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Francis G Spinale

Publications and source records attributed to Francis G Spinale.

71 records · Page 4Linked to original sources
PubMed2003

Changes in extracellular collagen matrix alter myocardial systolic performance.

The purpose of this study was to test the hypothesis that acute disruption of fibrillar collagen will decrease myocardial systolic performance without changing cardiomyocyte contractility. Isolated papillary muscles were treated either with plasmin (0.64 U/ml, 240 min) or untreated and served as same animal control. Plasmin treatment caused matrix metalloproteinase activation and collagen degradation as measured by gelatin zymography, hydroxyproline assays, and scanning electron microscopy. Plasmin caused a significant decrease in myocardial systolic performance. Isotonic shortening extent and isometric developed tension decreased from 0.17 +/- 0.01 muscle length (ML) and 45 +/- 4 mN/mm(2) in untreated muscles to 0.09 +/- 0.01 ML and 36 +/- 3 mN/mm(2) in treated muscles (P < 0.05). However, plasmin treatment (0.64 U/ml, 240 min) did not alter shortening extent or velocity in isolated cardiomyocytes. Acute disruption of the fibrillar collagen network caused a decrease in myocardial systolic performance without changing cardiomyocyte contractility. These data support the hypothesis that fibrillar collagen facilitates transduction of cardiomyocyte contraction into myocardial force development and helps to maintain normal myocardial systolic performance.

Animals↗
PubMed2002

Release of matrix metalloproteinases following alcohol septal ablation in hypertrophic obstructive cardiomyopathy.

OBJECTIVES: This study examined plasma levels of certain matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) species before and after alcohol-induced myocardial infarction (MI) in patients with hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND: Matrix metalloproteinases contribute to tissue remodeling, and endogenous control of MMP activity is achieved by the concordant release and binding of TIMPs. Animal models of MI have demonstrated a role for MMP activation in myocardial remodeling. However, the temporal relationship of MMP and TIMP release following a controlled myocardial injury in humans remains unknown. METHODS: Plasma levels for the gelatinases MMP-2 and MMP-9, and for the collagenases MMP-8 and MMP-13, as well as TIMP-1 profiles were examined (by enzyme-linked immunosorbent assay) at baseline and serially up to 60 h following alcohol injection into the septal perforator artery in order to induce an MI in 51 patients with HOCM (age 55 +/- 2 years). RESULTS: Plasma creatine kinase (MB isoform), indicating myocardial injury, increased 2,150% 18 h post-MI (p < 0.05). Plasma MMP-9 increased by over 400% and MMP-8 by over 100% from baseline values by 12 h post-MI (p < 0.05 vs. baseline). A similar temporal profile was not observed for MMP-2 and MMP-13. In addition, a concomitant increase in plasma TIMP-1 levels did not occur post-MI. As a result, MMP/TIMP stoichiometry (MMP-9/TIMP-1 ratio) increased significantly post-MI, suggestive of reduced TIMP-1 mediated MMP-9 inhibition, which would potentially enhance extracellular myocardial remodeling. CONCLUSIONS: These unique results demonstrated that induction of a controlled myocardial injury in humans, specifically through alcohol-induced MI, caused species- and time-dependent perturbations of MMP/TIMP stoichiometry that would facilitate myocardial remodeling in the early post-MI setting.

Alcohols↗
PubMed2002

Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice.

Recent studies have been directed at modulating the heart failure process through inhibition of activated matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency alters the course of postinfarction chamber remodeling and induced chronic myocardial infarction (MI) in wild-type (WT) and TIMP-1(-/-) mice. Left ventricular (LV) pressure-volume loops obtained from WT and TIMP-1(-/-) mice demonstrated that LV end-diastolic volume [52 +/- 4 (WT) vs. 71 +/- 6 (TIMP-1(-/-)) microl] and LV end-diastolic pressure [9.0 +/- 1.2 (WT) vs. 12.7 +/- 1.4 (TIMP-1(-/-)) mmHg] were significantly increased in the TIMP-1(-/-) mice 2 wk after MI. LV contractility was reduced to a similar degree in the WT and TIMP-1(-/-) groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-1(-/-) mice, indicating that the hypertrophic response was more pronounced. The observed significant loss of fibrillar collagen in the TIMP-1(-/-) controls may have been an important contributory factor for the observed LV alterations in the TIMP-1(-/-) mice after MI. These findings demonstrate that TIMP-1 deficiency amplifies adverse LV remodeling after MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-1.

