The effects of growth hormone supplementation on left ventricular function with the development of congestive heart failure.
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Animals↗
Biomedical subjects
F G Spinale
Publications and source records attributed to F G Spinale.
Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure.
BACKGROUND: Release of growth hormone (GH), putatively through alterations in insulin growth factor-1 (IGF-1) levels, has been implicated to influence left ventricular (LV) myocardial structure and function. The objective of this study was to determine contributory mechanisms by which GH supplementation may influence LV function with the development of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were assigned to the following groups: (1) chronic pacing at 240 bpm for 3 weeks (n = 10), (2) chronic pacing and GH supplementation (200 microg x kg(-1) x d(-1), n = 10), and (3) controls (n = 8). GH treatment increased IGF-1 plasma levels by nearly 2.5-fold throughout the pacing protocol. In the untreated pacing CHF group, LV fractional shortening was reduced and peak wall stress increased. In the pacing CHF and GH groups, LV fractional shortening was higher and LV wall stress lower than untreated CHF values. Steady-state myocyte velocity of shortening was reduced with pacing CHF and was unchanged from CHF values with GH treatment. In the presence of 25 nmol/L isoproterenol, the change in myocyte shortening velocity was reduced in the untreated CHF group and increased in the GH-treated group. LV sarcoplasmic reticulum Ca(2+)-ATPase abundance was reduced with pacing CHF but was normalized with GH treatment. CONCLUSIONS: Short-term GH supplementation improved LV pump function in pacing CHF as a result of favorable effects on LV remodeling and contractile processes. Thus, GH supplementation may serve as a novel therapeutic modality in developing CHF.
Animals↗
Matrix metalloproteinase inhibition during the development of congestive heart failure : effects on left ventricular dimensions and function.
The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi, rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CHF, LV fractional shortening was reduced (19+/-1 versus 45+/-1%), and end-diastolic dimension increased (5.67+/-0.11 versus 3.55+/-0.05 cm), compared with baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shortening increased (25+/-2%) and the end-diastolic dimension was reduced (4.92+/-0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and was significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte length was increased with pacing CHF compared with controls (180+/-3 versus 125+/-4 microm, P<0.05) and was reduced in the CHF/MMPi group (169+/-4 microm, P<0.05). Basal-state myocyte shortening velocity was reduced with pacing CHF compared with controls (33+/-2 versus 66+/-1 microm/s, P<0.05) and was unchanged in the CHF/MMPi group (31+/-2 microm/s). Using an ex vivo assay system, myocardial MMP activity was increased with pacing CHF and was reduced with chronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dilation and reduced wall stress. These results suggest that increased myocardial MMP activity contributes to LV myocardial remodeling in developing CHF.
Animals↗
Amlodipine therapy in congestive heart failure: hemodynamic and neurohormonal effects at rest and after treadmill exercise.
This study examined the acute effects of amlodipine treatment on left ventricular pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF), both at rest and with treadmill exercise. A total of 14 pigs were studied under control conditions and after the development of pacing-induced CHF (240 beats per minute, 3 weeks, n = 7) or with CHF and acute amlodipine treatment for the last 3 days of pacing (1.5 mg/kg per day, n = 7). Under resting conditions, left ventricular stroke volume (mL) was reduced with CHF compared with the normal state (15+/-2 vs. 31+/-1, p<0.05) and increased with amlodipine treatment (23+/-4, p<0.05). At rest, systemic vascular resistance increased with CHF compared with the normal state (3,078+/-295 vs. 2,131+/-120 dyne x s cm(-5), p<0.05) and was reduced after amlodipine treatment (2,472+/-355 dyne x s cm(-5), p<0.05). With exercise, left ventricular stroke volume remained lower and systemic vascular resistance higher in the CHF group, but was normalized with amlodipine treatment. With exercise, left ventricular myocardial blood flow increased from resting values, but was reduced from the normal state with CHF (normal: 1.69+/-0.12 to 7.62+/-0.74 mL/min per gram vs. CHF: 1.26+/-0.12 to 4.77+/-0.45 mL/min per gram, both p<0.05) and was normalized with acute amlodipine treatment (1.99+/-0.35 to 6.29+/-1.23 mL/min per gram). Resting plasma norepinephrine was increased by >5-fold in the CHF group at rest and was not affected by amlodipine treatment. However, with exercise, amlodipine treatment blunted the increase in plasma norepinephrine by >50% when compared with untreated CHF values. Resting plasma endothelin levels increased with CHF compared with the normal state (10.9+/-0.9 vs. 2.8+/-0.4 fmol/mL, p<0.05) and was reduced with amlodipine treatment (7.5+/-1.5 fmol/mL, p<0.5). In other vascular beds, acute amlodipine treatment with CHF improved pulmonary and renal blood flow both at rest and with exercise; however, there were no effects observed on skeletal muscle blood flow. With the development of CHF, acute amlodipine treatment does not negatively influence left ventricular pump function, but rather may provide favorable hemodynamic and neurohormonal effects.
