太子参对心肌梗死后慢性心衰大鼠心功能与基质金属蛋白酶表达的影响

目的：研究太子参对心肌梗死诱导的慢性心衰大鼠心功能与基质金属蛋白酶（MMPs）表达和活性的作用。方法:采用结扎大鼠冠状动脉复制急性心肌梗死诱导慢性心衰动物模型，以血流动力学指标分析心功能，RT-PCR分析MMP-2与MMP-9的mRNA表达，酶谱法分析MMP-2与MMP-9的活力。结果:大鼠冠脉结扎6周后，心功能显著紊乱；左心室组织MMP-2与MMP-9 mRNA水平显著提高、酶活力增加。太子参水煎液连续灌胃给药5周，可显著改善心衰大鼠的血流动力学，抑制左心室组织MMP-2与MMP-9的活力和mRNA的水平增加（与模型组比较，差异显著，P<0.01，P<0.05）。结论:大鼠冠脉结扎6周形成慢性心衰模型，太子参水煎液可改善大鼠冠脉结扎所诱导的心衰，其机制可能与MMPs的表达和活性有关。     

Poly(ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke

Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP). Apoptosis-inducing factor (AIF) is a flavoprotein that is normally confined to the mitochondria, but translocates to the nucleus, as shown by in vitro models of neuronal injury. Using INO-1001, a novel potent inhibitor of PARP, we determined the role of PARP activation in the process of AIF translocation in a rat model of focal cerebral ischemia. The potency of INO-1001 as a PARP inhibitor and its cytoprotective potential in oxidant-challenged human neuronal SK-N-MC cells was first confirmed in vitro. PARP inhibition markedly reduced infarct size and improved neurological status in both transient and permanent models of MCA occlusion in Sprague-Dawley rats, with a therapeutic window of 6 h and 2 h in the transient and permanent ischemia models, respectively. The PARP inhibitor reduced the accumulation of poly(ADP-ribose) in the ischemic/reperfused hemisphere and reduced the accumulation of APP in the white matter of the affected hemisphere, consistently with protection against neuronal necrosis and axonal damage, respectively. Immunohistochemical analysis showed the appearance of AIF labeling in neuronal nuclei of the border zone ischemic area in the striatum after stroke. Cytoplasmatic (axonal) AIF staining was significantly diminished in the necrotic core of the striatum, while it was somewhat enhanced at the borderline ischemic territories of the white matter. Inhibition of PARP with INO-1001 reshifted the location of the apoptotic marker to the axons in the ipsilateral striatum. Thus, PARP inhibition is neuroprotective and regulates the ischemic nuclear translocation of AIF in stroke.     

Temporary mechanical circulatory support for severe cardiac failure: experimental study

We describe a technique for mechanical cardiac assistance in an acute model of severe cardiac failure. Cardiac dysfunction was induced by a high dose of halothane in 13 dogs. Seven served as controls. Following median sternotomy, a pneumatically driven device was implanted in the other six dogs in a para-aortic position, using a simple surgical technique without cardiopulmonary bypass. The aorta was cross-clamped during cardiac assistance. During hemodynamic studies, the seven control animals with induced cardiac failure showed high end-diastolic left ventricular and right atrial pressures with low cardiac index and systolic left ventricular and aortic pressures. All dogs in this group died within 30 minutes. Use of a monovalvular cardiac assist device in the experimental group of six dogs to pump blood from the aortic root to the descending aorta in a counterpulsation manner, confirmed good preservation of systemic hemodynamic parameters after induction of heart failure. All animals in this treated group survived more than 45 minutes. Hemodynamically, the device acts as a new ventricle and the impaired left ventricle functionally becomes a left atrium. This condition is clinically appropriate for recovery of left ventricular function in severe acute myocardial failure.     

Effect of angiotensin-converting enzyme inhibitors on non-diseased myocardium of experimental animals: potential clinical implications

Angiotensin-converting enzyme (ACE) inhibitors protect the hearts of patients with different levels of cardiac disorder. The greatest benefit seems to be achieved in subjects with most severe heart failure. Moreover, ACE inhibition is protective also in patients without manifested heart failure but with severe systolic left ventricular dysfunction. Data are presented that ACE inhibitors can alter the composition of the myocardium also in control: healthy animals. In rats and rabbits with non-diseased heart, chronic ACE inhibition reduced fibrotic tissue concentration in the left ventricle. We speculate that if this were applied to humans, ACE inhibition may prove to be of potential benefit in subjects with normal systolic function but with a trend to left ventricular filling abnormalities caused by increased ventricular stiffness. In these patients reduction of myocardial fibrotic tissue might prevent deterioration of diastolic function.     

