Study of the impact of intramyocardial implantation of stem cells on myocardial perfusion and contractility in patients with coronary heart disease concurrent with postinfarct cardiosclerosis and chronic heart failure

OBJECTIVE: to study of intramyocardial implantation of cultured bone marrow stem cells on myocardial perfusion and contractility in the surgical treatment of patients with coronary heart disease (CHD) and chronic heart failure (CHF), by synchronized single-photon emission computed tomography (SSPECT) of the myocardium. SUBJECTS AND METHODS: The study included 11 patients. Intramyocardial injection of cell injections into the myocardial periscarring areas was made at coronary bypass surgery. All the patients underwent 99mTc myocardial SSPECT MIBI before and 3, 6, 12 months after surgery. RESULTS AND CONCLUSIONS: Implantation of bone marrow stem cells into the left ventricular myocardium favorably affects left ventricular remodeling and contributes to the improvement of myocardial perfusion and contractility, as evidenced by 99mTc.     

Intense exercise causes decrease in expression of both endothelial NO synthase and tissue NOx level in hearts

Cardiac myocytes produce nitric oxide (NO). We studied the effects of intense exercise on the expression of NO synthase (NOS) and the tissue level of nitrite (NO(2)(-))/nitrate (NO(3)(-)) (i.e., NOx), which are stable end products of NO in the heart. Rats ran on a treadmill for 45 min. Immediately after this exercise, the heart was quickly removed. Control rats remained at rest during the same 45-min period. The mRNA level of endothelial NOS (eNOS) in the heart was markedly lower in the exercised rats than in the control rats. Western blot analysis confirmed downregulation of eNOS protein in the heart after exercise. Tissue NOx level in the heart was significantly lower in the exercised rats than in the control rats. The present study revealed for the first time that production of NO in the heart is decreased by intense exercise. Because NO attenuates positive inotropic and chronotropic responses to beta(1)-adrenergic stimulation in the heart, the decrease in cardiac production of NO by intense exercise may contribute to the acceleration of increase in myocardial contractility and heart rate during intense exercise.     

The interrelationship of doses and the pharmacological effects of cardiac peptides]

Low-molecular weight peptides prepared according to an original procedure from a cattle heart possess a protecting effect on the myocardium during ischemia. Peptides in doses of 10(-7) g/ml and less improve the indexes of contractility function of the isolated heart after total ischemia and correct respiration warranting cardiomyocytes survival during hypoxia. However, in different models high doses of heart peptides (5 x 10(-6) g/ml and more) are shown to inhibit contractility, to stop respiration, the action of the peptides increasing with myocardial ischemia degree.     

运动后心力及心率同时遥测的心力恢复趋势与心率恢复趋势的对比研究

为了更加全面地研究和评估心肌的变时性和变力性,研制了能够在运动场地同时采集心力和心率的心音信号遥测系统。采集了50名体育系学生和30名其他系学生在完成规定运动量的登梯运动后,5min内连续变化的心音信号。对采集的数据经过3次样条插值、均匀采样和小波变换滤波后,得到了平滑的心力恢复趋势曲线和心率恢复趋势曲线。统计分析表明,大负荷运动量下的心脏储备主要来自于心力储备而不是心率储备(P<0.001),和其他系学生相比,体育系学生具有的高水平心功能不仅在于具有更大的心力储备指数(P<0.001),而且还在于具有更快的心力恢复速度(P<0.001)。同时检测心力恢复趋势与心率恢复趋势会有益于全面评估心脏功能。     

Oxygen free radicals in volume overload heart failure

It has been suggested that oxygen free radicals (OFR) depress the excitation-contraction coupling in cardiac muscle. It is possible that a decrease in the cardiac contractility in the failing heart may be due to an increased OFR producing activity of polymorphonuclear (PMN) leukocytes. We studied the OFR producing activity (chemiluminescence) of PMN leukocytes from blood in dogs with heart failure due to chronic volume overload. The animals were divided into two groups: I) normal, (n = 10): II) dogs with mitral insufficiency (MI) of 6 to 9 months duration, (n = 10). Hemodynamic studies were done to establish the presence of heart failure. Blood samples were collected to measure PMN leukocyte chemiluminescence. There was a decrease in the cardiac index and index of myocardial contractility (dp/dt/IIP) and an increase in the left ventricular end-diastolic pressure in dogs with MI indicating left ventricular failure. The peak chemiluminescent activity of the PMN leukocytes in blood of dogs with failure was about four folds greater than that in the blood from normal dogs. These results suggest that there may be an increased OFR generation in dogs with volume overload heart failure. The decrease in the myocardial contractility in the failing heart might be due to an increase in the OFR produced by the PMN leukocytes.     