Animals↗
PubMed2002

Angiotensin II receptor blockade does not improve left ventricular function and remodeling in subacute mitral regurgitation in the dog.

OBJECTIVES: We hypothesized that angiotensin II type-1 (AT(1)) receptor blocker (AT(1)RB) would prevent adverse left ventricular (LV) remodeling and LV dysfunction when started at the outset of mitral regurgitation (MR). BACKGROUND: Little is known regarding the efficacy of AT(1)RB treatment of MR. METHODS: Mitral regurgitation was induced by chordal disruption in adult mongrel dogs. Six normal dogs (NLs) were compared to six untreated MR dogs (MR) and seven dogs treated with the receptor blocker irbesartan (MR+AT(1)RB) started 24 h after induction of MR (60 mg/kg p.o. b.i.d.) and continued for three months. RESULTS: Treatment with AT(1)RB decreased systemic vascular resistance but did not significantly improve cardiac output, LV end-diastolic dimension (LVEDD) or LVEDD/wall thickness compared to untreated MR dogs. Resting isolated cardiomyocyte length increased in MR versus NLs and was further increased in AT(1)RB dogs. Left ventricular end-systolic dimension increased to a greater extent from baseline in AT(1)RB dogs versus untreated MR dogs (29 +/- 9% vs. 12 +/- 6%, p < 0.05), despite a significantly lower LV peak systolic pressure in AT(1)RB dogs. Plasma-angiotensin (ANG) II was elevated greater than threefold in both MR and MR+AT(1)RB versus NLs. In contrast, intracardiac ANG II was increased greater than twofold in MR dogs versus NLs, but was normalized by AT(1)RB. CONCLUSIONS: The use of AT(1)RB decreased systemic vascular resistance and attenuated local expression of the renin-angiotensin system but did not prevent adverse LV chamber and cardiomyocyte remodeling. These results suggest that blockade of the AT(1) receptor does not improve LV remodeling and function in the early myocardial adaptive phase of MR.

Alabama↗
PubMed2002

Matrix metalloproteinases: regulation and dysregulation in the failing heart.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for myocardial extracellular protein degradation. Several MMP species identified within the human myocardium may be dysregulated in congestive heart failure (CHF). For example, MMPs that are expressed at very low levels in normal myocardium, such as collagenase-3 (MMP-13) and the membrane-type-1 MMPs, are substantially upregulated in CHF. However, MMP species are not uniformly increased in patients with end-stage CHF, suggesting that a specific portfolio of MMPs are expressed in the failing myocardium. With the use of animal models of CHF, a mechanistic relationship has been demonstrated with respect to myocardial MMP expression and the left ventricular (LV) remodeling process. The tissue inhibitors of the MMPs (TIMPs) are locally synthesized proteins that bind to active MMPs and thereby regulate net proteolytic activity. However, there does not appear to be a concomitant increase in myocardial TIMPs during the LV remodeling process and progression to CHF. This disparity between MMP and TIMP levels favors a persistent MMP activation state within the myocardium and likely contributes to the LV remodeling process in the setting of developing CHF. The elucidation of upstream signaling mechanisms that contribute to the selective induction of MMP species within the myocardium as well as strategies to normalize the balance between MMPs and TIMPs may yield some therapeutic strategies by which to control myocardial extracellular remodeling and thereby slow the progression of the CHF process.

Animals↗
PubMed2002

Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective.

