Neurohormones in an ovine model of compensated postinfarction left ventricular dysfunction

Clinical heart failure, often the result of myocardial infarction, may be preceded by a period of compensated left ventricular impairment. There is substantial need for an experimental model that reflects this human condition. In sheep, coronary artery ligation produced consistent left ventricular anteroapical myocardial infarctions resulting in chronic (5 wk), stable hemodynamic changes compared with sham controls, including reductions in ejection fraction (51 +/- 2 vs. 30 +/- 5%, P < 0.001), cardiac output (6.3 +/- 0.2 vs. 5.1 +/- 0.2 l/min, P < 0.01), and arterial pressure (93 +/- 2 vs. 79 +/- 3 mmHg, P < 0.001), and increases in cardiac preload (left atrial pressure, 3.3 +/- 0.1 vs. 8.3 +/- 1.3 mmHg, P < 0.001). These changes were associated with acute and sustained increases in plasma concentrations of atrial natriuretic peptide (ANP; 5 wk, 11 +/- 2 vs. 27 +/- 5 pmol/l, P < 0.001), brain natriuretic peptide (BNP; 3 +/- 0.2 vs. 11 +/- 2 pmol/l, P < 0.001), and amino-terminal pro-brain natriuretic peptide (NT-BNP; 17 +/- 3 vs. 42 +/- 12 pmol/l, P < 0.001). Significant correlations were observed between plasma levels of the natriuretic peptides (ANP, day 7 to week 5 samples; BNP and NT-BNP, day 1 to week 5 samples) and changes in left ventricular volumes and ejection fraction. In contrast, renin activity, aldosterone, catecholamines, and endothelin were not chronically elevated postinfarction and were not related to indexes of ventricular function. Coronary artery ligation in sheep produces the pathological, hemodynamic, and neurohormonal characteristics of compensated left ventricular impairment secondary to myocardial infarction. Plasma concentrations of the cardiac natriuretic peptides are sensitive markers of left ventricular dysfunction. This is a reproducible model that reflects the clinical condition and should prove suitable for investigating the pathophysiology of, and experimental therapies in, early left ventricular dysfunction.     

Increased thirst and vasopressin secretion after myocardial infarction in rats

Impaired regulation of salt and water balance in left ventricular dysfunction and heart failure can lead to pulmonary and peripheral edema and hyponatremia. Previous studies of disordered water regulation in heart failure have used models of low cardiac output with normal cardiac function (e.g., inferior vena cava ligation). We investigated thirst and vasopressin (AVP) secretion in a rat myocardial infarction model of chronic left ventricular dysfunction/heart failure in response to a 24-h water deprivation period. Thirst (implied from water drunk), hematocrit, plasma renin activity, and plasma AVP concentrations increased with water deprivation vs. ad libitum water access. Thirst and plasma AVP concentrations were significantly positively correlated with infarct size after 24-h water deprivation but not under ad libitum water access conditions. The mechanism by which this occurs is unclear but could involve increased osmoreceptor sensitivity, altered stimulation of baroreceptors, the renin-angiotensin system, or altered central neural control.     

Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It is characterized by fluid retention, shortness of breath, and fatigue, in particular on exertion. Heart failure is a growing public health problem, the leading cause of hospitalization, and a major cause of mortality. Ischemic heart disease is the main cause of heart failure.Ventricular remodelling refers to changes in structure, size, and shape of the left ventricle. This architectural remodelling of the left ventricle is induced by injury (e.g., myocardial infarction), by pressure overload (e.g., systemic arterial hypertension or aortic stenosis), or by volume overload. Since ventricular remodelling affects wall stress, it has a profound impact on cardiac function and on the development of heart failure. A model of permanent ligation of the left anterior descending coronary artery in mice is used to investigate ventricular remodelling and cardiac function post-myocardial infarction. This model is fundamentally different in terms of objectives and pathophysiological relevance compared to the model of transient ligation of the left anterior descending coronary artery. In this latter model of ischemia/reperfusion injury, the initial extent of the infarct may be modulated by factors that affect myocardial salvage following reperfusion. In contrast, the infarct area at 24 hr after permanent ligation of the left anterior descending coronary artery is fixed. Cardiac function in this model will be affected by 1) the process of infarct expansion, infarct healing, and scar formation; and 2) the concomitant development of left ventricular dilatation, cardiac hypertrophy, and ventricular remodelling.Besides the model of permanent ligation of the left anterior descending coronary artery, the technique of invasive hemodynamic measurements in mice is presented in detail.     

