Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphericalization of the left ventricular (LV) chamber shape in patients with mitral regurgitation (MR) contributes to increased LV wall stress and energy consumption. On the basis of previous observations, we hypothesized the existence of regional differences in the force-frequency relation (FFR) within the LV that may contribute to its shape. Accordingly, in the present study, we assessed regional variation in the FFR in patients undergoing surgery for chronic, nonischemic MR with class II-III heart failure symptoms and related our findings to the in vivo LV shape. FFRs (steady-state isometric twitches, 0.2-3.4 Hz, 37 degrees C) were evaluated in MR myocardium from the LV subepicardial free wall (MR-FW) and papillary muscle (MR-PM) and from the subepicardial free wall in coronary artery bypass graft patients with normal LV contraction patterns [nonfailing (NF)]. Ascending slope, optimal stimulation frequency, and maximal twitch tension of the FFR were depressed in MR-FW and MR-PM compared with NF (P < 0.05). FFR depression was greater in MR-PM than in MR-FW. Between 107 and 134 beats/min, twitch tension became weaker in MR-PM, whereas it increased in MR-FW. Elevation of intracellular cAMP with forskolin eliminated FFR depression in MR-FW but not in MR-PM. MR-PM also had a 35% lower myosin heavy chain content and slowed twitch kinetics. In MR patients, the echocardiographic end-diastolic LV shape (end-diastolic eccentricity index = long axis/short axis) correlated with the ratio of ascending FFR slopes such that the end-diastolic eccentricity index increased 10% per 15% increase in slope ratio (r = 0.88, P = 0.01). These regional differences in the frequency dependence of contractility between the free wall and papillary myocardium may contribute to changes in LV shape in MR as well as during exercise.
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PMID:Regional differences in the force-frequency relation of human left ventricular myocardium in mitral regurgitation: implications for ventricular shape. 1563 16

Thyroid hormones (TH) enhance cardiac function and reverse gene changes typical of pathological hypertrophy. However, reports in humans, but not animals, indicate that excess TH can cause heart failure. Also, the effects of TH on normal and cardiomyopathic hearts are likely to be different. The goal of this study was to characterize the effects of prolonged hyperthyroidism on cardiac function, chamber and cellular remodeling, and protein expression in both normal and cardiomyopathic hearts. Hyperthyroidism was induced in 3-mo-old normal BIO F1B and dilated cardiomyopathic BIO TO2 hamsters. After TH treatment for 10 days and 2 mo, hemodynamics, echos, myocyte length, histology, and protein expression were assessed. After 10 days and 2 mo, there were no differences between TO2-treated (Tx) and TO2-untreated (Untx) hamsters in chamber diameters or left ventricular function. After 2 mo of treatment, however, F1B-Tx showed evidence of dilated heart failure vs. F1B-Untx. Chamber diameters were increased, and ejection fraction and positive and negative changes in pressure over time were reduced. In F1B-Tx and TO2-Tx hamsters, beta-myosin isoform expression was reduced, whereas alpha-myosin increased significantly in F1B-Tx only. In TO2-Tx hamsters, the percent of viable myocardium was increased, and percent fibronecrosis was reduced vs. TO2-Untx. Myocyte length increased with TH treatment in both hamster strains. We conclude that 1) excess TH can induce heart failure in normal animals as observed in humans, 2) reversal of myosin heavy chain expression does not necessarily improve heart function, and 3) excess TH altered cellular remodeling but did not adversely affect chamber function or dimensions in TO2 hamsters.
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PMID:Effects of induced hyperthyroidism in normal and cardiomyopathic hamsters. 1597 57

Data regarding the effectiveness of chronic exercise training in improving survival in patients with congestive heart failure (CHF) are inconclusive. Therefore, we conducted a study to determine the effect of exercise training on survival in a well-defined animal model of heart failure (HF), using the lean male spontaneously hypertensive HF (SHHF) rat. In this model, animals typically present with decompensated, dilated HF between approximately 18 and 23 mo of age. SHHF rats were assigned to sedentary or exercise-trained groups at 9 and 16 mo of age. Exercise training consisted of 6 mo of low-intensity treadmill running. Exercise training delayed the onset of overt HF and improved survival (P < 0.01), independent of any effects on the hypertensive status of the rats. Training delayed the myosin heavy chain (MyHC) isoform shift from alpha- to beta-MyHC that was seen in sedentary animals that developed HF. Exercise was associated with a concurrent increase in cardiomyocyte length (approximately 6%), width, and area and prevented the increase in the length-to-width ratio seen in sedentary animals in HF. The increases in proteinuria, plasma atrial natriuretic peptide, and serum leptin levels observed in rats with HF were suppressed by low-intensity exercise training. No significant alterations in sarco(endo)plasmic reticulum Ca2+ ATPase, phospholamban, or Na+/Ca2+ exchanger protein expression were found in response to training. Our results indicate that 6 mo of low-intensity exercise training delays the onset of decompensated HF and improves survival in the male SHHF rat. Similarly, exercise intervention prevented or suppressed alterations in several key variables that normally occur with the development of overt CHF. These data support the idea that exercise may be a useful and inexpensive intervention in the treatment of HF.
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PMID:Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats. 1599 55