Amlodipine↗
Defects in matrix metalloproteinase inhibitory stoichiometry and selective MMP induction in patients with nonischemic or ischemic dilated cardiomyopathy.
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Cardiomyopathy, Dilated↗
Effects of angiotensin type-I receptor blockade on pericardial fibrosis.
BACKGROUND: Reoperative cardiac surgical procedures are associated with a significantly greater complication rate than that of the initial procedure. Enhanced collagen synthesis can occur due to increased production of angiotensin II (Ang-II) and subsequent activation of Ang AT(1) receptor. Accordingly, the goal of the current study is to test the hypothesis that increased Ang AT(1) receptor activity following pericardiotomy contributes to pericardial thickening and fibrosis. MATERIALS AND METHODS: Adult pigs were randomly assigned to three protocols: (1) pericardiotomy with 28-day recovery period (n = 5); (2) pericardiotomy with Ang AT(1) receptor blockade instituted throughout the 28-day recovery period using 60 mg/day valsartan (n = 5); and (3) sham controls (n = 6). Pericardium samples were collected and analyzed by biochemical and histomorphometrical methods. Pericardial fibrosis occurred postpericardiotomy as indicated by increased hydroxyproline content from normal value of 50 +/- 3 microg/mg to 75 +/- 4 microg/mg (P < 0. 05). RESULTS: Pericardial thickness was increased postpericardiotomy to 2.7 +/- 0.4 mm compared to normal values of 0.4 +/- 0.05 mm (P < 0.05). Ang AT(1) receptor blockade reduced pericardial thickness by 50% and the relative degree of fibrosis was comparable to that of the normal group. CONCLUSIONS: The results from this pericardial fibrosis animal model suggest that Ang AT(1) receptor activation contributes to the development of pericardial thickening and collagen accumulation in the postoperative period. Thus, Ang AT(1) receptor inhibition may provide a novel therapeutic strategy to prevent pericardial fibrosis that follows cardiac surgical procedures.
Angiotensin Receptor Antagonists↗
Inducible lethal ventricular arrhythmias in swine with pacing-induced heart failure.
INTRODUCTION: Rapid pacing-induced heart failure provides an excellent animal model for the study of heart failure. We studied the development of ventricular tachyarrhythmias using programmed stimulation in a pacing-induced heart failure model. We also studied action potential characteristics and the relationship between action potential and heart rate. METHODS AND RESULTS: Ten pigs were instrumented and were studied before the onset and every week after rapid pacing was instituted. Weekly echocardiograms and programmed stimulation were done in a sedated state. In vitro electrophysiologic studies were done on left ventricular myocardium in 4 heart-failure animals and 4 controls. All animals developed progressive heart failure with left ventricular dilatation and reduced percentage fractional shortening. No arrhythmias were induced at baseline or the first and second weeks. Ventricular fibrillation was induced in one animal on the third week and 4 animals on week 4, while there was no appreciable worsening in echocardiographic indices of ventricular dysfunction between weeks 3 and 4. Ventricular effective refractory period was unchanged during the 4 weeks. In vitro studies showed action potential prolongation in heart failure myocardium. However, action potential duration at pacing rates >100 bpm were similar to controls. No early or delayed afterdepolarizations were observed. CONCLUSION: This study demonstrated an increased susceptibility to ventricular fibrillation with the development of heart failure which was not related to the degree of ventricular dysfunction. Also, the normalization of action potential duration at higher heart rates suggests that the increased incidence of inducible ventricular fibrillation in this model may not be solely due to prolonged action potential duration.
Animals↗
Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest.