A new model of congestive heart failure in rats

Current rodent models of ischemia/infarct or pressure-volume overload are not fully representative of human heart failure. We developed a new model of congestive heart failure (CHF) with both ischemic and stress injuries combined with fibrosis in the remote myocardium. Sprague-Dawley male rats were used. Ascending aortic banding (Ab) was performed to induce hypertrophy. Two months post-Ab, ischemia-reperfusion (I/R) injury was induced by ligating the left anterior descending (LAD) artery for 30 min. Permanent LAD ligation served as positive controls. A debanding (DeAb) procedure was performed after Ab or Ab + I/R to restore left ventricular (LV) loading properties. Cardiac function was assessed by echocardiography and in vivo hemodynamic analysis. Myocardial infarction (MI) size and myocardial fibrosis were assessed. LV hypertrophy was observed 4 mo post-Ab; however, systolic function was preserved. LV hypertrophy regressed within 1 mo after DeAb. I/R for 2 mo induced a small to moderate MI with mild impairment of LV function. Permanent LAD ligation for 2 mo induced large MI and significant cardiac dysfunction. Ab for 2 mo followed by I/R for 2 mo (Ab + I/R) resulted in moderate MI with significantly reduced ejection fraction (EF). DeAb post Ab + I/R to reduce afterload could not restore cardiac function. Perivascular fibrosis in remote myocardium after Ab + I/R + DeAb was associated with decreased cardiac function. We conclude that Ab plus I/R injury with aortic DeAb represents a novel model of CHF with increased fibrosis in remote myocardium. This model will allow the investigation of vascular and fibrotic mechanisms in CHF characterized by low EF, dilated LV, moderate infarction, near-normal aortic diameter, and reperfused coronary arteries.     

Enhanced early after-myocardial infarction concentration of TNF-alpha subsequently increased circulating and myocardial adrenomedullin in spontaneously hypertensive rats

Both inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the cardiac protective peptide adrenomedullin (AM) are increased in cardiac tissues and plasma in patients with myocardial infarction (MI) and chronic heart failure. Recently they have been increasingly recognized as important factors in the pathophysiology of MI and resultant congestive heart failure. Compared with sham-operated spontaneously hypertensive rats (SHR), we investigated myocardial immunoreactivity of TNF-alpha and AM and also their mutual relations in vivo in SHR+MI. Residual myocardial depression after MI was studied also in isolated perfused hearts. In chronic experiments, 24 and 48 h after permanent ligation of the descending anterior branch of the left coronary artery, we examined hemodynamics, plasma and myocardial peptide levels. Left ventricular function was assessed in isolated perfused hearts subjected to "global ischemia and reperfusion" and after induction of "calcium paradox". Circulating and myocardial TNF-alpha concentrations increased early after MI in SHR. Studies with global ischemia and calcium paradox in isolated heart showed early myocardial depression and calcium-dependent gradual increase of left-ventricular end-diastolic pressure. In the SHR+MI myocardial AM concentrations were increased 9- and 49-fold after respective 24 h and culminated 48 h following MI. Circulating and myocardial AM was increased in SHR+MI in association with TNFalpha-induced myocardial depression. The both studied cardiac parameters displayed the beneficial effect of the enhanced myocardial AM concentration.     

