox potential towards accumulation of reducing equivalents were observed. The reduction of energy charge was not correlated to the decrease of blood flow. In skinned myofibres, the ratio of O₂ utilised in the presence and in absence of ADP (an index of phoshorilating efficiency) was reduced from 8.9 ± 1.9 to 2.7 ± 0.2 (p < 0.001) and from 5.7 ± 1.0 to 2.0 ± 0.3 (p < 0.01) in soleus and EDL, respectively. Activity of the different complexes of respiratory chain was investigated by means of specific inhibitors, showing major abnormalities at the level of complex I. In fact, inhibition of VO₂ by rotenone was decreased from 83.5 ± 3.2 to 36.4 ± 9.6 % (p < 0.005) and from 81.8 ± 6.1 to 38.2 ± 7.4 % (p < 0.005) in soleus and EDL, respectively. Conclusions: In rats with CHF, abnormalities of oxidative phosphorylation of muscles occur and complex I of the respiratory chain seem to be primarily affected. The metabolic alterations of skeletal muscles in CHF may be explained, at least in part, by an impaired O₂ utilisation. Received: 22 February 2002, Returned for 1. revision: 14 March 2002, 1. Revision received: 5 June 2002, Returned for 2. revision: 21 June 2002, 2. Revision received: 23 August 2002, Accepted: 12 September 2002 Correspondence to: Dr. C. Ceconi     

Low frequency spectral component of heart rate variability and myocardial beta-adrenoceptor density after acute myocardial infarction

Objective The low frequency spectral component (LF; 0.04–0.15 Hz) of heart rate variability (HRV) is considered to be an index of sympathetic modulation of sinus node activity under physiological conditions, although the relationship is less clearly defined in non-physiological conditions. Several cardiovascular diseases are characterized by an absent or blunted 24-h pattern of the LF spectral component. The aim of the present study was to investigate the relationship between chronically increased neural sympathetic efferent drive to the heart, quantified in terms of downregulation of myocardial β-receptors, and the 24-h power of the LF spectral component in patients after acute myocardial infarction. Methods In 24 patients, HRV was analyzed for a 24-h period, one month after an uncomplicated Q wave myocardial infarction. The following time domain measures and spectral components were calculated: mean RR, SDNN, SDANN, RMSSD, SDNN index, pNN50, and very low frequency (VLF), low frequency (LF) and high frequency (HF) spectral components. The density of β-adrenoceptors was measured in vivo by positron emission tomography (PET) with ¹¹C-CGP-12177. Results Post-AMI patients had normal plasma levels of adrenaline and noradrenaline (respectively 1.48 ± 0.18 and 0.28 ± 0.03 IU/L) but reduced myocardial β-adrenoceptor density (6.86 ± 0.24 pmol/g). Patients had similar heart rates but lower values of SDNN and SDANN compared with control subjects. The absolute and normalized power of the spectral components were similar in the two groups, but the usual day-night oscillation was blunted in patients. Moreover, the day-night change in the power of the LF spectral component was positively related (r = 0.51; p < 0.001) to the myocardial β-adrenoceptor density. Conclusions The loss of the day-night oscillation of the LF spectral component appears to be a significant marker of sustained sympathetic over-activity in post-AMI patients. Received: 6 June 2001, Returned for revision: 26 June 2001, Revision received: 8 August 2001, Accepted: 28 August 2001     

急性下壁心肌梗死并心力衰竭的临床特征及预后

目的 :分析急性下壁心肌梗死 (AIMI)并心力衰竭 (心衰 )的临床特征及预后。方法 :记录 180例AIMI患者中并心衰者的临床特征及住院并发症 ,行常规 12导联心电图及右胸导联心电图 ,并与无心衰者比较。结果 :AIMI并心衰者 41例 (占 2 2 .8% )。并心衰组较无心衰组年龄大〔6 5 .3± 10 .8)岁∶ (6 1.1± 10 .1)岁〕、肌酸激酶 (CK)峰值高〔(2 70 0 .4± 2 0 87.7) IU / L∶ (1879.1± 16 0 3.1) IU / L〕,右室梗死 (31.7%∶ 5 .8% )及高度房室传导阻滞 (39.0 %∶ 17.3% )发生率高 ,胸前导联 V4～ 6 ST段压低为主者比例高 (5 6 .1%∶ 2 4.5 % ) ,住院病死率高(4 6 .3%∶ 17.3% )。 L ogistic回归分析显示 AIMI并心衰与 CK峰值、右室梗死、胸前导联 V4～ 6 ST段压低及死亡率独立相关 ,而与年龄及高度房室传导阻滞不相关。结论 :AIMI并心衰者胸前 V4～ 6 导联 ST段压低及右室梗死发生率高 ,CK峰值高。 AIMI并心衰住院病死率高 ,预后差 ,为一高危亚组。     

Development and course of heart failure after a myocardial infarction in younger and older people