Activation of poly(ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging

Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of endothelial dysfunction associated with atherosclerosis, hypertension and aging. Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury and circulatory shock. Here we investigated the role of PARP activation in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension and aging. Retired breeder spontaneously hypertensive rats (SHR, 40 weeks old) and apolipoprotein E knockout mice (apoE-Ko, 10 weeks old) were treated for 20 weeks with vehicle or the potent PARP inhibitor PJ34. In the vehicle-treated SHR rats and apoE-Ko mice (kept on atherogenic diet) there was a significant loss of endothelial function, as measured by the relaxant responsiveness of vascular rings to acetylcholine. SHR rats also developed severe hypertension and cardiac hypertrophy. Treatment with the PARP inhibitor did not influence high blood pressure and cardiac hypertrophy in SHR rats, but it improved Ach-induced, NO-mediated vascular relaxation. In addition to the beneficial effects of chronic treatment with PARP inhibitor, 1-h in vitro incubation of aortic rings from SHR rats with PJ34 (3 micromol/l) was also able to improve the endothelial dysfunction. In contrast, in apoE-Ko mice PJ34 treatment did not affect the parameters studied. Thus, PARP activation contributes to the pathogenesis of endothelial dysfunction associated with hypertension and aging, but not in the current experimental model of atherosclerosis.     

A mouse model of reverse cardiac remodelling following banding-debanding of the ascending aorta

Aim: Myocardial remodelling during pressure overload might contribute to development of heart failure. Reverse remodelling normally occurs following aortic valve replacement for aortic stenosis; however, the details and regulatory mechanisms of reverse remodelling remain unknown. Thus, an experimental model of reverse remodelling would allow for studies of this process. Although models of aortic banding are widely used, only few reports of debanding models exist. The aim of this study was to establish a banding–debanding model in the mouse with repetitive careful haemodynamic evaluation by high‐resolution echocardiography. Methods: C57Bl/6 mice were subjected to ascending aortic banding and subsequent debanding. Cardiac geometry and function were evaluated by echocardiography, and left ventricular myocardium was analysed by histology and quantitative real‐time polymerase chain reaction. Results: The degree of aortic banding was controlled by non‐invasive estimation of the gradient, and we found a close correlation between left ventricular mass estimated by echocardiography and weight at the time of killing. Aortic banding led to left ventricular hypertrophy, fibrosis and expression of foetal genes, indicating myocardial remodelling. Echocardiography revealed concentric left ventricular remodelling and myocardial dysfunction. Following debanding, performed via a different incision, there was rapid regression of left ventricular weight and normalization of both cardiac geometry and function by 14 days. Conclusions: We have established a reproducible and carefully characterized mouse model of reverse remodelling by banding and debanding of the ascending aorta. Such a model might contribute to increased understanding of the reversibility of cardiac pathology, which in turn might give rise to new strategies in heart failure treatment.     

Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease: in vivo and in vitro studies on collagen matrix regulation

Summary The interstitial space of the myocardium is composed of nonmyocyte cells and a highly organized collagen network which serves to maintain the architecture and mechanical behavior of the myocardial walls. It is the myocardial collagen matrix that determines myocardial stiffness in the normal and structurally remodeled myocardium. In hypertensive heart disease, the heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for collagen synthesis and degradation, explains the appearance of diastolic and/or systolic dysfunction of the left ventricle that leads to symptomatic heart failure. Several lines of evidence suggest that circulating and myocardial renin-angiotensin systems (RAS) are involved in the regulation of the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In cultured adult rat cardiac fibroblasts angiotensin II was shown to directly stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation, that would lead to collagen accumulation. In the spontaneously hypertensive rat, an appropriate experimental model for primary hypertension in man, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness due to interstitial fibrosis could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.     

甘氨酸对缺氧/复氧离体大鼠心脏功能的作用

目的：观察甘氨酸(glycine, GLY)对缺氧/复氧离体心脏功能的影响，探讨甘氨酸对心肌缺血-再灌注 (ischemia/reperfusion, I/R)损伤的防治作用及其机制。方法：利用Langendorff灌流装置复制心肌缺氧/复氧(hypoxia/reoxygenation, H/R)模型，观察不同浓度GLY处理后心脏左室收缩压（left ventricular systolic pressure, LVSP）、左室舒张末压（left ventricular end diastolic pressure, LVEDP）、左室发展压 (left ventricular developed pressure, LVDP=LVSP-LVEDP)、左室收缩压最大上升/下降速率(the maximum rising and dropping rates of left ventricular pressure, dp/dtmax and dp/dtmin)，并在相应的时点分别测定冠脉流出液中的超氧化物歧化酶(superoxide dismutase, SOD)活性和丙二醛(malondialdehyde, MDA)的水平。结果：H/R后各时点大鼠心功能各指标均低于缺氧前；GLY处理组复氧后心功能各指标均高于H/R组，并拮抗损伤导致的SOD减少和MDA升高。结论：一定浓度的GLY能显著改善缺氧/复氧心肌的舒缩功能，其机制可能与其提高SOD活性抑制脂质过氧化反应有关。     