Hemodynamic effects of procainamide and quinidine and the influence of beta-blockade before and after experimental myocardial infarction.

The use of antiarrhythmie drugs in combination has been limited because of possible side effects secondary to myocardial depression in the acute myocardial infarction patient. Therefore, we investigated in intact dogs (group I) the hemodynamic interaction of propranolol plus procainamide (subgroup A) or quinidine (subgroup B) and in dogs after experimental myocardial infarction produced by coronary artery ligation (group II). Infusion of procainamide (30 mg/kg over 5 min) in animals of group IA produced a significant (P less than 0.05) decrease of 30% in mean aortic pressure, a decrease of 40% in left ventricular dp/dt and 29% in cardiac output. When procainamide was reinfuse after propranolol (1 mg/kg), its hemodynamic effects were not significantly different from those observed before propranolol in both groups IA and IIA. Infusion of quinidine (10 mg/kg over 5 min) in animals of group IB (intact dogs) also produced significant decreases of 24% in mean aortic pressure and 38% in dp/dt while cardiac output was unchanged. However, these hemodynamic changes were seen only after beta-blockade and were significantly different from those obtained before propranolol, where heart rate increased by 14%, dp/dt by 30%, and cardiac output by 35%. These changes occurred despite a similar reduction in mean aortic pressure. This drug combination produced similar response in animals after coronary artery ligation (group IIB). In conclusion, we feel that the administration of propranolol does not prevent the depressive circulatory effects of procainamide. The combined use of quinidine and propranolol also has a negative circulatory effect although not as marked as the effects observed after procainamide with propranolol.     

A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart

The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.     

The Early Variation of Left Ventricular Strain after Aortic Valve Replacement by Three-Dimensional Echocardiography

Aortic stenosis (AS) and aortic incompetence (AI) are common aortic valve diseases. Both may deteriorate into irreversible myocardial dysfunction and will increase the risk of sudden death. In this study, we aimed to investigate the early variation trend of left ventricular function by three-dimensional speckle tracking echocardiography (3D-STE) in the patients who underwent cardiac surgeries for aortic valve disease. Twenty patients with severe aortic AS and 16 patients with severe AI were enrolled. All of them underwent the aortic valve replacement (AVR) procedures. The patients’ global longitudinal strain (GLS) and global circumferential strain (GCS) were evaluated by 3D-STE before surgery and at 1 week after surgery. In addition, GLS and GCS were followed at 1 month as well as 3 months after AVR. In AS patients, the GCS after AVR altered little both at 1 week (p = 0.562) and at 1 month (p = 0.953) compared with the data before the surgery. And it increased significantly at 3 months of follow-up observation compared to that before AVR (p<0.05). Meanwhile, GLS increased progressively after AVR and improved significantly at 3 months after surgery (p<0.05). For the AI patients, GLS as well as GCS decreased at 1 week after AVR compared to those data at baseline (p<0.05). However, these two parameters recovered at 1 month after AVR. Furthermore, GLS and GCS improved significantly at 3 months after the surgery (p<0.05). Therefore, both GLS and GCS were influenced by AVR and would be improved at 3 months after surgery both in AS patients or AI patients. GLS and GCS can be finely evaluated by 3D-STE, and they are helpful to determine the variation tendency of left ventricular function in patients with AVR.     

Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse the maladaptive remodeling that results in heart failure. We sought to determine the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on heart failure produced by myocardial infarction in the rat and to assess whether up to 4 wk of treatment delay results in beneficial effects. Male Sprague-Dawley rats were subjected to coronary artery ligation (or a sham procedure) and followed for up to 3 mo, at which time hypertrophy and hemodynamics were determined. EMD was provided in the diet, and treatment commenced immediately or 2-4 wk after ligation. EMD significantly reduced hemodynamic abnormalities, including the elevation in left ventricular end-diastolic pressure, and diminished the loss of systolic function with all treatment protocols. Left ventricular dilatation and hypertrophy, as assessed by heart weight, cell size, and atrial natriuretic peptide (ANP) expression, were similarly reversed to sham or near-sham levels. In addition, the increased plasma ANP and pro-ANP values were reversed to levels not significantly different from sham. Surprisingly, virtually all beneficial effects were identical with all treatment protocols. These effects were observed in the absence of infarct size reduction or blood pressure-lowering effects. Our results suggest that NHE-1 inhibition attenuates and reverses postinfarction remodeling and heart failure with a treatment delay of up to 4 wk after infarction. The effect is independent of infarct size or afterload reduction, indicating a direct effect on the myocardium.     

The role of cardiac biochemical markers in aortic stenosis

Calcified aortic stenosis is one of the most common causes of heart failure in the elderly. Current guidelines recommend aortic valve replacement in patients with severe disease and evidence of decompensation based on either symptoms or impaired systolic ejection fraction. However, symptoms are often subjective whilst impaired ejection fraction is not a sensitive marker of ventricular decompensation. Interest has surrounded the use of cardiac biochemical markers as objective measures of left ventricular decompensation in aortic stenosis. We will first examine mechanisms of release of biochemical markers associated with myocardial wall stress (BNP/NT-proBNP), myocardial fibrosis (markers of collagen metabolism, galectin-3, soluble ST2) and myocyte death/myocardial ischemia (high-sensitivity cardiac troponins, heart-type fatty acid binding protein, myosin-binding protein C); and discuss future directions of these markers.     

Beta2-microglobulin knockout mice treated with anti-asialoGM1 exhibit improved hemodynamics and cardiac contractile function during acute intra-abdominal sepsis

We previously showed that beta2-microglobulin knockout mice treated with anti-asialoGM1 (beta2M/alphaAsGM1 mice) exhibit less hypothermia, reduced production of proinflammatory cytokines, less metabolic acidosis, and improved survival after cecal ligation and puncture (CLP) compared with wild-type mice. The present study was designed to assess hemodynamics and left ventricular contractility at 18 h after CLP. Arterial pressure was measured by carotid artery cannulation, and left ventricular pressure-volume loops were obtained by insertion of a 1.4-F conductance catheter into the left ventricle. Heart rate, stroke volume, and cardiac output were not significantly different between wild-type and beta2M/alphaAsGM1 mice after CLP. However, beta2M/alphaAsGM1 mice exhibited improved mean arterial pressure and systemic vascular resistance compared with wild-type mice. Myocardial function was also better preserved in beta2M/alphaAsGM1 mice as indicated by improved left ventricular pressure development over time, time-varying maximum elastance, endsystolic pressure-volume relationship, and preload recruitable stroke work. Overall, this study shows that cardiovascular collapse characterized by hypotension, myocardial depression, and low systemic vascular resistance occurs after CLP in wild-type mice. However, beta2M/alphaAsGM1 mice exhibit improved hemodynamics and cardiac contractile function after CLP that may account, in part, for our previously observed survival benefit.     

Pyridostigmine Restores Cardiac Autonomic Balance after Small Myocardial Infarction in Mice