Transient left ventricular (LV) dysfunction can occur after hypothermic hyperkalemic cardioplegic arrest. This laboratory has developed an isolated LV myocyte system of simulated cardioplegic arrest and rewarming in order to examine cellular and molecular events that may contribute to the LV dysfunction after cardioplegic arrest. Contractile function was examined using high-speed video microscopy after reperfusion and rewarming. After cardioplegic arrest and reperfusion, indices of myocyte contractility were reduced by over 40% from normothermic control values. The capacity of the myocyte to respond to an inotropic stimulus was examined through beta-adrenergic receptor stimulation with isoproterenol. After cardioplegic arrest, the contractile response to isoproterenol was reduced by over 50% from normothermic values. The next series of studies focused upon preventing these changes in myocyte contractile processes after cardioplegic arrest. First, the cardioplegic solutions were augmented with adenosine or an ATP-sensitive potassium channel opener, aprikalim. Both adenosine and aprikalim augmentation significantly improved myocyte function compared with cardioplegia alone values. A potential intracellular mechanism for the protective effects of either adenosine or the ATP-sensitive potassium channel is the activation of protein kinase C (PKC). A brief period of PKC activation before cardioplegic arrest provided protective effects on myocyte contractility with subsequent reperfusion and rewarming. In another set of studies, the potential protective effects of the active form of thyroid hormone (T3) were examined. In myocytes pretreated with T3, myocyte contractile function and beta-adrenergic responsiveness were significantly improved after hypothermic cardioplegic arrest and rewarming. Thus, endogenous means of providing improved myocardial protection during prolonged cardioplegic arrest can be achieved through a brief period of PKC activation or pretreatment with T3. Future studies, which more carefully deduce the basis for these pretreatment effects, will likely yield novel methods by which to protect myocyte contractile processes during cardioplegic arrest.
Adenosine↗
The structure and function of the cardiac myocyte: a review of fundamental concepts.
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Action Potentials↗
Novel approaches to retard ventricular remodeling in heart failure.
While the etiologies of congestive heart failure (CHF) are diverse, a common event in the progression of this disease process is LV remodeling, increased wall stress, and subsequent pump dysfunction. Therapeutic approaches for CHF have been focused upon reducing LV afterload through vasodilator therapy, or by blocking/interrupting the effects of neurohormonal stimuli. However, another therapeutic approach would be to directly intervene in the LV remodeling process with CHF. An important determinant in the maintenance of myocyte shape, alignment and transduction of myocyte shortening into an overall ejection is the structural support provided by the fibrillar collagen matrix. As in most tissue remodeling processes, LV myocardial remodeling with CHF is accompanied by changes in the structure and composition of the collagen matrix. Matrix metalloproteinases (MMPs) are an endogenous family of zinc-dependent enzymes which have been identified to be responsible for matrix remodeling and alterations in MMP expression and activity have been identified in clinical and animal models of CHF. Moreover, alterations in the tissue inhibitors of MMPs (TIMPs) have also been identified to occur in the end-stage CHF myocardium. Thus, it is very likely that increased MMP activity and reduced inhibitory control of the TIMPs contribute to the LV remodeling process with CHF. A number of bioactive peptides and cytokines influence MMP and TIMP expression and activity. In addition, pharmacologically active MMP inhibitors have been synthesized and are currently under study. Accordingly, the control of MMP and TIMP expression and activity within the failing myocardium represents a new and potentially significant therapeutic target for CHF.
Heart Failure↗
Matrix metalloproteinase synthesis and expression in isolated LV myocyte preparations.
In several cardiac disease states, alterations in myocyte and extracellular matrix (ECM) structure occur with left ventricular (LV) remodeling and are associated with changes in matrix metalloproteinase (MMP) activity. Although nonmyocyte cell types have been implicated as sites for synthesis and expression of MMPs within the ECM, whether the LV myocyte itself expresses specific types and active forms of MMPs remains unknown. Accordingly, isolated Ca(2+)-tolerant LV porcine myocytes (10(5) cells/ml) in which selective disaggregation and resuspension was performed (13 independent experiments) were plated on basement membrane substrates including Matrigel, collagen IV, laminin, and fibronectin as well as poly-L-lysine. After 24-h incubation, LV myocyte conditioned media were subjected to zymography, a specific MMP-2 proteolytic capture assay, immunoblotting, and ELISA for detection of MMP activity and relative content of the 72-kDa gelatinase MMP-2. Although robust zymographic activity [(pixels. mm(2))/cell] was observed in conditioned media from LV myocytes plated on collagen IV (1,673 +/- 297), fibronectin (1,530 +/- 281), and poly-L-lysine (2,545 +/- 560), proteolytic activity appeared to be lower in conditioned media from LV myocytes plated on Matrigel (842 +/- 83) and laminin (1,329 +/- 238). MMP-2 proteolytic activity was increased by approximately eightfold in conditioned media taken from LV myocytes plated on poly-L-lysine compared with that of Matrigel. With respect to each of the adhesion substrates, MMP-2 content was at least 50% lower in LV myocyte conditioned media taken from Matrigel and laminin. Immunofluorescent labeling of LV myocytes yielded a strong signal for MMP-2 within the myocyte and along the sarcolemmal surface. In conclusion, this study demonstrated for the first time that adult LV myocytes synthesize and express members of the MMP family and thus may potentially participate in the LV remodeling process through synthesis and secretion of MMPs.
