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.     

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.     

Diastolic myofilament dysfunction in the failing human heart

In recent years, it has become evident that heart failure is not solely due to reduced contractile performance of the heart muscle as impaired relaxation is evident in almost all heart failure patients. In more than half of all heart failure patients, diastolic dysfunction is the major cardiac deficit. These heart failure patients have normal (or preserved) left ventricular ejection fraction, but impaired diastolic function evident from increased left ventricular end-diastolic pressure. Perturbations at the cellular level which cause impaired relaxation of the heart muscle involve changes in Ca²⁺-handling proteins, extracellular matrix components, and myofilament properties. The present review discusses the deficits in myofilament function observed in human heart failure and the most likely underlying causal protein changes. Moreover, the consequences of impaired myofilament function for in vivo diastolic dysfunction are discussed taking into account the reported changes in Ca²⁺ handling.     

Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure

Overactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) contributes to the development of cell dysfunction and tissue injury in various pathophysiological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury, heart transplantation, diabetic cardiomyopathy and chronic heart failure. In recent studies, we have demonstrated the beneficial effects of a novel ultrapotent PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction and remodeling in rat model of advanced aging-associated chronic heart failure and in a mouse model of heart failure induced by aortic banding. In the current study, we have investigated the effect of INO-1001 on the development of heart failure induced by permanent ligation of the left anterior descending coronary artery, heart failure induced by doxorubicin and acute myocardial dysfunction induced by bacterial endotoxin. In the coronary ligation model, a significantly depressed left ventricular performance and impaired vascular relaxation of aortic rings were found, and PARP inhibition significantly improved both cardiac function and vascular relaxation. In the doxorubicin model, a single injection of doxorubicin induced high mortality and a significant decrease in left ventricular systolic pressure, +dP/dt, -dP/dt, stroke volume, stroke work, ejection fraction and cardiac output. Treatment with the PARP inhibitor reduced doxorubicin-induced mortality and markedly improved cardiac function. PARP inhibition did not interfere with doxorubicin's antitumor effect. In the endotoxin model of cardiac dysfunction, PARP inhibition attenuated the suppression of myocardial contractility elicited by endotoxin. The current data strengthen the view that PARP inhibition may represent an effective approach for the experimental therapy of various forms of acute and chronic heart failure.     

Cardiac function during mild hypothermia in pigs: increased inotropy at the expense of diastolic dysfunction

Aim: The induction of mild hypothermia (MH; 33 °C) has become the guideline therapy to attenuate hypoxic brain injury after out-of-hospital cardiopulmonary resuscitation. While MH exerts a positive inotropic effect in vitro, MH reduces cardiac output in vivo and is thus discussed critically when severe cardiac dysfunction is present in patients. We thus assessed the effect of MH on the function of the normal heart in an in vivo model closely mimicking the clinical setting. Methods: Ten anaesthetized, female human-sized pigs were acutely catheterized for measurement of pressure–volume loops (conductance catheter), cardiac output (Swan-Ganz catheter) and for vena cava inferior occlusion. Controlled MH (from 37 to 33 °C) was induced by a vena cava inferior cooling catheter. Results: With MH, heart rate (HR) and whole body oxygen consumption decreased, while lactate levels remained normal. Cardiac output, left ventricular (LV) volumes, peak systolic and end-diastolic pressure and dP/dt_max did not change significantly. Changes in dP/dt_min and the time constant of isovolumetric relaxation demonstrated impaired active relaxation. In addition, MH prolonged the systolic and shortened the diastolic time interval. Pressure–volume analysis revealed increased end-systolic and end-diastolic stiffness, indicating positive inotropy and reduced end-diastolic distensibility. Positive inotropy was preserved during pacing, while LV end-diastolic pressure increased and diastolic filling was substantially impaired due to delayed LV relaxation. Conclusion: MH negatively affects diastolic function, which, however, is compensated for by decreased spontaneous HR. Positive inotropy and a decrease in whole body oxygen consumption warrant further studies addressing the potential benefit of MH on the acutely failing heart.     

Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic β-adrenoreceptor activation in rats

We evaluated the relationship between myocardial norepinephrine release or inotropic responsiveness to adrenergic stimulation and intrinsic myocardial function after the progression to pump dysfunction induced by chronic β-adrenoreceptor activation (isoproterenol [ISO], 0.1 mg/kg/day for 1 month or 6 months) in rats. Left ventricular (LV) systolic chamber dysfunction occurred after 6 months, but not after 1 month of β-adrenoreceptor activation, as evidenced by reduced LV endocardial fractional shortening determined by echocardiography and a decrease in the slope of the LV systolic pressure–volume relations assessed in isolated, perfused heart preparations. A reduced pump function at 6 months of ISO administration was associated with chamber dilatation, while LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress–strain relations (isolated heart preparations), indices of intrinsic myocardial function, were unchanged. After 1 month of ISO administration, reduced β₁- and β₂-adrenoreceptor-mediated and sustained α-adrenoreceptor-mediated inotropic responses were noted. Nevertheless, increased inotropic potency of β-adrenoreceptor agonists and upregulation of α-adrenoreceptor-mediated contractile responses were noted after 6 months of ISO administration. Increased adrenergic–inotropic responsiveness after 6 months of ISO administration was associated with depleted LV norepinephrine stores, as evidenced by reduced desipramine-stimulated norepinephrine concentrations in the coronary effluent. In conclusion, in the progression from compensated cardiac hypertrophy to pump dysfunction after chronic sympathetic activation, a preserved intrinsic myocardial contractility is accounted for by paradoxical upregulation of adrenergic-mediated contractile responses.     

Left ventricular performance during exercise in long-term type 1 diabetic men: an echocardiographic study

M-mode echocardiograms were recorded and digitized during semisupine bicycle exercise in 10 young (less than 40 years) long-term (greater than or equal to 12 years) type 1 diabetic men, without heart symptoms, and 10 controls. Recordings were done at rest, during workloads of 50 and 100 W and 1, 3 and 5 min post-exercise. The groups were comparable at rest. Exercise intervention caused a higher heart rate and systolic blood pressure response in the diabetics. Overall, diabetics had a smaller left ventricular (LV) end-diastolic dimension, but it did not change during exercise within either group; LV end-systolic dimensions (ESD), however, decreased in both. The fractional shortening, normalized peak shortening rate and systolic blood pressure/ESD ratio increased in both groups. However, fractional shortening was lower in the diabetics during peak exercise, while the two latter variables of LV systolic function were similar to the controls. Furthermore, fractional shortening during peak exercise remained lower in the diabetics even when adjusted for systolic blood pressure by covariance analysis. Therefore, the decreased LV performance during exercise in the diabetic subjects is most likely secondary to reduced LV diastolic filling, as indicated by their smaller end-diastolic dimension, rather than due to decreased contractility or a higher afterload.     

Preload maintenance and the left ventricular response to prolonged exercise in men

This study examined whether left ventricular function was reduced during 3 h of semi-recumbent ergometer cycling at 70% of maximal oxygen uptake while preload to the heart was maintained via saline infusion. Indices of left ventricular systolic function (end-systolic blood pressure-volume relationship, SBP/ESV) and diastolic filling (ratio of early to late peak filling velocities into the left ventricle, E:A) were calculated during recovery and compared with baseline resting data. During exercise in seven healthy, trained male subjects, an arterial catheter allowed continuous assessment of arterial pressure, stroke volume (SV), cardiac output ( ) and an index of contractility (dP/dt(max)). A venous catheter assessed that central venous pressure (CVP) was maintained throughout rest, exercise and 10 min into recovery. Both systolic blood pressure and heart rate (HR) increased with the onset of exercise (from 132 +/- 5 to 185 +/- 19 mmHg and from 66 +/- 9 to 135 +/- 23 beats min(-1); increases from rest to the end of the first 5 min of exercise in SBP and HR, respectively) but systolic blood pressure did not change from 30 to 180 min of exercise ( approximately 150 mmHg), while heart rate only increased by 8 +/- 9 beats min(-1) (means +/- s.d.; P > 0.05). The attenuated increase in HR compared with other studies suggests that the maintained CVP ( approximately 5 mmHg) helped to prevent cardiovascular drift in this protocol. Stroke volume, and dP/dt(max) were all increased with the onset of exercise (from 85 +/- 8 to 120 +/- 18 ml, from 5.4 +/- 1.3 to 16.5 +/- 3.3 l min(-1) and from 14.4 +/- 4 to 28 +/- 8 mmHg s(-1); values from rest to the end of the first 5 min of exercise for SV, and dP/dt(max), respectively) and were maintained during exercise. There was no difference in the SBP/ESV ratio from pre- to postexercise. Conversely, E:A was reduced from 2.0 +/- 0.4 to 1.6 +/- 0.5 postexercise (P < 0.05), returning to normal values at 24 h postexercise. This change in diastolic filling could not be fully explained (r(2) = 0.39) by an increased heart rate and, with CVP unchanged, it is likely to represent some depression of intrinsic relaxation properties of left ventricular myocytes. Three hours of semi-supine cycling resulted in no evidence of a depression in left ventricular systolic function, while left ventricular diastolic function declined postexercise.     