Usefulness of Speckle Tracking Imaging to Assess Myocardial Contractility in Intra-Abdominal Hypertension: Study in a Mini-Pig Model

This study evaluated the usefulness of speckle tracking imaging (STI) in assessment of myocardial contractility in intra-abdominal hypertension experimentally induced in mini-pigs. To this effect, 12 mini-pigs were anesthetized with intravenous injection of 3?% sodium pentobarbital, hemorrhaged to reach the shock status, and resuscitated with excessive volume of lactated Ringer??s solution. The animals were either sham-operated (study group 1) or underwent treatment with intra-abdominal volume increment (study group 2). Observations were made prior to induction of shock, 1?h after shock, 2?h after induction of intra-abdominal hypertension, and 8 and 12?h after treatment. The heart rate and mean artery pressure were conventionally measured. STI was used to assess radial and circumferential strains of segmental ventricular wall. The results obtained demonstrated that myocardial contractility, as manifested by radial and circumferential strains of different ventricular wall segments, was decreased after induction of intra-abdominal hypertension. Treatment with intra-abdominal volume increment was able to decrease heart rate and intra-bladder pressure (indicator of effectiveness of treatment) and significantly improved myocardial contractility of involved ventricular wall segments. In conclusion, STI is a useful method to assess myocardial regional functions.     

Computer analysis of ventricular pressure recordings: evaluation of myocardial contractility on the dog heart in situ]

The contractile indices Vmax (maximum shortening velocity of the contractile element) and ARPD (power averaged rate of power density generation) which have been shown to be unaffected by alterations in preload and afterload were computed from isovolumic left ventricular pressure data of dogs. The two indices were tested for their ability to detect changes in contractility induced by a positive inotropic drug (Isoprenalin). Whereas a good correlation was found between ARPD and Vmax (coefficient of correlation 0,895) the index ARPD was more sensitive to augmentation of myocardial contractility; also because it is simpler to obtain computationally and more appropriate for the intact heart from a theoretical point of view. ARPD should be useful especially for quantification of acute changes in myocardial contractility.     

Use of balloon catheters for intraoperative control of resting myocardial pressure during cardioplegia

Twenty-two patients operated on for aortal, mitral and multivalvular prosthesis under pharmacological cardioplegia were examined for the purpose of monitoring myocardial resting tension by the tensometric method and by using modified balloon catheters. The results demonstrated that the use of the balloon catheters permits making not only qualitative and quantitative assessments of myocardial lesions and a prompt evaluation of the function of the arrested heart but also the initial myocardial contractility and the restoration of myocardial contractility after cardioplegic arrest by controlling the contraction and relaxation myocardial rate.     

Interaction of adrenergic and purinergic receptors in the regulation of rat myocardial contractility in postnatal ontogeny

β-Adrenergic receptor agonist isoproterenol and purinergic receptor agonist 2-methylthio-ATP have a positive effect on the myocardial contractile force and show different efficiencies depending on the age of animals. The maximum inotropic effect of agonists on the ventricular myocardial contractility was observed in 21-day-old rat pups. The study of a combined effect of isoproterenol and 2-methylthio-ATP showed that an increase in the sympathetic regulatory effects on the heart of 21-day-old animals, against the background of a high functional activity of β-adrenergic receptors and P2X receptors of the heart, a combined administration of the agonists led to a mutually complementing effect of an increase in the myocardial contractility.     

Effect of Inula racemosa root extract on cardiac function and oxidative stress against isoproterenol-induced myocardial infarction

The cardioprotective potential of Inula racemosa root hydroalcoholic extract against isoproterenol-induced myocardial infarction was investigated in rats. The rats treated with isoproterenol (85 mg/kg, s.c.) exhibited myocardial infarction, as evidenced by significant (P < 0.05) decrease in mean arterial pressure, heart rate, contractility, relaxation along with increased left ventricular end diastolic pressure, as well as decreased endogenous myocardial enzymatic and non-enzymatic antioxidants. Isoproterenol also significantly (P < 0.05) induced lipid peroxidation and increased leakage of myocyte injury marker enzymes. Pretreatment with I. racemosa extract (50, 100 or 200 mg/kg per day, p.o.) for 21 consecutive days, followed by isoproterenol injections on days 19th and 20th significantly (P < 0.05) improved cardiac function by increasing the heart rate, mean arterial pressure, contractility and relaxation along with decreasing left ventricular end diastolic pressure. Pretreatment with I. racemosa also significantly (P < 0.05) restored the reduced form of glutathione and endogenous antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase from the heart, which were depleted after isoproterenol administration. In addition to restoration of antioxidants, I. racemosa significantly (P < 0.05) inhibited lipid peroxidation and prevented the leakage of myocytes specific marker enzymes creatine phosphokinase-MB and lactate dehydrogenase from the heart. Thus, it is concluded that I. racemosa protects heart from isoproterenol-induced myocardial injury by reducing oxidative stress and modulating hemodynamic and ventricular functions of the heart. Present study findings demonstrate the cardioprotective effect of I. racemosa and support the pharmacological relevance of its use and cardioprotection mechanism in ischemic heart disease as well as substantiate its traditional claim.     