CardioClasp: a new passive device to reshape cardiac enlargement

In dilated heart failure, geometric distortions place an extra load on the myocardial cells. If this extra burden can be eliminated, the myocardial wall stress would decrease leading to improved systolic ventricular performance. In a dilated heart failure model, we wanted to see whether the CardioClasp (which uses two indenting bars to reshape the left ventricle [LV] as two widely communicating "lobes" of reduced radius) could improve systolic performance by passively reshaping the LV and reducing the wall stress. In mongrel dogs (n = 7; 25-27 kg), rapid ventricular pacing (210 ppm 1st week to 240 ppm 4th week) induced dilated heart failure. After 4 weeks, LV performance was evaluated at baseline and with the CardioClasp by measuring LV end-diastolic and peak LV systolic pressure, LV +dP/dt, LV -dP/ dt, and cardiac output. With the Clasp on, LV wall stress was reduced to 58.6+/-3.5 from 108.3+/-8.2 g/cm2. The fractional area of contraction (FAC) with the Clasp on (28.4+/-4.4) was significantly increased (p < 0.05) from baseline (20.8+/-4.6) and consistent with improved systolic performance. Cardiac output, LV peak systolic and end-diastolic pressures, and regional myocardial blood flow were unaltered. The Clasp was able to acutely reshape the left ventricle, while preserving the contractile mass, and reduced the tension on the myocardial cells and increased the fractional area of contraction without decreasing the systolic blood pressure.     

阿托伐他汀通过调节钠-钙交换体改善心力衰竭大鼠心脏功能

目的:探讨阿托伐他汀对心力衰竭大鼠心脏功能及心肌细胞钠-钙交换体表达的影响。方法:结扎大鼠冠状动脉左前降支8周,制备心肌梗死后心力衰竭模型。随机分3组,即假手术组、心力衰竭组与阿托伐他汀治疗组,分别于结扎后第2天给予安慰剂或阿托伐他汀治疗。8周后测定大鼠心脏功能及钠-钙交换体蛋白表达水平。培养原代乳鼠心肌细胞,通过缺氧模型分析阿托伐他汀对细胞内钙水平的影响。结果:阿托伐他汀治疗组较心衰组BNP水平降低,左室舒张末内径缩小,左室短轴缩短率升高。阿托伐他汀治疗明显降低心力衰竭时钠-钙交换体蛋白表达量,抑制缺氧诱导细胞内钙水平增加。结论:阿托伐他汀治疗改善心功能,可能与影响心力衰竭心肌细胞钠-钙交换体的表达及功能有关。     

感染性和内毒素性休克大鼠动脉组织中硫化氢的变化

探讨内源性硫化氢 (H2 S)在感染性和内毒素性休克大鼠血管组织中的含量变化及意义。用盲肠结扎穿孔法制备大鼠感染性休克模型和静脉注射内毒素法制备内毒素休克大鼠模型 ,观察大鼠血液动力学、代谢变化及测定内源性硫化氢含量和一氧化氮含量 ,并计算其相关性。感染性及内毒素性休克大鼠的血液动力学参数均明显低于对照组 ,而左室舒张末压明显高于对照组 (P <0 0 1) ,血糖明显低于对照组 (P <0 0 1) ,血乳酸水平明显高于对照组(P <0 0 1)。感染性和内毒素性休克大鼠动脉组织中H2 S含量明显高于对照组 ,(均P <0 0 1)。休克大鼠血管H2 S含量与血压、心功能及低血糖的程度呈高度负相关 (均P <0 0 1)。以上结果说明内源性H2 S可能参与休克过程中的病理生理调节     