Background Acute myocardial infarction （AMI） is a common cause of heart failure （HF）, which can develop soon after AMI and may persist or resolve or develop late. HF after an MI is a major source of mortality. The cumulative incidence, prevalence and resolution of HF after MI in different age groups are poorly described. This study describes the natural history of HF after AMI according to age. Methods Patients with AMI during 1998 were identified from hospital records. HF was defined as treatment of symptoms and signs of HF with loop diuretics and was considered to have resolved if loop diuretic therapy could be stopped without recurrence of symptoms. Patients were cate- gorised into those aged 〈 65 years, 65-75 years, and 〉 75 years. Results Of 896 patients, 311,297 and 288 were aged 〈 65, 65-75 and 〉75 years and of whom 24%, 57% and 82% had died respectively by December 2005. Of these deaths, 24 （8%）, 68 （23%） and 107 （37%） oc- curred during the index admission, many associated with acute HF. A further 37 （12%）, 63 （21%） and 82 （29%） developed HF that persisted until discharge, of whom 15, 44 and 62 subsequently died. After discharge, 53 （24%）, 55 （40%） and 37 （47%） patients developed I-IF for the first time, of whom 26%, 62% and 76% subsequently died. Death was preceded by the development of HF in 35 （70%）, 93 （91%） and 107 （85%） in aged 〈 65 years, 65-75 years and 〉75 years, respectively. Conclusions The risk of developing HF and of dying after an MI in- creases progressively with age. Regardless of age, most deaths after a MI are preceded by the development of HF.     

Role of sodium-hydrogen exchange in cardiac hypertrophy and heart failure: a novel and promising therapeutic target

The myocardial sodium-hydrogen exchanger (NHE), and more specifically the NHE-1 isoform is now well-recognized to be a major contributor to ischemic and reperfusion injury. Recent evidence suggests that NHE-1 is also potential candidate for targeted intervention in terms of attenuation of the remodelling and hypertrophic processes which contributes to heart failure. Experimental studies have shown that NHE-1 inhibitors attenuate cardiomyocyte hypertrophy induced by various factors and reduce heart failure in vivo, independently of infarct size reduction. Although the precise cellular mechanisms for NHE-1 involvement remain to be elucidated, current data suggest a potentially effective new therapeutic approach for the treatment of heart failure via NHE-1 inhibition. Received: 23 April 2001 / Accepted: 4 May 2001     

AXL receptor tyrosine kinase is increased in patients with heart failure

Background

AXL is a membrane receptor tyrosine kinase highly expressed in the heart and has a conspicuous role in cardiovascular physiology. The role of AXL in heart failure (HF) has not been previously addressed.

Methods and results

AXL protein was enhanced 6-fold in myocardial biopsies of end-stage HF patients undergoing heart transplantation compared to controls from heart donors (P < 0.0001). Next, we performed a transversal study of patients with chronic HF (n = 192) and a group of controls with no HF (n = 67). sAXL and BNP circulating levels were quantified and clinical and demographic data were collected.sAXL levels in serum were higher in HF (86.3 ± 2.0 ng/mL) than in controls (67.8 ± 2.0 ng/mL; P < 0.0001). Also, sAXL correlated with several parameters associated with worse prognosis in HF. Linear regression analysis indicated that serum creatinine, systolic blood pressure and atrial fibrillation, but not BNP levels, were predictive of sAXL levels. Cox regression analysis indicated that high sAXL values at enrollment time were related to the major HF events (all-cause mortality, heart transplantation and HF hospitalizations) at one year follow-up (P < 0.001), adding predictive value to high BNP levels.

Conclusions

Myocardial expression and serum concentration of AXL is elevated in HF patients compared to controls. Furthermore, peripheral sAXL correlates with parameters associated with the progression of HF and with HF events at short term follow-up. All together these results suggest that sAXL could belong to a new molecular pathway involved in myocardial damage in HF, independent from BNP.     

Temporal changes in the subcellular distribution of protein kinase C in rabbit heart during global ischemia

Our recent studies utilizing an in vivo regional ischemia model revealed no changes in the subcellular distribution of protein kinase C (PKC) in dog and rabbit hearts after repeated 5 min episodes of preconditioning ischemia/reperfusion. However, 10 min of sustained ischemia resulted in an increase in PKC activity in the membrane fraction. These findings indicate that prolonged ischemia may cause changes in the subcellular distribution of PKC. However, the detailed time course of these changes during sustained severe ischemia is poorly resolved. Thus, our objective was to study temporal changes in PKC distribution in the cytosolic, nuclear, and membrane fractions isolated from globally ischemic rabbit heart. Hearts were removed under deep anesthesia, placed into normal saline at 37°C, and repeatedly sampled from apex to base at baseline, 2, 5, and 10 min into global ischemia, with matched samples obtained in every heart. PKC activity was increased at 2 min into global ischemia in both the nuclear fraction (1069±75 vs 893±49 pmol/min/g at baseline; p=0.05) and the membrane fraction (1374±95 vs 1187±59 pmol/min/g at baseline; p<0.05) with persistent translocation observed at 5 and 10 min into the protocol. Thus, direct biochemical determination of PKC activity in the isolated rabbit heart revealed increased activity in the nuclear and the membrane fractions as early as 2 min into global ischemia. Received: 27 August 1997, Returned for revision: 17 September 1997, Revision received: 13 October 1997, Accepted: 6 November 1997     