Animals↗
Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry.
The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.
Angiotensin-Converting Enzyme Inhibitors↗
The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure.
OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) CONTROL: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.
Animals↗
ATP-sensitive potassium channel activation before cardioplegia. Effects on ventricular and myocyte function.
BACKGROUND: Pretreatment with potassium channel openers (PCOs) has been shown to provide protective effects in the setting of myocardial ischemia. The goal of the present study was to examine whether PCO pretreatment would provide protective effects on left ventricular (LV) and myocyte function after cardioplegic arrest. METHODS AND RESULTS: The first study quantified the effects of PCO pretreatment on LV myocyte contractility after simulated cardioplegic arrest. LV porcine myocytes were randomly assigned to 3 groups: (1) normothermic control: 37 degrees C x 2 hours (n = 116); (2) cardioplegia: K+ 24 mEq/L, 4 degrees C x 2 hours followed by reperfusion and rewarming (n = 62); and (3) PCO/cardioplegia: 5 minutes of PCO treatment (50 mumol/L, SR47063, 37 degrees C; n = 94) followed by cardioplegic arrest and rewarming. Myocyte contractility was measured after rewarming by videomicroscopy. The second study determined whether the effects of PCO pretreatment could be translated to an in vivo model of cardioplegic arrest. Pigs (weight 30 to 35 kg) were assigned to the following: (1) cardioplegia: institution of cardiopulmonary bypass (CPB) and cardioplegic arrest (K+ 24 mEq/L, 4 degrees C x 2 hours) followed by reperfusion and rewarming (n = 8); and (2) PCO/cardioplegia: institution of CPB, antegrade myocardial PCO perfusion without recirculation (500 mL of 50 mumol/L, SR47063, 37 degrees C), followed by cardioplegic arrest (n = 6). LV function was examined at baseline (pre-CPB) and at 0 to 30 minutes after separation from CPB by use of the preload-recruitable stroke work relation (PRSWR; x 10(5) dyne.cm/mm Hg). LV myocyte velocity of shortening was reduced after cardioplegic arrest and rewarming compared with normothermic control (37 +/- 3 vs 69 +/- 3 microns/s, P < 0.05) and was improved with 5 minutes of PCO treatment (58 +/- 3 microns/s). In the intact experiments, the slope of the PRSWR was depressed in the cardioplegia group compared with baseline with separation from CPB (1.07 +/- 0.15 vs 2.57 +/- 0.11, P < 0.05) and remained reduced for up to 30 minutes after CPB. In the PCO-pretreated animals, the PRSWR was higher after cessation of CPB when compared with the untreated cardioplegia group (1.72 +/- 0.07, P < 0.05). However, in the PCO pretreatment group, 50% developed refractory ventricular fibrillation by 5 minutes after CPB, which prevented further study. CONCLUSIONS: PCO pretreatment improved LV myocyte contractile function in an in vitro system of cardioplegic arrest. The in vivo translation of this improvement in contractile performance with PCO pretreatment was confounded by refractory arrhythmogenesis. Thus the application of PCO pretreatment as a protective strategy in the setting of cardiac surgery may be problematic.
Adenosine Triphosphate↗
Activation of matrix metalloproteinases in the failing human heart: breaking the tie that binds.
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Cardiac Output, Low↗
Chronic amlodipine treatment during the development of heart failure.