Isometric force production and ATPase activity were determined simultaneously in single human skeletal muscle fibers (n = 97) from five healthy volunteers and nine patients with chronic heart failure (CHF) at 20 degrees C. The fibers were permeabilized by means of Triton X-100 (1% vol/vol). ATPase activity was determined by enzymatic coupling of ATP resynthesis to the oxidation of NADH. Calcium-activated actomyosin (AM) ATPase activity was obtained by subtracting the activity measured in relaxing (pCa = 9) solutions from that obtained in maximally activating (pCa = 4.4) solutions. Fiber type was determined on the basis of myosin heavy chain isoform composition by polyacrylamide SDS gel electrophoresis. AM ATPase activity per liter cell volume (+/-SE) in the control and patient group, respectively, amounted to 134 +/- 24 and 77 +/- 9 microM/s in type I fibers (n = 11 and 16), 248 +/- 17 and 188 +/- 13 microM/s in type IIA fibers (n = 14 and 32), 291 +/- 29 and 126 +/- 21 microM/s in type IIA/X fibers (n = 3 and 5), and 325 +/- 32 and 205 +/- 21 microM/s in type IIX fibers (n = 7 and 9). The maximal isometric force per cross-sectional area amounted to 64 +/- 7 and 43 +/- 5 kN/m(2) in type I fibers, 86 +/- 11 and 58 +/- 4 kN/m(2) in type IIA fibers, 85 +/- 6 and 42 +/- 9 kN/m(2) in type IIA/X fibers, and 90 +/- 5 and 59 +/- 5 kN/m(2) in type IIX fibers in the control and patient group, respectively. These results indicate that, in CHF patients, significant reductions occur in isometric force and AM ATPase activity but that tension cost for each fiber type remains the same. This suggests that, in skeletal muscle from CHF patients, a decline in density of contractile proteins takes place and/or a reduction in the rate of cross-bridge attachment of approximately 30%, which exacerbates skeletal muscle weakness due to muscle atrophy.
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PMID:Depression of force production and ATPase activity in different types of human skeletal muscle fibers from patients with chronic heart failure. 1605 11

Changes in myosin heavy chain (MHC) isoform expression and protein composition occur during cardiac disease and it has been suggested that even a minor shift in MHC composition may exert a considerable effect on myocardial energetics and performance. Here an overview is provided of the cellular basis of the energy utilisation in cardiac tissue and novel data are presented concerning the economy of myocardial contraction in diseased atrial and ventricular human myocardium. ATP utilisation and force development were measured at various Ca(2+) concentrations during isometric contraction in chemically skinned atrial trabeculae from patients in sinus rhythm (SR) or with chronic atrial fibrillation (AF) and in ventricular muscle strips from non-failing donor or end-stage failing hearts. Contractile protein composition was analysed by one-dimensional gel electrophoresis. Atrial fibrillation was accompanied by a significant shift from the fast alpha-MHC isoform to the slow beta-MHC isoform, whereas both donor and failing ventricular tissue contained almost exclusively the beta-MHC isoform. Simultaneous measurements of force and ATP utilisation indicated that economy of contraction is preserved in atrial fibrillation and in end-stage human heart failure.
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PMID:Myosin heavy chain composition and the economy of contraction in healthy and diseased human myocardium. 1608 76

Diabetic heart failure may be causally associated with alterations in cardiac energy metabolism and insulin resistance. Mice with heart-specific overexpression of peroxisome proliferator-activated receptor (PPAR)alpha showed a metabolic and cardiomyopathic phenotype similar to the diabetic heart, and we determined tissue-specific glucose metabolism and insulin action in vivo during hyperinsulinemic-euglycemic clamps in awake myosin heavy chain (MHC)-PPARalpha mice (12-14 weeks of age). Basal and insulin-stimulated glucose uptake in heart was significantly reduced in the MHC-PPARalpha mice, and cardiac insulin resistance was mostly attributed to defects in insulin-stimulated activities of insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase, Akt, and tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Interestingly, MHC-PPARalpha mice developed hepatic insulin resistance associated with defects in insulin-mediated IRS-2-associated PI 3-kinase activity, increased hepatic triglyceride, and circulating interleukin-6 levels. To determine the underlying mechanism, insulin clamps were conducted in 8-week-old MHC-PPARalpha mice. Insulin-stimulated cardiac glucose uptake was similarly reduced in 8-week-old MHC-PPARalpha mice without changes in cardiac function and hepatic insulin action compared with the age-matched wild-type littermates. Overall, these findings indicate that increased activity of PPARalpha, as occurs in the diabetic heart, leads to cardiac insulin resistance associated with defects in insulin signaling and STAT3 activity, subsequently leading to reduced cardiac function. Additionally, age-associated hepatic insulin resistance develops in MHC-PPARalpha mice that may be due to altered cardiac metabolism, functions, and/or inflammatory cytokines.
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PMID:Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver. 1612 38

