Reduction In Contractile Performance Research Articles

Profiling the Biomechanical Responses to Workload on the Human Myocyte to Explore the Concept of Myocardial Fatigue and Reversibility: Rationale and Design of the POWER Heart Failure Study.

It remains unclear why some patients develop heart failure without evidence of structural damage. One theory relates to impaired myocardial energetics and ventricular-arterial decoupling as the heart works against adverse mechanical load. In this original study, we propose the novel concept of myocardial fatigue to capture this phenomenon and aim to investigate this using human cardiomyocytes subjected to a modern work-loop contractility model that closely mimics in vivo cardiac cycles. This proof-of-concept study (NCT04899635) will use human myocardial tissue samples from patients undergoing cardiac surgery to develop a reproducible protocol to isolate robust calcium-tolerant cardiomyocytes. Thereafter, work-loop contractility experiments will be performed over a range of preload, afterload and cycle frequency as a function of time to elicit any reversible reduction in contractile performance (i.e. fatigue). This will provide novel insight into mechanisms behind heart failure and myocardial recovery and serve as a valuable research platform in translational cardiovascular research.

Investigating a dose-response relationship between high-fat diet consumption and the contractile performance of isolated mouse soleus, EDL and diaphragm muscles.

Recent evidence has demonstrated an obesity-induced, skeletal muscle-specific reduction in contractile performance. The extent and magnitude of these changes in relation to total dose of high-fat diet consumption remains unclear. This study aimed to examine the dose-response relationship between a high-fat diet and isolated skeletal muscle contractility. 120 female CD1 mice were randomly assigned to either control group or groups receiving 2, 4, 8 or 12 weeks of a high-calorie diet (N = 24). At 20weeks, soleus, EDL or diaphragm muscle was isolated (n = 8 in each case) and isometric force, work loop power output and fatigue resistance were measured. When analysed with respect to feeding duration, there was no effect of diet on the measured parameters prior to 8weeks of feeding. Compared to controls, 8-week feeding caused a reduction in normalised power of the soleus, and 8- and 12-week feeding caused reduced normalised isometric force, power and fatigue resistance of the EDL. Diaphragm from the 12-week group produced lower normalised power, whereas 8- and 12-week groups produced significantly lower normalised isometric force. Correlation statistics indicated that body fat accumulation and decline in contractility will be specific to the individual and independent of the feeding duration. The data indicate that a high-fat diet causes a decline in muscle quality with specific contractile parameters being affected in each muscle. We also uniquely demonstrate that the amount of fat gain, irrespective of feeding duration, may be the main factor in reducing contractile performance.

The effect of obesity on the contractile performance of isolated mouse soleus, EDL, and diaphragm muscles.

The effect of obesity on isolated muscle function is surprisingly underresearched. The present study is the first to examine the effects of obesity on isolated muscle performance using a method that more closely represents real-world muscle function. This work uniquely establishes a muscle-specific profile of mechanical changes in relation to underpinning mechanisms. These findings may be important to understanding the negative cycle of obesity and in designing interventions for improving weight status.

Pathomechanisms in heart failure: the contractile connection.

Heart failure is a multi-factorial progressive disease in which eventually the contractile performance of the heart is insufficient to meet the demands of the body, even at rest. A distinction can be made on the basis of the cause of the disease in genetic and acquired heart failure and at the functional level between systolic and diastolic heart failure. Here the basic determinants of contractile function of myocardial cells will be reviewed and an attempt will be made to elucidate their role in the development of heart failure. The following topics are addressed: the tension generating capacity, passive tension, the rate of tension development, the rate of ATP utilisation, calcium sensitivity of tension development, phosphorylation of contractile proteins, length dependent activation and stretch activation. The reduction in contractile performance during systole can be attributed predominantly to a loss of cardiomyocytes (necrosis), myocyte disarray and a decrease in myofibrillar density all resulting in a reduction in the tension generating capacity and likely also to a mismatch between energy supply and demand of the myocardium. This leads to a decline in the ejection fraction of the heart. Diastolic dysfunction can be attributed to fibrosis and an increase in titin stiffness which result in an increase in stiffness of the ventricular wall and hampers the filling of the heart with blood during diastole. A large number of post translation modifications of regulatory sarcomeric proteins influence myocardial function by altering calcium sensitivity of tension development. It is still unclear whether in concert these influences are adaptive or maladaptive during the disease process.

Competitive displacement of phosphoinositide 3-kinase from β-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling

Adverse remodeling after myocardial infarction (MI) determines the progression of heart failure. Failing hearts are characterized by downregulation of beta-adrenergic receptor (beta-AR) signaling in part because of increased beta-AR kinase 1 activity. Our previous studies have shown that overexpression of the phosphoinositide kinase (PIK) domain of phosphoinositide 3-kinase (PI3K), prevents beta-AR downregulation and enhances adrenergic agonist responsiveness by inhibiting the targeting of PI3K to the beta-AR complex. To investigate whether preventing beta-AR downregulation in the heart ameliorates cardiac function post-MI, transgenic mice with cardiac-specific overexpression of the PIK domain peptide (TgPIK) underwent left coronary artery ligation and were subsequently followed by serial echocardiography at 4, 8, 12, 16, and 20 wk. Despite having similar infarction sizes, TgPIK mice showed better systolic function, less cardiac dilatation, and improved hemodynamic response to dobutamine compared with littermate controls after MI. To test that displacement of PI3K from the beta-AR complex, but not the total loss of PI3K-gamma, is critical for amelioration of cardiac function, mice lacking the PI3K-gamma (PI3K-gamma-KO) underwent MI, and their cardiac function was assessed 20 wk post-MI. Serial echocardiographic measurements showed severe reduction in contractile performance in PI3K-gamma-KO compared with TgPIK mice. Furthermore, significant beta-AR downregulation and desensitization were only seen in infarcted wild-type and PI3K-gamma-KO mice and not in TgPIK mice. Together, these results demonstrate that adverse remodeling of the ventricle after MI can be attenuated by a strategy that prevents recruitment of PI3K to the plasma membrane and restores normal beta-AR function.