Remodelling of the heart after myocardial infarction

In the first few hours after the onset of coronary occlusion the infarct zone stretches due to myocyte slippage. Subsequently the noninfarct zone develops volume overload hypertrophy with series addition of new sarcomeres and fibre elongation. Dilatation is detrimental as it increases ventricular wall stress and oxygen demand, and re-entry of electrical impulses may be influenced by stretching of the ischaemic scar resulting in ventricular fibrillation. Left ventricular remodelling and dilatation is a progressive process which begins early and continues in the months after infarction. The major determinants of the extent of remodelling are infarct size and patency of the infarct-related artery. Late reperfusion may reverse initial infarct dilatation and decrease left ventricular volumes by inducing calcium-activated contracture of the actomyosin complex. Expansion may also be inhibited by acceleration of healing, splinting of the infarct zone by salvage of subepicardial cells, and blood in the coronary arteries and veins supporting the infarct zone. End-systolic volume is the strongest predictor of long-term prognosis after infarction. A number of therapies including thrombolysis, angiotensin-converting enzyme (ACE) inhibition and nitrates have been shown to decrease left ventricular dilatation. The optimal time for commencement, dose, duration and the effects of combinations of therapy are yet to be determined.     

Opposing effects on infarction of delta and kappa opioid receptor activation in the isolated rat heart: implications for ischemic preconditioning

δ-Opioid receptors are known to participate in the protection found following ischemic preconditioning (IPC), but the role of κ-receptors in IPC is currently controversial. Langendorff-perfused rat hearts received 35 min regional ischemia and 2 h reperfusion. PC (2 cycles 5 min global ischemia) substantially reduced infarct size. Pharmacological PC with the δ-agonist DADLE (10 nmol/L) had similar protective effects. However, higher dose DADLE (1 μmol/L) had a less beneficial effect, and in conjunction with the δ-antagonist naltrindole unexpectedly increased infarct size (61.5 ± 2.0%, p < 0.05 v 45.9 ± 2.3% in controls) sugggesting a non-δ effect. The universal κ-opioid agonist bremazocine (30 nmol/L) increased infarct size (61.3 ± 1.6%, p < 0.05 v controls), an effect abrogated by the selective κ₁-antagonist nor-binaltorphimine (BNI). Since opiates are known to have anti-adrenergic effects, which hypothetically may help to mediate IPC, cyclic AMP levels were measured in DADLE and in bremazocine-treated hearts. Decreased levels of cyclic AMP at the start of the regional ischemic period were found in low dose DADLE hearts (0.485 ± 0/020, n = 8, vs controls, 0.654 ± 0.025 nmol/g wet weight, p < 0.001), but not in high dose DADLE nor in bremazocine treated hearts. Thus, in the isolated rat heart κ₁-opioid receptor activation exacerbates infarct size through an as yet unknown mechanism, suggesting that there could be an “anti-preconditioned state”. In contrast, δ-activity mediates protection which may be associated with a reduction of tissue cyclic AMP levels. Received: 16 November 1999, Accepted: 7 December 1999     

静脉注射艾司洛尔治疗急性心肌梗死并发急性心力衰竭的疗效及安全性

目的探讨静脉注射艾司洛尔治疗急性心肌梗死(AMI)并发急性心力衰竭(AHF)的临床疗效。方法入选11例AMI患者并发AHF、心功能KillipⅡ～Ⅲ级,在常规标准抗缺血、抗心力衰竭治疗效果欠佳,且伴有血压和心率较基线水平升高的条件下,给予静脉注射艾司洛尔(负荷剂量0.5 mg/kg 1 min内静脉注射,继之0.05 mg.kg-1.min-1持续静脉泵入),观察患者治疗前后生命体征、临床表现及X线胸片肺淤血程度的变化。结果 (1)与治疗前比较,11例患者接受静脉注射艾司洛尔治疗(中位给药时间38.5 h)后,收缩压降低[(109±16)mm Hg比(136±18)mm Hg]、舒张压降低[(61±8)mm Hg比(77±11)mm Hg]、心率减慢[(71±11)次/min比(96±31)次/min],差异均有统计学意义(均为P<0.05);(2)11例患者经治疗后,心力衰竭症状均明显缓解,肺部啰音均明显减少,X线胸片肺淤血程度均明显减轻;(3)11例患者治疗过程中均未发生低血压、严重缓慢性心律失常等不良反应。结论对于AMI患者,若病程中发生以缺血为诱因的AHF且伴有血压、心率较基础水平升高,可在常规治疗基础上,加用静脉注射艾司洛尔,可以获得良好的临床疗效,并且无明显不良反应。