Chronic heart failure is characterized by changes in skeletal muscle that contribute to exercise intolerance and muscle weakness. To determine whether changes in the quantity and isoform distribution of key myofibrillar proteins are related to altered gene expression, we measured skeletal muscle myofibrillar mRNA abundance in nine heart failure patients (mean +/- SE; 63 +/- 3 yr) and nine controls (70 +/- 3 yr). In addition, we assessed the relationship of circulating levels of anabolic and catabolic hormones, as well as local expression of insulin-like growth factor (IGF)-I, to myofibrillar mRNA abundance. Heart failure patients were characterized by lower abundance of mRNA encoding the myosin heavy chain (MHC) I isoform (P < 0.01), whereas MHC IIa and MHC IIx mRNA did not differ between groups. Actin mRNA was also lower in heart failure patients compared with controls (P < 0.001). The expression of each MHC isoform transcript correlated with its respective protein product (MHC I: r = 0.656, P < 0.01; MHC IIa: r = 0.489, P < 0.05; MHC IIx: r = 0.505, P < 0.05; n = 18 for all). In addition to changes in myofibrillar transcripts, we found lower (P < 0.01) skeletal muscle IGF-1Ea mRNA content in heart failure patients. Myofibrillar mRNA levels were positively associated with skeletal muscle IGF-1Ea transcript levels (range of r values: 0.663-0.765; P values: <0.01 to <0.001) and modestly associated with circulating markers of immune activation (range of r values: -0.487 to -0.555; P values: <0.05 to <0.03). Our findings suggest that alterations in skeletal muscle MHC content and isoform distribution in heart failure may derive, in part, from changes in MHC gene expression. The relationships of myofibrillar mRNA content to both local and circulating hormones further suggest that alterations in the balance between anabolic and catabolic hormones in heart failure patients may influence skeletal muscle myofibrillar protein phenotype by altering gene expression.
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PMID:Skeletal muscle myofibrillar mRNA expression in heart failure: relationship to local and circulating hormones. 1614 80

Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.
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PMID:Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. 1621 Apr 42

Chronic heart failure remains a leading cause of mortality. Although granulocyte colony-stimulating factor (G-CSF) is reported to have a beneficial affect on postinfarction cardiac remodeling and dysfunction when administered before the onset of or at the acute stage of myocardial infarction (MI), its effect on established heart failure is unknown. We show here that subcutaneous administration of G-CSF greatly improves the function of murine hearts failing due to a large, healed MI. G-CSF changed the geometry of the infarct scar from elongated and thin to short and thick, induced hypertrophy among surviving cardiomyocytes, and reduced myocardial fibrosis. Expression of G-CSF receptor was confirmed in failing hearts and was upregulated by G-CSF treatment. G-CSF treatment also led to activation of signal transducer and activator of transcription-3 and induction of GATA-4 and various sarcomeric proteins such as myosin heavy chain, troponin I and desmin. Expression of metalloproteinase-2 and -9 was also increased in G-CSF-treated hearts, while that of tumor necrosis factor-alpha, angiotensin II type 1 receptor (AT1) and transforming growth factor-beta1 was reduced. Although activation of Akt was noted in G-CSF-treated hearts, vessel density was unchanged, and apoptosis was too rare to exert a meaningful effect. No bone marrow-derived cardiomyocytes or vascular cells were detected in the failing hearts of green fluorescent protein chimeric mice. Finally, beneficial effects of G-CSF on cardiac function were found persisting long after discontinuing the treatment (2 weeks). Collectively, these findings suggest G-CSF administration could be an effective approach to treating chronic heart failure following a large MI.
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PMID:Treatment with granulocyte colony-stimulating factor ameliorates chronic heart failure. 1630 79

Modifications in thick filament protein content and performance are thought to underlie contraction-relaxation dysfunction in human heart failure. It has been found that myofibrillar Mg.ATPase is reduced in failing myocardium, which may be due in part to the reduction in alpha-myosin heavy chain (MHC) isoform content from approximately 5-10% in normal myocardium to <2% in failing myocardium. The physiological importance of this seemingly small amount of alpha-MHC appears substantiated by the development of cardiopathologies in humans with mutated alpha-MHC at normal abundance. Therefore, the replacement of alpha-MHC by beta-MHC (possessing slower actomyosin enzymatic kinetics) may underlie to a significant degree the reduced myocardial shortening velocity and reduced relaxation function in human heart failure. The atrial isoform of myosin essential light chain (ELC) may replace up to 25% of the ventricular isoform in failing ventricles and in so doing promotes myocardial shortening velocity. An elevated accumulation of the higher performing atrial-ELC, unlike the reduced content of the higher performing alpha-MHC, is therefore considered a compensatory response in heart failure. Phosphorylation of the myofilament proteins myosin regulatory light chain and troponin-I are both reduced in heart failure and collectively result in an elevated myofilament sensitivity to calcium activation, which inhibits relaxation function. These and other modifications in thick filament proteins, as discussed in this review, directly affect mechanical power output and relaxation function of the myocardium and thereby may be considered to cause or in some cases to compensate for the otherwise ineffective myocardial performance in heart failure.
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PMID:Thick filament proteins and performance in human heart failure. 1641 42


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