A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. Recent clinical and experimental studies have noted that increased release of tumor necrosis factor alpha (TNF-alpha) can contribute to LV myocardial remodeling. Experimental studies have noted that the induction of TNF-alpha can result in LV dilation and proceed to LV pump dysfunction. The biological effects of TNF-alpha are mediated through TNF receptors that are present on all nucleated cells in the heart. TNF receptor activation can induce a number of cellular and molecular events which contribute to LV remodeling in CHF, and include changes in myocyte size and viability and alterations in myocardial structure/composition. In vitro studies have demonstrated that TNF receptor activation can cause the induction of a proteolytic system. This proteolytic system, the matrix metalloproteinases (MMPs), is upregulated in models of LV dysfunction and possesses the capacity to degrade a wide variety of extracellular matrix components. Therefore, one pathway by which TNF-alpha can influence LV myocardial remodeling is through the induction of a specific portfolio of MMP species. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling will provide new insight into this disease process and future therapeutic modalities.

Animals↗
PubMed2002

Cardiorenal effects of adenosine subtype 1 (A1) receptor inhibition in an experimental model of heart failure.

BACKGROUND: Elaboration of a number of bioactive substances, including adenosine, occurs in heart failure (HF). Adenosine, through the adenosine subtype 1 (A1) receptor, can reduce renal perfusion pressure and glomerular filtration rate and increase tubular sodium reabsorption, which can affect natriuresis and aquaresis. Accordingly, the present study examined the acute effects of selective A1 receptor blockade on hemodynamics and renal function in a model of HF. STUDY DESIGN: HF was induced in adult pigs (n = 19) by chronic pacing (240 beats/min for 3 weeks). The pigs were then instrumented for hemodynamic and renal function measurements. After baseline measurements were taken, pigs received either A1 block [ 1 mg/kg BG9719 (1,3-dipropyl-8-[2(5,6-epoxynorbornyl)]xanthine; n = 9)] or infusion of vehicle (n = 10), and measurements were repeated at intervals for up to 2 hours. Normal controls (n = 7) were included for comparison. RESULTS: Cardiac output remained unchanged between the A1 block and vehicle groups throughout the study. Pulmonary vascular resistance fell 38% from baseline at 10 minutes post-A1 block in the HF group (p < 0.05) with no change in the vehicle group. At 10 minutes post-A1 block, urine flow increased sixfold and sodium excretion increased over 10-fold (for both, p < 0.05) with no change in the vehicle group. At 10 minutes post-A1 block, creatinine clearance increased with no change in the vehicle group. At 10 minutes post-A1 block, plasma renin activity had increased over threefold (p <0.05), and it returned to baseline levels by 30 minutes post-A1 block. CONCLUSIONS: The unique findings from this study were threefold. First, increased A1 receptor activation contributes to renal mediated fluid retention in HF. Second, selective A1 blockade can induce diuresis without hemodynamic compromise and with possible benefit to pulmonary resistance in a model of HF. A1 blockade transiently increased plasma renin activity with no change in hemodynamics. These unique results suggest that selective A1 blockade can be a useful adjunctive diuretic in the setting of HF.

Animals↗
PubMed2002

Extracellular degradative pathways in myocardial remodeling and progression to heart failure.

A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. The myocardial extracellular matrix is composed of structural proteins and biologically active molecules that contribute to the maintenance of LV myocardial architecture and function. A family of proteolytic enzymes responsible for myocardial extracellular protein degradation is the matrix metalloproteinases (MMPs). A number of MMP species have been identified within the human myocardium and are increased with the development of CHF. Certain MMPs that are expressed at very low levels in normal myocardium such as collagenase-3 (MMP-13) and the membrane-type MMPs (MT-MMPs) are substantially upregulated in CHF and likely contribute to the pathologic remodeling that occurs within the myocardium. However, not all MMP species are uniformly increased in patients with end-stage CHF, suggesting that a specific portfolio or cassette of MMPs are expressed in the failing myocardium. The necessary next steps for improving our understanding of this myocardial MMP system include (1) the identification of the MMP species that are upregulated in CHF, (2) elucidation of the upstream signaling pathways that contribute to MMP induction, (3) the development of methods to detect early myocardial MMP activation in patients with developing CHF, and (4) the examination of the effects of pharmacologic modulators of the MMP system in animal models of CHF. The results from these future studies may yield some novel therapeutic strategies by which to control myocardial extracellular remodeling and thereby slow the progression of the CHF process.