慢性心衰大鼠下丘脑室旁核瞬时外向钾通道蛋白Kv4.2和Kv4.3低表达促进肾交感神经兴奋性

 目的: 观察慢性心衰大鼠下丘脑室旁核内瞬时外向钾通道蛋白Kv4.2和Kv4.3的变化及其对交感神经活性的影响。方法: 采用冠状动脉左前降支结扎术建立大鼠心衰模型或假手术模型,造模4周后超声心动图测定心功能;酶联免疫吸附法测定血浆去甲肾上腺素(NE)及血清N端前脑钠肽(NT-proBNP)含量;Western blot和real-time PCR法测定室旁核内Kv4.2和Kv4.3的表达情况;室旁核部位注射钾通道阻滞剂4-氨基吡啶(4-AP),电生理记录仪记录血压、心率和肾交感神经放电的变化。结果: 与假手术组比,心衰组大鼠心功能明显降低,血浆NE及血清NT-proBNP明显升高,室旁核内Kv4.2和Kv4.3表达明显下调;注射4-AP后导致血压、心率和交感神经放电升高,但心衰组的升高幅度小于假手术组。结论: 心力衰竭时室旁核内Kv4.2和Kv4.3表达下调并伴有交感神经放电增加,促进心衰进展。     

Role of cardiac sympathetics in the tonic circulatory restraint by vagal afferents.

In anesthetized cats with aortic nerves sectioned and carotid arteries occluded, we determined the role of cardiac sympathetic nerves on the tonic inhibitory restraint by cardiac vagal afferents on the cardiovascular system. The effect of afferent vagal blockade on mean arterial pressure and cardiac contractility was determined when sympathetic tone to the heart was altered. Bilateral cardiac sympathectomy produced a significant decrease in left ventricular dP/dt and attenuated the arterial pressure response to afferent vagal cold block to less than 40% of the control. The increase in dP/dt normally observed with vagal blockade was also reduced significantly. Increasing dP/dt by efferent stimulation of cardiac sympathetic nerves restored the arterial pressure response to vagal blockade to near control levels. While the vagal inhibitory activity appeared to be dependent on the resting dP/dt, left ventricular peak pressure did not seem to be contributing to the reflex. Thus, the inhibitory effects of vagally mediated reflexes from the heart which contribute to arterial pressure regulation appear to be influenced by changes in cardiac contractility induced by cardiac sympathetic nerve stimulation.     

Role of peptido-leukotrienes in the genesis of early ventricular arrhythmias during acute myocardial ischaemia in rats

Changes in cardiac ventricular concentrations of peptidoleukotrienes (peptido-LTs) following coronary artery ligation and the effects of lipoxygenase inhibition and leukotriene antagonism on the cardiovascular responses to acute myocardial ischaemia were studied in pentobarbitone-anaesthetised rats. It was found that the left ventricular peptido-LT levels significantly increased at 2.5 and 5 min after left coronary artery ligation while the changes in right ventricle were not statistically significant. Pretreatment with nordihydroguaiaretic acid 25, 50 or 100 mg/kg caused marked depletion of ventricular peptido-LT content, but did not significantly prevent the blood pressure or heart rate changes, the occurrence of ventricular tachycardia or fibrillation, or the mortality of the animals following coronary artery ligation. Administration of SK&F 102922, even at doses which caused marked decreases in blood pressure and heart rate, also did not significantly alter the cardiovascular changes and the mortality rate induced by left coronary artery ligation. It is, therefore, suggested that the occurrence of ventricular arrhythmias and haemodynamic changes during the early phase of acute myocardial ischaemia may not be due to the augemented synthesis of peptido-LTs in cardiac tissue.     

糖尿病在糖尿病大鼠心肌梗死后心力衰竭形成中的效应

目的： 评估糖尿病在链脲霉素（STZ）诱导的血糖不加控制的糖尿病大鼠急性心肌梗死（AMI）后心力衰竭(HF)形成中的效应。方法：所有SD大鼠随机分组,糖尿病组经腹腔内注射STZ（65mg/kg）诱导糖尿病,70 d后所有AMI组结扎冠状动脉左前降支建立AMI模型。确定AMI前后各时点观察大鼠的生存率,心肌超微结构的变化,进行血流动力学分析、心肌纤维化测定及左心肥厚的评估。结果：结扎左冠状动脉前降支后,糖尿病大鼠的左心功能恶化及左室重构的速度均较非糖尿病大鼠显著。在早期阶段,糖尿病与非糖尿病大鼠心肌纤维化相似,而1月后却出现显著差别。结论：糖尿病大鼠AMI后心力衰竭进展明显加速。     

Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model

As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (AAV)-S100A1 gene therapy in a preclinical large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and animals, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca(2+)) handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered, by retrograde coronary venous delivery, AAV serotype 9 (AAV9)-S100A1 to the left ventricular, non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed these functional and structural changes by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca(2+) cycling, sarcoplasmic reticulum calcium handling, and energy homeostasis. Transgene expression was restricted to cardiac tissue, and extracardiac organ function was uncompromised. This translational study shows the preclinical feasibility of long-term therapeutic effectiveness of and a favorable safety profile for cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.     