The effect of pyridostigmine (PYR) - an acetylcholinesterase inhibitor - on hemodynamics and cardiac autonomic control, was never studied in conscious myocardial infarcted mice. Telemetry transmitters were implanted into the carotid artery under isoflurane anesthesia. Seven to ten days after recovery from the surgery, basal arterial pressure and heart rate were recorded, while parasympathetic and sympathetic tone (ΔHR) was evaluated by means of methyl atropine and propranolol. After the basal hemodynamic recording the mice were subjected to left coronary artery ligation for producing myocardial infarction (MI), or sham operation, and implantation of minipumps filled with PYR or saline. Separate groups of anesthetized (isoflurane) mice previously (4 weeks) subjected to MI, or sham coronary artery ligation, were submitted to cardiac function examination. The mice exhibited an infarct length of approximately 12%, no change in arterial pressure and increased heart rate only in the 1st week after MI. Vagal tone decreased in the 1^st week, while the sympathetic tone was increased in the 1^st and 4^th week after MI. PYR prevented the increase in heart rate but did not affect the arterial pressure. Moreover, PYR prevented the increase in sympathetic tone throughout the 4 weeks. Concerning the parasympathetic tone, PYR not only impaired its attenuation in the 1^st week, but enhanced it in the 4^th week. MI decreased ejection fraction and increased diastolic and systolic volume. Therefore, the pharmacological increase of peripheral acetylcholine availability by means of PYR prevented tachycardia, increased parasympathetic and decreased sympathetic tone after MI in mice.     

Induction of heat shock protein 72 in the failing heart is attenuated after an exposure to heat shock

Induction of heat shock protein (Hsp) 72 in the right ventricular muscle of the rat with heart failure following acute myocardial infarction (AMI) was examined. AMI was induced by the left coronary artery ligation (CAL). The animals at the 8th, but not 2nd, week after CAL revealed a decrease in cardiac output index (COI), suggesting that heart failure had developed by 8 weeks after CAL. Increases in the right ventricular developed pressure and the ratios of right ventricle/body weight and lung/body weight at the 2nd and 8th weeks showed the development of the right ventricular hypertrophy. After measurement of hemodynamic parameters, the hearts isolated from animals at the 2nd and 8th weeks after CAL (2w- and 8w-CAL hearts, respectively) were perfused and subjected to heat shock (at 42 degrees C, for 15 min) followed by 6-h perfusion. At the end of perfusion, Hsp72 content in the left ventricle without infarct area (viable LV) and the right ventricle (RV) was determined by the Western immunoblotting method. The production of myocardial Hsp72 in the viable LV and RV of the 2w-CAL heart increased after an exposure to heat shock. In contrast, induction of Hsp72 in the viable LV and RV of the 8w-CAL heart was blunted. The results suggest that the development of heart failure following AMI may result in a decrease in the ability for Hsp72 induction not only in the viable LV but also in the RV, leading to contractile dysfunction of the heart.     

Time course of right ventricular remodeling in rats with experimental myocardial infarction

Right ventricular (RV) weight increases dependent on time after myocardial infarction (MI) and on MI size. The sequential changes in RV volume and hemodynamics and their relations to left ventricular (LV) remodeling after MI are unknown. We therefore examined the time course of RV remodeling in rats with LV MI. MI was produced by left coronary artery ligation. Four, eight, and sixteen weeks later, LV and RV hemodynamic measurements were performed and pressure-volume curves were obtained. For serial measurement of RV volumes and performance, cine-MRI was performed 2 and 8 wk after MI. The ratios of beta-myosin heavy chain (MHC) to alpha-MHC and skeletal to cardiac alpha-actin were determined for the RV and LV after large MI or sham operation. RV weight increased in rats with MI, as did RV volume. RV pressure-volume curves were shifted toward larger volumes 16 wk after large MI. RV systolic pressure increased gradually over time; however, the gain in RV weight was always in excess of RV systolic pressure. The ratios of skeletal to cardiac alpha-actin and beta-MHC to alpha-MHC were increased after MI in both ventricles in a similar fashion. Because RV wall stress was not increased after infarction, mechanical factors may not conclusively explain hypertrophy, which maintained balanced loading conditions for the RV even after large LV infarction.     