慢性高输出量型心功能不全发展过程中心室舒、缩功能和顺应性的变化及其与心泵功能的关系

本文研究了大鼠慢性高输出量型心功能不全发展过程中心室舒,缩功能和顺应性的变化规律及其与心泵功能的关系。疾病模型采用动静脉造瘘(ACF)加单侧肾动脉缩窄(RAS)的方法建立。本实验中,全部ACF+RAS大鼠均呈现出慢性高输出量型心功能不全的特征,在静息状态下心脏指数(CI)显著升高,而心泵贮备功能(CORF)却不同程度地降低。结果表明:随心泵功能的恶化,心室的舒、缩功能进行性降低,心室的舒张顺应性显著升高,心室的舒,缩性能和顺应性在心功能不全发展的不同阶段对心泵功能所起的作用不同。     

Exercise-induced cardiac hypertrophy: a substrate for sudden death in athletes?

Cardiac hypertrophy is a general term signifying an increase in cardiac mass in response to applied stress. In mild, early hypertrophy, cardiac myocyte contractile performance may be normal or enhanced, whereas in severe hypertrophy associated with cardiac failure, myocyte contraction is reduced in amplitude and increased in duration. In contrast to the varied contractile response, the duration of electrical excitation shows similar changes in both mild and severe hypertrophy. Action potential duration in mid-myocardial and sub-epicardial layers is increased, which is associated with ventricular arrhythmias (in a similar manner to the long QT syndromes from other causes), based on afterdepolarizations and enhanced automaticity. Single-cell studies following exercise training in animal models show that exercise-induced cardiac hypertrophy displays features similar to mild, compensated hypertrophy from other causes. Developed shortening of unloaded single cells is increased or unchanged, and developed force in single myocytes is enhanced. Action potential duration is increased, apart from in the sub-endocardial layer. As with mild hypertrophy from other causes, this will be pro-arrhythmic because of altered dispersion of repolarization and enhanced automaticity. Major abnormalities of the ECG in man include frequent and complex ventricular ectopy, ST segment changes and prolongation of repolarization. In this review a case is presented for regarding exercise-induced cardiac hypertrophy as being no different from mild cardiac hypertrophy resulting from other, pathological causes. The cellular electrophysiological changes are sufficient to account for many of the abnormalities of the ECG, including high-grade ventricular ectopy. Sudden death in trained athletes who have no evidence of specific heart disease may be a direct consequence of cardiac hypertrophy and altered repolarization.     

Myocardial structural, contractile and electrophysiological changes in the guinea-pig heart failure model induced by chronic sympathetic activation

Widely used murine models of adrenergic-induced cardiomyopathy offer little insight into electrical derangements seen in human heart failure owing to profound differences in the characteristics of ventricular repolarization in mice and rats compared with humans. We therefore sought to determine whether sustained adrenergic activation may produce a clinically relevant heart failure phenotype in the guinea-pig, an animal species whose ventricular action potential shape and restitution properties resemble those determined in humans. Isoprenaline (ISO), a β-adrenoceptor agonist, was infused at variable dosage and duration using either subcutaneously implanted osmotic minipumps or daily injections, in an attempt to establish the relevant treatment protocol. We found that 3 months of daily ISO injections (final dose of 1 mg kg(-1), i.p.) promote heart failure evidenced by cardiac hypertrophy [increased cardiac weights, left ventricular (LV) posterior wall thickness, myocyte cross-sectional area and LV protein content], cardiac dilatation (increased LV internal diameters), basal systolic dysfunction (reduced LV fractional shortening determined by echocardiography and flattened LV systolic pressure-volume and stress-strain relationships assessed in isolated, perfused heart preparations), reduced contractile reserve in the presence of acute β-adrenoceptor stimulation, and pulmonary oedema (increased lung weights). These changes were associated with prolongation of LV epicardial action potential, effective refractory period and QT interval, an upward shift of the electrical restitution curve determined over a wide range of diastolic intervals, and reduced maximal restitution slope. The physiological right ventricular-to-LV difference in action potential duration was eliminated in ISO-treated hearts, thereby contributing to impaired activation-to-repolarization coupling and reversed right ventricular-to-LV difference in repolarization time. In summary, we establish the guinea-pig model of ISO-induced cardiomyopathy, which enables the correlation of detrimental structural and contractile changes with repolarization abnormalities typically seen in human heart failure.     