Animals↗
PubMed2002

Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure.

BACKGROUND: Changes in myocardial matrix metalloproteinases (MMPs) and the inhibitors of MMPs (TIMPs) have been demonstrated in congestive heart failure (CHF). The first objective of this study was to measure plasma profiles of MMPs and TIMPs in CHF patients (n = 24; 62 +/- 3 years; left ventricular ejection fraction [LVEF] = 24 +/- 2%) and age-matched nonfailing patients (n = 48; 63 +/- 2 years; LVEF >/= 55%). Cytokines such as tumor necrosis factor (TNF)-alpha can induce MMP expression in vitro. The second objective of this study was to determine the relationship between soluble TNF-alpha receptors (TNFR1; TNFR2) and MMP plasma profiles. METHODS AND RESULTS: Plasma levels of MMP-2, MMP-9, MMP-8, TIMP-1, TIMP-2, TNF-alpha, TNFR1, and TNFR2 were measured by enzyme-linked immunosorbent assay kits. Plasma MMP-9 levels were increased in CHF patients (25 +/- 6 versus 72 +/- 15 ng/mL, P <.05). Interestingly, plasma levels of MMP-8 were decreased in CHF patients (16 +/- 2 versus 9 +/- 2 ng/mL, P <.05). The MMP-9/TIMP-1 ratio was increased by 3-fold, whereas the MMP-9/TIMP-2 ratio was increased by 16-fold in CHF patients (both P <.05). With a 48-week follow-up in CHF patients, an absolute reduction in plasma TNFR1 from baseline was accompanied by reduced MMP-9 levels (-30 +/- 16 ng/mL; P =.058), whereas stable or increased plasma TNFR1 resulted in persistently elevated MMP-9 levels. CONCLUSIONS: The unique findings of this study were 2-fold. First, a discordant change in plasma MMP and TIMP levels occurred in CHF patients. Second, changes in cytokine activity were related to changes in plasma MMP levels. These changes in MMP/TIMP levels likely reflect the progression and/or acceleration of the LV remodeling process in CHF. Thus serial measurements of plasma MMP/TIMP levels may hold diagnostic/prognostic significance in CHF patients.

Aged↗
PubMed2002

Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog.

We studied the gradual onset of pressure overload (PO) induced by a mildly constricting aortic band in 8-wk-old puppies (n = 8) that increased to 98 +/- 11 mmHg at 9 mo. Left ventricular (LV) weight/body weight was increased in PO versus sham-operated littermate controls [8.11 +/- 0.60 (SE) vs. 4.46 +/- 0.38 g/kg, P < 0.001]. LV end-diastolic diameter, diastolic pressure, and fractional shortening did not differ in PO versus control dogs. There were no inducible arrhythmias in response to an aggressive electrophysiological stimulation protocol in PO dogs. Furthermore, isolated cardiomyocyte function did not differ between control and PO dogs. LV angiotensin II (ANG II) levels were increased (68 +/- 12 vs. 20 +/- 5 pg/g, P < 0.01) as steady-state ANG II type 1 (AT(1)) receptor mRNA was decreased 40% and endothelial nitric oxide synthase mRNA levels were increased 2.5-fold in PO versus control dogs (P < 0.05). Total ANG II receptor binding sites of freshly prepared cardiac membranes demonstrated no difference in the dissociation constant, but there was a 60% decrease in maximum binding (B(max)) in PO versus control dogs (P < 0.01). LV ANG II levels correlated negatively with AT(1) receptor mRNA levels (r = -0.75, P < 0.01) and total AT(1) receptor B(max) (r = -0.77, P < 0.02). These results suggest that LV ANG II negatively regulates AT(1) receptor expression and that this is an adaptive response to chronic PO before the onset of myocardial failure in the young dog.

Adaptation, Physiological↗
PubMed2002

TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling.