大鼠心肌肥厚时左心室心房钠尿肽基因的转录

本工作运用ANF放射免疫测定和ANF核酸分子杂交的方法,测定了大鼠腹主动脉部分结扎引起心肌肥厚时血浆ANF及左心室ANF mRNA水平的变化。结果表明,心肌肥厚大鼠的血浆ANF及左心室ANF mRNA水平都明显升高,提示大鼠心肌肥厚可以促进其左心室ANF基因的转录和表达。此外,本工作还证明细胞内钙离子调节剂牛磺酸和血管松弛剂肼苯哒嗪可以分别促进和抑制大鼠心肌肥厚诱导的左心室ANF基因的转录和表达。     

Myocardial renin is neither necessary nor sufficient to initiate or maintain ventricular hypertrophy

We tested the hypothesis that the myocardial renin-angiotensin system (RAS) is both necessary and sufficient to initiate and maintain all classes of ventricular hypertrophy. Myocardial and plasma renin and angiotensinogen were measured in rats during initiation and maintenance of ventricular hypertrophy associated with DOCA implants and 1% NaCl drinking water, with and without the AT(1) ANG II receptor blocker losartan. Additional groups of rats were given a low-sodium diet (0.04%) for 3 wk. Ventricular hypertrophy was initiated within 7 days and maintained for 35 days in DOCA-treated rats despite significantly low myocardial and plasma renin, normal or low myocardial and plasma angiotensinogen, or the presence of losartan. Furthermore, there was no ventricular hypertrophy in low-salt diet-fed animals despite increased myocardial and plasma renin levels and normal angiotensinogen levels. Therefore, the myocardial RAS is not necessary to initiate or maintain cardiac hypertrophy in DOCA-treated rats and is not sufficient to initiate cardiac hypertrophy in low-salt diet-fed rats. Additionally, myocardial renin and angiotensinogen were significantly correlated with corresponding plasma levels.     

Plasma profiles of circulating granulocyte-macrophage colony-stimulating factor and soluble cellular adhesion molecules in acute myocardial infarction. Contribution to post-infarction left ventricular dysfunction

No in vivo data exist about the relationship of circulating granulocyte-macrophage colony stimulating factor (GM-CSF) and soluble adhesion molecules ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) to the severity of acute myocardial infarction (AMI) and the pathophysiological events of post-infarction left ventricular dysfunction. We investigated the kinetics of these inflammatory mediators in the plasma of patients with AMI, and correlated the findings with the clinical severity of the disease during the first week of hospitalization as well as the degree of left ventricular dysfunction one month after the AMI. Plasma levels of inflammatory markers were determined in 41 AMI patients (all received thrombolytic treatment) by ELISA assays, serially during the first week of hospitalization and one month after hospital admission. Patients (n = 20) with uncomplicated AMI (Killip class I) were classified as group A, patients (n = 21) with AMI complicated by heart failure manifestations (Killip classes II and III) were classified as group B, while 20 age- and sex-matched volunteers were used as healthy controls. A sustained increase in GM-CSF, sICAM-1 and sVCAM-1 plasma concentrations was observed only in group B during the first week of the study. Patients from group B exhibited significantly higher levels of GM-CSF (P < 0.01), sICAM-1 (P < 0.05) and sVCAM-1 (P < 0.01) than patients from group A and the healthy controls (P < 0.001). In group B patients, significant correlations were observed between the peak of GM-CSF levels and the peak of serum creatine kinase-MB (r = 0.42; P < 0.05), white blood cell counts (r = 0.67; P < 0.001) and LVEF (r =- 0.51; P < 0.01). At one month follow-up, patients (n = 17) with severe post-infarction left ventricular dysfunction (LVEF 35%). Significant correlations were observed between GM-CSF levels and left ventricular end-diastolic volume index (r = 0.55; P < 0.001) or left ventricular end-systolic volume index (r = 0.49; P = 0.001). We have found a significant elevation of plasma GM-CSF and soluble adhesion molecules during the course of AMI, with the highest values in patients with AMI complicated by heart failure manifestations and severe left ventricular dysfunction. These monocyte-related inflammatory mediators may actively contribute to the pathophysiology of the disease and post-infarction cardiac dysfunction.     