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.     

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

The effects of hypercholesterolemia on the myocardium per se include electrophysiological and mechanical alterations. Since gap junctions are essential in electromechanical coupling throughout the heart, we examined the correlation between the temporal expression of cardiac connexin 43 (Cx43), contractile function, and conduction velocity in cholesterol-fed rabbits. After a 12-week feeding period, serum cholesterol levels gradually increased (P<0.001). In contrast, expression of cardiomyocyte Cx43 protein progressively decreased (60% reduction at 12 weeks, P<0.001). Such a reduction was also demonstrated by immunoconfocal microscopy, which further showed redistribution of Cx43 gap junctions at the lateral cell membrane. The downregulation of Cx43 protein was associated with increased levels of Cx43 mRNA (3.5 -fold at 12 weeks, P<0.001) and phosphorylated c-Jun N-terminal kinase (three-fold at 12 weeks, P=0.001). Functionally, although fractional shortening of the left ventricle remained unchanged throughout the feeding protocol, the cholesterol-fed rabbits had a reduced cardiac cycle-dependent variation of integrated backscatters, a decreased mitral ring systolic velocity, and an increased modified Tei index (all P<0.001), all of which indicated impaired intrinsic myocardial contractility and attenuated ventricular systolic performance. In Langendorff-perfused hearts of cholesterol-fed rabbits, decreased conduction velocity was observed (P<0.005). Withdrawal of the cholesterol-enriched diet for 18 weeks restored the contractile parameters and Cx43 protein expression. These findings suggest that Cx43 is highly involved in the molecular mechanism of hypercholesterolemia-induced cardiac contractile dysfunction and dysrhythmias.     

The positive action of refracterin on the reserve potentials and metabolism of the myocardium during its overload in toxic-allergic myocarditis

Heart overloading due to pressure as a result of 8 periodic full aortic constriction in heart failure (HF) caused by 10-day toxic-allergic myocarditis (TAM) leads to deterioration of heart contractility (pump function). This is explained by additional decline in functional activity of all three systems of cardiomyocyte responsible for contraction-relaxation. In particular, by a sharp fall of ATP and CP content in the myocardium, a 400% decrease in myofibril power, 200% reduction in efficiency of contraction and marked deterioration of calcium transport. The resultant exhaustion of myocardial reserve brought 70% lethality among the animals. Under the above conditions coordination between the systolic and diastolic cardiac functions, correlation between myocardial functional activity and subcellular systems of cardiomyocyte are impaired. In pressure heart overloading refracterin initiates profound metabolic rearrangements improving metabolism, remodelling of the system of energy supply, reestablishment of systemic homeostasis, normalization of cardiomyocyte and cardiac reserves.     

In Process Citation

Heart overloading due to pressure as a result of 8 periodic full aortic constriction in heart failure (HF) caused by 10-day toxic-allergic myocarditis (TAM) leads to deterioration of heart contractility (pupm function). This is explained by additional decline in functional activity of all three systems of cardiomyocyte responsible for contraction-relaxation. In particular, by a sharp fall of ATP and CP content in the myocardium, a 400% decrease in myofibril power, 200% reduction in efficiency of contraction and marked deterioration of calcium transport. The resultant exhaustion of myocardial reserve brought 70% lethality among the animals. Under the above conditions coordination between the systolic and diastolic cardiac functions, correlation between myocardial functional activity and subcellular systems of cardiomyocyte are impaired. In pressure heart overloading refracterin initiates profound metabolic rearrangements improving metabolism, remodelling of the system of energy supply, reestablishment of systemic homeostasis, normalization of cardiomyocyte and cardiac reserves.     

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.     