犬冠状动脉阻力的胆碱能调节

本实验在麻醉开胸犬,采用冠状动脉左旋支恒流灌注,于搏动的和心室纤颤(VF)的心脏,研究了电刺激迷走神经(VNS)及冠状动脉内注入乙酰胆碱(ACh)对冠状动脉阻力的影响。当 VNS 和冠脉内给 ACh 时,(1)心肌内小冠状动脉阻力显著减低,而心外膜大冠状动脉阻力并无明显变化;(2)冠状动脉左旋支总阻力的减低幅度在 VF 的心脏比在搏动的心脏显著减小。以上结果表明,迷走-ACh 扩张冠脉的作用主要是舒张心肌内小冠状动脉,并可通过减低心肌收缩力而间接降低冠状动脉阻力。     

Inducible and myocyte-specific inhibition of PKCalpha enhances cardiac contractility and protects against infarction-induced heart failure

Mice null for the gene encoding protein kinase Calpha (Prkca), or mice treated with pharmacologic inhibitors of the PKCalpha/beta/gamma isoforms, show an augmentation in cardiac contractility that appears to be cardioprotective. However, it remains uncertain if PKCalpha itself functions in a myocyte autonomous manner to affect cardioprotection in vivo. Here we generated cardiac myocyte-specific transgenic mice using a tetracycline-inducible system to permit controlled expression of dominant negative PKCalpha in the heart. Consistent with the proposed function of PKCalpha, induction of dominant negative PKCalpha expression in the adult heart enhanced baseline cardiac contractility. This increase in cardiac contractility was associated with a partial protection from long-term decompensation and secondary dilated cardiomyopathy after myocardial infarction injury. Similarly, Prkca null mice were also partially protected from infarction-induced heart failure, although the area of infarction injury was identical to controls. Thus, myocyte autonomous inhibition of PKCalpha protects the adult heart from decompensation and dilated cardiomyopathy after infarction injury in association with a primary enhancement in contractility.     

Na+ overload-induced mitochondrial damage in the ischemic heart

Ischemia induces a decrease in myocardial contractility that may lead more or less to contractile dysfunction in the heart. When the duration of ischemia is relatively short, myocardial contractility is immediately reversed to control levels upon reperfusion. In contrast, reperfusion induces myocardial cell death when the heart is exposed to a prolonged period of ischemia. This phenomenon is the so-called "reperfusion injury". Numerous investigators have reported the mechanisms underlying myocardial reperfusion injury such as generation of free radicals, disturbance in the intracellular ion homeostasis, and lack of energy for contraction. Despite a variety of investigations concerning the mechanisms for ischemia and ischemia-reperfusion injury, ionic disturbances have been proposed to play an important role in the genesis of the ischemia-reperfusion injury. In this present study, we focused on the contribution of Na+ overload and mitochondrial dysfunction during ischemia to the genesis of this ischemia-reperfusion injury.     

Negative inotropism of hyperthermia increases oxygen cost of contractility in canine hearts

Heart temperature affects left ventricular (LV) function and myocardial metabolism. However, how and whether increasing heart temperature affects LV mechanoenergetics remain unclear. We designed the present study to investigate effects of increased temperature by 5 degrees C from 36 degrees C on LV contractility and energetics. We analyzed the LV contractility index (E(max)) and the relation between the myocardial oxygen consumption (MVO(2)) and the pressure-volume area (PVA; a measure of LV total mechanical energy) in isovolumically contracting isolated canine hearts during normothermia (NT) and hyperthermia (HT). HT reduced E(max) by 38% (P < 0.01) and shortened time to E(max) by 20% (P < 0.05). HT, however, altered neither the slope nor the unloaded MVO(2) of the MVO(2)-PVA relation. HT increased the oxygen cost of contractility (the incremental ratio of unloaded MVO(2) to E(max)) by 49%. When Ca(2+) infusion restored the reduced LV contractility during HT to the NT baseline level, the unloaded MVO(2) in HT exceeded the NT value by 36%. We conclude that HT-induced negative inotropism accompanies an increase in the oxygen cost of contractility.     

Combined pulmonary stenosis and insufficiency preserves myocardial contractility in the developing heart of growing swine at midterm follow-up.