Essential myosin light chain as a target for caspase-3 in failing myocardium.

Programmed cell death involves the activation of caspase proteases that can mediate the cleavage of vital cytoskeletal proteins. We have recently reported that, in failing cardiac myocytes, caspase-3 activation is associated with a reduction in contractile performance. In this study we used a modified yeast two-hybrid system to screen for caspase-3 interacting proteins of the cardiac cytoskeleton. We identified ventricular essential myosin light chain (vMLC1) as a target for caspase-3. By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE(135)G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance. Adenoviral gene transfer of the caspase inhibitor p35 in vivo prevented caspase-3 activation and vMLC1 cleavage, with positive impact on contractility. These data suggest that direct cleavage of vMLC1 by activated caspase-3 may contribute to depression of myocyte function by altering cross-bridge interaction between myosin and actin molecules. Therefore, activation of apoptotic pathways in the heart may lead to contractile dysfunction before cell death.

The role of calcium in the regulation of glucose uptake in isolated working rat heart.

Catecholamines or ischemia may increase myocardial glucose uptake by an increase in intracellular calcium. We tested the hypothesis that increasing or decreasing extracellular calcium supply would change glucose uptake. Hearts were perfused for 60 min at a physiological workload with Krebs-Henseleit buffer containing glucose (5 mM) and oleate (0.4 mM; bound to 1% BSA). Calcium concentration was 2.5 mM. In group A (control; n = 12), insulin (1 mU/ml) was added at 30 min. In Group B (n = 7), the calcium concentration was increased to 5.0 and 7.5 mM at 20 min and 40 min, respectively. In Group C (n = 7), verapamil was added at 20 min (0.25 microM) and 40 min (1.0 microM) to decrease calcium influx. In group D (n = 7), EDTA was added at 20 min (0.5 mM) and at 40 min (1.5 mM) to decrease the free extracellular calcium. Glucose uptake was measured by 3H2O production from [2-3H]glucose and cardiac work was measured simultaneously. Cardiac power in group B was 8.24 +/- 0.60 mW at 2.5 mM calcium, 9.45 +/- 0.50 mW at 5 mM calcium and 7.99 +/- 0.99 mW at 7.5 mM calcium (n.s.). The addition of verapamil decreased contractile function in a dose-dependent manner (8.50 +/- 0.74 vs. 3.11 +/- 0.84 vs. 1.48 +/- 0.39 mW, p < 0.01) suggesting that verapamil decreased cytosolic calcium concentration. A similar dose-dependent reduction in contractile performance was observed in the EDTA group (8.44 +/- 0.81 vs. 7.42 +/- 0.96 vs. 4.03 +/- 1.32 mW, p < 0.01). Glucose uptake was 1.35 +/- 0.11 micromol/min/g dry weight under control conditions. Glucose uptake increased threefold with the addition of insulin. Increasing extracellular [Ca2+] did not affect glucose uptake. Decreasing Ca2+ availability showed a trend towards a decrease in glucose uptake (n.s.), which was minor compared to the decrease in contractile function. We conclude that extracellular calcium does not regulate glucose uptake in the isolated working rat heart in the presence of glucose and fatty acids as substrates. The trend of decreased glucose uptake when calcium supply was limited may be due to dramatically reduced energy demand and not directly due to changes in calcium.

Influence of oxygen radicals generated by xanthine oxidase in the isolated perfused rat heart.

To investigate the cardiac effects of enzymatically generated oxygen radicals isolated Langendorff rat heart preparations were perfused with hypoxanthine (0.96 mmol X litre-1) plus xanthine oxidase (0.025 U X ml-1). Oxygen radicals produced an immediate increase in coronary flow. After 10 min a pronounced reduction in contractile performance, as well as in concentrations of high energy phosphates, was seen. Electron microscopical examination showed damage with cellular oedema as a prominent finding. These effects were all effectively reversed by the specific enzymes, superoxide dismutase and catalase, proving that they were due to oxygen radicals.

EFFECT OF CYCLOPROPANE ON CONTRACTILE PERFORMANCE OF CARDIAC MUSCLE WITH EXPERIMENTAL CHRONIC HEART FAILURE

The effect of cyclopropane on contractile performance of papillary muscles obtained from cats with congestive heart failure induced by pulmonary artery constriction was studied and compared with non-operated normal animals. A significant depression of contractile performance in the papillary muscles of cats with congestive heart failure was observed along with elevated right ventricular pressure and reduced cardiac index. In both groups of muscles, cydopropane caused a shift of the force-velocity curve to the left and downward. At an equipotent anaesthetic concentration (MAC) of cyclopropane, reduction in contractile performance was similar in both muscles. When changes in velocity of shortening and maximal isometric force in muscles with congestive heart failure were compared with the control values of normal muscles at MAC, the depression was 49% and 44% respectively. However, the effect of cyclopropane on the diseased muscle was significantly less than that of either isoflurane or halothane.