FALSE ANEURYSM OF THE LEFT VENTRICLE: CASE REPORT WITH PRE- AND POSTOPERATIVE EVALUATION

A 66-year-old woman developed chronic congestive heart failure after myocardial infarction of the anterior wall of the left ventricle. Angiographic studies revealed total proximal occlusion of the left anterior descending coronary artery and a large saccular aneurysm located on the anteroapical aspect of the left ventricle. Resection of a false aneurysm at operation resulted in improved cardiac function, and the patient made an uneventful recovery. Repeat evaluation six months later confirmed normal cardiac hemodynamics and left ventricular angiographic characteristics. To our knowledge, this is the first documented case of normalized heart function resulting from resection of a false aneurysm of the left ventricle. Functional classification according to the New York Heart Association improved dramatically, rising from Class IV preoperatively to Class I after operation.     

Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats

Calcineurin has recently been implicated as a mediator in the signaling pathways that transform intracellular calcium signals to the phenotype of myocardial hypertrophy. The present study was conducted to examine the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on myocardial hypertrophy and remodeling during congestive heart failure (CHF) in rats. After ligation of the left coronary artery, rats were randomized to treatment with CsA or vehicle for 14 days. Compared with vehicle, CsA substantially attenuated myocardial hypertrophy in the CHF rats as assessed by alterations in ventricular weight-to-tibial length ratios (P < 0.05). Myocardial gene expression of skeletal alpha-actin was also reduced in the failing left ventricle (LV) after treatment with CsA (P < 0. 05), although the mRNA levels were still substantially elevated relative to those of sham rats. CsA-induced inhibition of compensatory myocardial hypertrophy in the CHF rats led to increased dilatation of the LV cavity and reduced fractional shortening and peak positive and negative first derivatives of LV pressure (P < 0. 05). Plasma renin and endothelin-1 levels were increased in the CHF-CsA rats, providing humoral cues of aggravated cardiac function. Thus this study supports a crucial role of calcineurin-dependent pathways in the mechanisms of compensatory myocardial hypertrophy during CHF. In addition, our data indicate that inhibition of compensatory myocardial hypertrophy exerts detrimental effects on cardiac remodeling and function after myocardial infarction.     

Changes in fatty acid compositions of myocardial lipids in rats with heart failure following myocardial infarction

Changes in fatty acid composition of myocardial lipids were examined in rats with heart failure following myocardial infarction. Left ventricular systolic pressure (LVSP) was decreased and left ventricular end-diastolic pressure (LVEDP) was elevated 24 h, 1 and 12 weeks after left coronary artery ligation (CAL), suggesting the development of heart failure at these periods in this model. Hearts were isolated 24 h, 1 week and 12 weeks after the operation. Myocardial lipids in the infarcted scar tissue, non-infarcted remaining left ventricle including interseptum and right ventricle were separated into phospholipid (PL), triacylglycerol (TG), diacylglycerol (DAG) and free fatty acid (FFA) fractions. In the scar tissue PL content markedly decreased whereas TG, DAG and FFA contents increased 24 h after CAL. Despite a marked decrease in constituted fatty acids of PL fraction in the scar tissue the percentage of arachidonic acid in PL was elevated 12 weeks after CAL, suggesting that release of arachidonic acid during PL degradation was suppressed. In the non-infarcted viable left ventricle PL content remained unchanged throughout the experiment whereas TG, DAG and FFA contents were elevated 24 h after CAL. Despite no changes in PL and other lipid contents in the non-infarcted tissue the percentage of linoleic acid in PL was reduced and that of docosahexaenoic acid in PL was elevated 12 weeks after CAL. Our findings showed that myocardial lipid composition of the non-infarcted left ventricle was altered only in an early stage of the development of heart failure and fatty acid compositions of PL was exchanged in a late stage of the development of heart failure. The exchange may be related to cardiac dysfunction or myocardial remodelling in the rat with heart failure.