Exercise training in adverse cardiac remodeling

Cardiac remodeling in response to a myocardial infarction or chronic pressure-overload is an independent risk factor for the development of heart failure. In contrast, cardiac remodeling produced by regular physical exercise is associated with a decreased risk for heart failure. There is evidence that exercise training has a beneficial effect on disease progression and survival in patients with cardiac remodeling and dysfunction, but concern has also been expressed that exercise training may aggravate pathological remodeling and dysfunction. Here we present studies from our laboratory into the effects of exercise training on pathological cardiac remodeling and dysfunction in mice. The results indicate that even in the presence of a large infarct, exercise training exerts beneficial effects on the heart. These effects were mimicked in part by endothelial nitric oxide synthase (eNOS) overexpression and abrogated by eNOS deficiency, demonstrating the importance of nitric oxide signaling in mediating the cardiac effects of exercise. Exercise prior to a myocardial infarction was also cardioprotective. In contrast, exercise tended to aggravate pathological cardiac remodeling and dysfunction in the setting of pressure-overload produced by an aortic stenosis. These observations emphasize the critical importance of the underlying pathological stimulus for cardiac hypertrophy and remodeling, in determining the effects of exercise training. Future studies are needed to define the influence of exercise type, intensity and duration in different models and severities of pathological cardiac remodeling. Together such studies will aid in optimizing the therapy of exercise training in the setting of cardiovascular disease.     

Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice

IntroductionHeme oxygenase-1 (HO-1) is a cytoprotective enzyme induced by stress. Heart failure is a condition of chronic stress-induced remodeling and is often accompanied by comorbidities such as age and hypertension. HO-1 is known to be protective in the setting of acute myocardial infarction. The role of HO-1 in heart failure is not known, particularly in the setting of pressure overload.MethodsMice with alpha-myosin heavy chain restricted expression of HO-1 were aged for 1 year. In addition, mice underwent transverse aortic constriction (TAC) or were infused with isoproterenol (ISO) to induce heart failure.ResultsHO-1 transgenic mice developed spontaneous heart failure after 1 year compared to their wild-type littermates and showed accelerated cardiac dysfunction 2 weeks following TAC. Wild-type mice undergoing pressure overload demonstrated extensive interstitial fibrosis that was prevented by HO-1 overexpression, yet HO-1 transgenic mice had reduced capillary density, contractile reserve, and elevated end-diastolic pressure. However, HO-1 transgenic mice had significantly attenuated ISO-induced cardiac dysfunction, interstitial fibrosis, and hypertrophy compared to control. Isolated cardiomyocytes from HO-1 transgenic mice treated with ISO did not show evidence of hypercontracture/necrosis and had reduced NADH oxidase activity.ConclusionsHO-1 is an effective mechanism for reducing acute myocardial stress such as excess beta-adrenergic activity. However, in our age and pressure overload models, HO-1 showed detrimental rather than therapeutic effects in the development of heart failure.     

Cardiomyocyte contractility and calcium handling partially recover after early deterioration during post‐infarction failure in rat

The aim of the study was to determine whether progression of heart failure is associated with deterioration of cardiomyocyte function. Cell dimensions, contractility and calcium transients were measured in cardiomyocytes isolated from the left ventricle of female Wistar rats 1, 4, and 13 weeks after coronary artery ligation or sham‐operation. Relative cardiomyocyte shortening decreased from 26% in controls to 11% 1 week after myocardial infarction and recovered to 18 and 20% after 4 and 13 weeks, respectively. Diastolic and systolic calcium concentrations increased markedly 1 week after myocardial infarction with subsequent reduction after 4 and 13 weeks. Time to 50% relaxation was prolonged by 31% after 1 week and 20% after 4 and 13 weeks with corresponding changes in diastolic calcium clearance. Cardiomyocyte length increased by 6, 24, and 26% after 1, 4 and 13 weeks, respectively, whereas myocyte width increased by 4, 11 and 27%. Cardiomyocytes adjacent to the infarct hypertrophied more and initially had more markedly impaired function than in the remote area. Left ventricular diastolic diameter assessed by echocardiography increased by 47, 66 and 84% after 1, 4 and 13 weeks, respectively, and systolic diameter increased by 120, 162 and 194%. Left ventricular end‐diastolic pressure increased from 6 mmHg to 24, 25 and 36 mmHg. Whereas initial deterioration of cardiac function is associated with reduced cardiomyocyte contractile function, chronic heart failure progression is not accompanied by further impairment of intrinsic cardiomyocyte contractility in this model. Cardiomyocyte hypertrophy and dysfunction are more marked adjacent to the infarction.