The cytokine tumor necrosis factor (TNF)-alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-alpha. This study tested the central hypothesis that administration of a TNF-alpha blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-alpha blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously, n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 +/- 12 vs. 118 +/- 10 ml, P < 0.05) and was reduced with TNF block (97 +/- 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 +/- 9,593 vs. 87,247 +/- 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 +/- 10% and 118 +/- 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-alpha contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.

Animals↗
PubMed2002

Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment.

To determine whether and to what extent one component of the extracellular matrix, fibrillar collagen, contributes causally to abnormalities in viscoelasticity, collagen was acutely degraded by activation of endogenous matrix metalloproteinases (MMPs) with the serine protease plasmin. Papillary muscles were isolated from normal cats and cats with right ventricular pressure overload hypertrophy (POH) induced by pulmonary artery banding. Plasmin treatment caused MMP activation, collagen degradation, decreased the elastic stiffness constant, and decreased the viscosity constant in both normal and POH muscles. Thus, whereas many mechanisms may contribute to the abnormalities in myocardial viscoelasticity in the POH myocardium, changes in fibrillar collagen appear to play a predominant role.

Animals↗
PubMed2002

Effects of adrenomedullin on human myocyte contractile function and beta-adrenergic response.

BACKGROUND: Adrenomedullin has been demonstrated to cause systemic vasodilation, and increased plasma adrenomedullin levels have been observed in cardiovascular disease states such as heart failure. While adrenomedullin receptors have been localized to the myocardium, the effects of adrenomedullin on human myocyte contractility remained unknown. METHODS AND RESULTS: Left ventricular myocytes were isolated from myocardial biopsies of patients (n = 16) undergoing elective coronary artery bypass surgery with normal left ventricular ejection fractions (51 +/- 1%). A total of 233 left ventricular myocytes were studied by videomicroscopy. Myocyte shortening velocity (microm/s) was measured at baseline and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The change in myocyte shortening velocity with increasing concentrations of adrenomedullin was computed. At all concentrations, adrenomedullin reduced myocyte shortening velocity from baseline values (P < 0.05). Next, the potential interaction of adrenomedullin with the beta-adrenergic receptor system was examined using 25 nM isoproterenol. The beta-adrenergic receptor-mediated increase in the myocyte shortening velocity was blunted with adrenomedullin (29 +/- 7 vs 63 +/- 13 microm/s, P < 0.05). CONCLUSIONS: These unique findings demonstrate that adrenomedullin reduced contractility in isolated human left ventricular myocytes and exhibited a negative interaction with the beta-adrenergic receptor system. Past studies have shown that adrenomedullin induces nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism. Thus, while adrenomedullin causes systemic vasodilation, this peptide can also exert a negative contractile effect in human left ventricular myocytes.

Adrenomedullin↗
PubMedDate not supplied

Large animal models of congestive heart failure: a critical step in translating basic observations into clinical applications.

Congestive heart failure (CHF) is a clinical syndrome in which pathophysiologic underpinnings include left ventricular (LV) dysfunction, remodeling, and increased neurohormonal activation. Accordingly, large animal constructs must be developed that mimic this disease process in order to define new pharmacologic and surgical treatment strategies. Multiple large animal species have been used for these purposes. For instance, canine coronary artery microembolization has been used to generate ischemia-induced LV dilation and dysfunction. Sheep have been subjected to total acute coronary artery occlusion to evaluate ischemia-induced mitral valve insufficiency. Rapid ventricular pacing has been used in both dogs and pigs to reproduce the characteristics of dilated cardiomyopathy. Each model is associated with advantages and disadvantages. Therefore findings derived from the study of large animal models of LV failure must be carefully evaluated. With proper interpretation, important insights into the pathogenesis of CHF may be realized. Furthermore, these models may be used in conjunction with imaging modalities such as magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography to elucidate the identification of cellular and extracellular alterations associated with LV failure. Thus large animal models of CHF are critical components in the effort to translate basic observations into beneficial clinical applications.

Animals↗