Inhibition of left ventricular remodelling preserves chamber systolic function in pressure-overloaded mice

Controversy exists whether the development of left-ventricular hypertrophy (LVH) is a mechanism able to prevent cardiac dysfunction under conditions of pressure overload. In the present study we re-assessed the long-term effects of attenuating LVH by using L- and D-propranolol, which are equally able to inhibit the development of LVH induced by aortic banding. The aortic arch was banded proximal to the left common carotid artery in 71 CD-1 mice that were then assigned randomly to receive L-propranolol, D-propranolol (both 80 mg/kg per day) or vehicle. Concurrently, sham-operated mice were given L-propranolol, D-propranolol or vehicle. LV dimension and performance were evaluated under isoflurane anaesthesia by cine-magnetic resonance imaging, echocardiography and cardiac catheterization up to 8 weeks after surgery. After 2 weeks of pressure overload, the vehicle-treated banded mice had enhanced LV weight, normal chamber size and increased relative wall thickness (concentric hypertrophy), whereas L-propranolol- or D-propranolol-banded mice showed a markedly blunted hypertrophic response, i.e. normal chamber size and normal relative wall thickness, as well as preserved systolic LV chamber function. After 4 weeks, the vehicle-treated banded mice showed LV enlargement with a reduced relative wall thickness (eccentric remodelling) and a clear-cut deterioration in LV systolic function. In contrast, L-propranolol- or D-propranolol-treated banded mice showed normal chamber size with a normal relative wall thickness and preserved systolic function. A distinct histological feature was that in banded mice, L-or D-propranolol attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. At the 8-week stage, LV dysfunction was present in propranolol-treated banded mice although it was much less severe than in vehicle-treated banded mice. It is concluded that (i) deterioration of LV systolic performance is delayed if LV hypertrophy is inhibited, (ii) banding-induced deterioration of LV systolic function is associated with LV eccentric remodelling and (iii) the antihypertrophic effect of propranolol is due to a selective action on cardiomyocytes rather than on collagen accumulation     

Exercise preconditioning attenuates pressure overload-induced pathological cardiac hypertrophy

Pathological cardiac hypertrophy, a common response of the heart to a variety of cardiovascular diseases, is typically associated with myocytes remodeling and fibrotic replacement, cardiac dysfunction. Exercise preconditioning (EP) increases the myocardial mechanical load and enhances tolerance of cardiac ischemia-reperfusion injury (IRI), however, is less reported in pathological cardiac hypertrophy. To determine the effect of EP in pathological cardiac hypertrophy, Male 10-wk-old Sprague-Dawley rats (n=30) were subjected to 4 weeks of EP followed by 4-8 weeks of pressure overload (transverse aortic constriction, TAC) to induce pathological remodeling. TAC in untrained controls (n=30) led to pathological cardiac hypertrophy, depressed systolic function. We observed that left ventricular wall thickness in end diastole, heart size, heart weight-to-body weight ratio, heart weight-to-tibia length ratio, cross-sectional area of cardiomyocytes and the reactivation of fetal genes (atrial natriuretic peptide and brain natriuretic peptide) were markedly increased, meanwhile left ventricular internal dimension at end-diastole, systolic function were significantly decreased by TAC at 4 wks after operation (P < 0.01), all of which were effectively inhibited by EP treatment (P < 0.05), but the differences of these parameters were decreased at 8 wks after operation. Furthermore, EP treatment inhibited degradation of IκBα, and decreased NF-κB p65 subunit levels in the nuclear fraction, and then reduced IL2 levels in the myocardium of rats subject to TAC. EP can effectively attenuate pathological cardiac hypertrophic responses induced by TAC possibly through inhibition of degradation of IκB and blockade of the NF-κB signaling pathway in the early stage of pathological cardiac hypertrophy.     

Role of cannabinoid receptors in the regulation of cardiac contractility during ischemia/reperfusion

We studied the effect of selective ligands of cannabinoid (CB) receptors on contractility of isolated Langendorff-perfused rat heart under conditions of 45-min total ischemia and 30-min reperfusion. Perfusion with a solution containing selective CB receptor agonist HU-210 for 10 min before ischemia increased the severity of reperfusion contractile dysfunction. This drug decreased left ventricular developed pressure and maximum rates of contraction and relaxation, but had no effect on heart rate and end-diastolic pressure. The negative inotropic effect of the drug was transitory and disappeared after 5-min reperfusion. Pretreatment with selective CB1 receptor antagonist SR141716A and selective CB2 receptor antagonist SR144528 had no effect on heart rate and myocardial contractility during reperfusion. Our results indicate that stimulation of CB receptors can increase the degree of reperfusion-induced cardiac contractile dysfunction. However, endogenous cannabinoids are not involved in the development of myocardial contractile dysfunction during ischemia/reperfusion of the isolated heart. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 11, pp. 500–504, November, 2006