This study was conducted to determine the effects of chronic combined pulmonary stenosis and pulmonary insufficiency (PSPI) on right (RV) and left ventricular (LV) function in young, growing swine. Six pigs with combined PSPI were studied, and data were compared with previously published data of animals with isolated pulmonary insufficiency and controls. Indexes of systolic function (stroke volume, ejection fraction, and cardiac functional reserve), myocardial contractility (slope of the end-systolic pressure-volume and change in pressure over time-end-diastolic volume relationship), and diastolic compliance were assessed within 2 days of intervention and 3 mo later. Magnetic resonance imaging was used to quantify pulmonary insufficiency and ventricular volumes. The conductance catheter was used to obtain indexes of the cardiac functional reserve, diastolic compliance, and myocardial contractility from pressure-volume relations acquired at rest and under dobutamine infusion. In the PSPI group, the pulmonary regurgitant fraction was 34.3 +/- 5.8%, the pressure gradient across the site of pulmonary stenosis was 20.9 +/- 20 mmHg, and the average RV peak systolic pressure was 70% systemic at 12 wk follow-up. Biventricular resting cardiac outputs and cardiac functional reserves were significantly limited (P < 0.05), LV diastolic compliance significantly decreased (P < 0.05), but RV myocardial contractility significantly enhanced (P < 0.05) compared with control animals at 3-mo follow-up. In the young, developing heart, chronic combined PSPI impairs biventricular systolic pump function and diastolic compliance but preserves RV myocardial contractility.     

The effects of sodium pentobarbital or ether anesthesia on spontaneous and electrochemically-induced gonadotropin release.

Studies were undertaken in the isolated blood perfused dog heart to determine the nature of the myocardial refractoriness induced by veratrum alkaloids. The initial intracoronary injection of cryptenamine acetates (Unitensin) was always associated with an increase in myocardial contractility and a loss of myocardial potassium. Subsequent doses produced refractoriness with respect to both the contractile and potassium responses. Acetylstrophanthidin still produced an inotropic and potassium losing effect duct of the glycoside was potentiated whereas the contractile response was not.     

Prevention of disorders of the electric stability of the heart in experimental infarct using adaptation to hypoxia

It has been shown on rats preadapted to hypoxia in an altitude chamber that myocardial infarction induced by ligation of the coronary artery was accompanied by less disturbances in the electrical stability of the heart, namely by a twofold decrease in ventricular fibrillation threshold and a considerable decrease in the heart ectopic activity. Preliminary adaptation provided the maintenance of myocardial contractility in infarction.     

Cardiac matrix: A clue for future therapy

Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium myocyte (EM) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by EM coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases.     

Regulation of Cardiac Muscle Contractility

The heart's physiological performance, unlike that of skeletal muscle, is regulated primarily by variations in the contractile force developed by the individual myocardial fibers. In an attempt to identify the basis for the characteristic properties of myocardial contraction, the individual cardiac contractile proteins and their behavior in contractile models in vitro have been examined. The low shortening velocity of heart muscle appears to reflect the weak ATPase activity of cardiac myosin, but this enzymatic activity probably does not determine active state intensity. Quantification of the effects of Ca⁺⁺ upon cardiac actomyosin supports the view that myocardial contractility can be modified by changes in the amount of calcium released during excitation-contraction coupling. Exchange of intracellular K⁺ with Na⁺ derived from the extracellular space also could enhance myocardial contractility directly, as highly purified cardiac actomyosin is stimulated when K⁺ is replaced by an equimolar amount of Na⁺. On the other hand, cardiac glycosides and catecholamines, agents which greatly increase the contractility of the intact heart, were found to be without significant actions upon highly purified reconstituted cardiac actomyosin.     

The coronary vasculature and the myocardium

The effect of bradykinin (BK) on myocardial inotropic state was tested on 5 isolated rat heart preparations, in which a proper ballon was placed to record left ventricular pressure, whose developed systolic value was taken as an index of contractility. A reduction of developed left ventricular pressure was observed when BK was added to the perfusion oxygenated Tyrode solution. However, when BK was given after 1-amino-benzotriazole, an inhibitor of Cytochrome P-450 (Cyt P-450), developed pressure did not change. Since Cyt P-450 is known to act on arachidonic acid inducing the production of epoxiecocistrienoic acids (EETs) which hyperpolarizes myocardial fibres, it was argued that the reduction in contractility by bradykinin was the result of the hyperpolarizing effect of EETs. The fact that the concentration of Cyt P-450 is higher in the vascular endothelial cells than in the sarcolemma of the myocytes and the observation that the coronary resistance decreases together with the contractility suggest that the endothelium plays a pivotal role in mediating the negative inotropic effect of BK.