BACKGROUND: This study examined the effects of chronic amlodipine treatment on left ventricular (LV) pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF) both at rest and with treadmill exercise. In an additional series of in vitro studies, LV myocyte contractile function was examined. METHODS AND RESULTS: Sixteen pigs were studied under normal control conditions and after the development of chronic pacing-induced CHF (240 bpm, 3 weeks, n=8) or chronic pacing and amlodipine (1.5 mg . kg-1 . d-1, n=8). Under ambient resting conditions, LV stroke volume (mL) was reduced with CHF compared with the normal control state (16+/-2 versus 31+/-2, P<0.05) and increased with concomitant amlodipine treatment (29+/-2, P<0.05). At rest, systemic and pulmonary vascular resistance (dyne . s-1 . cm-5) increased with CHF compared with the normal control state (3102+/-251 versus 2156+/-66 and 1066+/-140 versus 253+/-24, respectively, both P<0.05) and were reduced with amlodipine treatment (2108+/-199 and 480+/-74, respectively, P<0.05). With CHF, LV stroke volume remained reduced and was associated with a 40% reduction in myocardial blood flow during treadmill exercise, whereas chronic amlodipine treatment normalized LV stroke volume and improved myocardial blood flow. Resting and exercise-induced plasma norepinephrine levels were increased by >5-fold in the CHF group and were reduced by 50% from CHF values with chronic amlodipine treatment. Resting plasma endothelin (fmol/mL) increased with CHF compared with the normal state (10.4+/-0.9 versus 3.1+/-0.3, P<0.05) and was reduced with amlodipine treatment (6.6+/-1.1, P<0.5). With CHF, LV myocyte velocity of shortening ( microm/s) was reduced compared with normal controls (39+/-1 versus 64+/-1, P<0.05) and was increased with chronic amlodipine treatment (52+/-1, P<0.05). CONCLUSIONS: Chronic amlodipine treatment in this model of developing CHF produced favorable hemodynamic, neurohormonal, and contractile effects in the setting of developing CHF.
Amlodipine↗
Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy.
BACKGROUND: One of the hallmarks of dilated cardiomyopathy (DCM) is left ventricular (LV) remodeling. The matrix metalloproteinases (MMPs) are a family of enzymes that contribute to extracellular remodeling in several disease states. Additionally, a family of inhibitors called tissue inhibitors of MMPs (TIMPs) has been shown to exist and to tightly regulate MMP activity. However, the types of MMPs and TIMPs expressed within the normal and DCM LV myocardium and the relation to MMP activity remain unexplored. METHODS AND RESULTS: Relative LV myocardial MMP activity was determined in the normal (n=8) and idiopathic DCM (n=7) human LV myocardium by substrate zymography. Relative LV myocardial abundance of interstitial collagenase (MMP-1), stromelysin (MMP-3), 72 kD gelatinase (MMP-2), 92 kD gelatinase (MMP-9), TIMP-1, and TIMP-2 were measured with quantitative immunoblotting. LV myocardial MMP zymographic activity increased with DCM compared with normal (984+/-149 versus 413+/-64 pixels, P<.05). With DCM, LV myocardial abundance of MMP-1 decreased to 16+/-6% (P<.05), MMP-3 increased to 563+/-212% (P<.05), MMP-9 increased to 422+/-64% (P<.05), and MMP-2 was unchanged when compared with normal. LV myocardial abundance of TIMP-1 and TIMP-2 increased by >500% with DCM. A high-molecular-weight immunoreactive band for both TIMP-1 and TIMP-2, suggesting a TIMP/MMP complex, was increased >600% with DCM. CONCLUSIONS: This study demonstrated increased LV myocardial MMP activity and evidence for independent regulatory mechanisms of MMP and TIMP expression with DCM. These findings suggest that selective inhibition of MMP species within the LV myocardium may provide a novel therapeutic target in patients with DCM.
Adolescent↗
Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats.
BACKGROUND: Although patients with heart failure express elevated circulating levels of tumor necrosis factor-alpha (TNF-alpha) in their peripheral circulation, the structural and functional effects of circulating levels of pathophysiologically relevant concentrations of TNF-alpha on the heart are not known. METHODS AND RESULTS: Osmotic infusion pumps containing either diluent or TNF-alpha were implanted into the peritoneal cavity of rats. The rate of TNF-alpha infusion was titrated to obtain systemic levels of biologically active TNF-alpha comparable to those reported in patients with heart failure (approximately 80 to 100 U/mL), and the animals were examined serially for 15 days. Two-dimensional echocardiography was used to assess changes in left ventricular (LV) structure (remodeling) and LV function. Video edge detection was used to assess isolated cell mechanics, and standard histological techniques were used to assess changes in the volume composition of LV cardiac myocytes and the extracellular matrix. The reversibility of cytokine-induced effects was determined either by removal of the osmotic infusion pumps on day 15 or by treatment of the animals with a soluble TNF-alpha antagonist (TNFR:Fc). The results of this study show that a continuous infusion of TNF-alpha led to a time-dependent depression in LV function, cardiac myocyte shortening, and LV dilation that were at least partially reversible by removal of the osmotic infusion pumps or treatment of the animals with TNFR:Fc. CONCLUSIONS: These studies suggest that pathophysiologically relevant concentrations of TNF-alpha are sufficient to mimic certain aspects of the phenotype observed in experimental and clinical models of heart failure.
Animals↗