Showing papers by "Francis G. Spinale published in 2000"
TL;DR: Increased LV myocardial MMP activity and selective upregulation of MMPs with nonischemic and ischemic forms of DCM occurred and a local MMP induction/activation system was identified in isolated normal human LV myocytes that was upregulated with DCM.
Abstract: Background—Matrix metalloproteinases (MMPs) contribute to matrix remodeling in disease states such as tumor metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to...
476 citations
TL;DR: Increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states and Regulation of myocardian MMPexpression and activity may be an important therapeutic target for controlling myocardia matrix remodeling in the setting of developing heart failure.
Abstract: A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.
224 citations
TL;DR: The results suggest that the type of overload stimulus may selectively influence myocardial MMP activity and expression, which in turn would affect the overall LV myocardIAL remodeling process in LV overload.
Abstract: Left ventricular (LV) pressure (PO) or volume (VO) overload is accompanied by myocardial remodeling, but mechanisms that contribute to this progressive remodeling process remain unclear. The matrix...
129 citations
TL;DR: Results suggest that constitutive TIMP-1 expression participates in the maintenance of normal LV myocardial structure and time-dependent effects on LV geometry and function are suggested.
128 citations
TL;DR: It is concluded that institution of bradycardia is a major mechanism by which beta-blockers are effective for restoration of contractile function in a model of LV dysfunction.
Abstract: Background—It is clear that β-blockers are effective for treatment of congestive heart failure, but their mechanism of action remains controversial. Hypothesized mechanisms include normalization of β-receptor function and myocardial protection from the effects of catecholamines, possibly by the institution of bradycardia. We hypothesized that β-blockade–induced bradycardia was an important mechanism by which these agents were effective for correction of LV dysfunction. Methods and Results—In 2 groups of dogs with mitral regurgitation and LV dysfunction, β-blockers were instituted. In 1 group that received β-blockers and pacing (group β+P), a pacemaker prevented the natural bradycardia that β-blockers cause. In both groups, substantial LV dysfunction developed. Before β-blockade, the end-systolic stiffness constant decreased from 3.5±0.1 to 2.7±0.2 (P<0.01) at 3 months in group β+P. A similar reduction occurred in the group that eventually received only β-blockers (group βB). In group βB, end-systolic stif...
105 citations
TL;DR: Low magnesium levels in pediatric patients undergoing heart surgery are associated with an increased incidence of junctional ectopic tachycardia in the immediate postoperative period.
79 citations
TL;DR: These results demonstrate that neurohormonal factors released post-CABG can cause RA vasoconstriction, and that calcium channel antagonists are not equally effective in abrogating that response.
41 citations
TL;DR: Endothelin levels after CPB remained persistently increased for at least 24 hours after surgery and were associated with increased myocardial production of endothelin, suggesting that the increasedendothelin observed in the early postoperative period may contribute to a complex recovery from coronary artery bypass graft surgery.
39 citations
TL;DR: A local ET-1 system exists at the level of the myocyte, and determinants of ET-2 biosynthesis are selectively regulated within this myocardial compartment in CHF, demonstrating compartmentalization ofET-1 in theMyocardial interstitium and enhanced ET- 1 uptake with CHF.
Abstract: Increased plasma levels of endothelin-1 (ET-1) have been identified in congestive heart failure (CHF), but local myocardial interstitial ET-1 levels and the relation to determinants of ET-1 synthes...
35 citations
Journal Article•
TL;DR: Although V(1a) or AT(1) block reduced LV loading conditions, only dual block resulted in improved LV and myocyte shortening.
Abstract: With developing congestive heart failure (CHF), activation of the vasopressin V 1a and angiotensin II type 1 (AT 1 ) receptors can occur. In the present study, we examined the direct effects of V 1a receptor blockade (V 1a block), selective AT 1 receptor blockade (AT 1 block), and dual V 1a /AT 1 receptor blockade (dual block) with respect to left ventricular (LV) function and contractility during the progression of CHF. LV and myocyte functions were examined in pigs with pacing CHF (rapid pacing, 240 beats/min, 3 weeks, n = 10), pacing CHF with concomitant V 1a block (SR49059, 60 mg/kg, n = 8), pacing CHF with concomitant AT 1 block (irbesartan, 30 mg/kg, n = 7), or pacing CHF with dual block ( n = 7). LV end-diastolic dimension and peak wall stress were reduced in all receptor blockade groups compared with CHF values. However, LV fractional shortening was increased only in the dual block group compared with CHF values (29 ± 3 versus 21 ± 2, P P 1a or AT 1 block reduced LV loading conditions, only dual block resulted in improved LV and myocyte shortening.
34 citations
TL;DR: In this paper, the effects of ET-1 exposure on human left ventricular (LV) myocyte contractility were examined from myocardial biopsies taken from patients undergoing elective coronary artery bypass.
TL;DR: Combined AT1 and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance.
Abstract: Background—The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT1) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF). Methods and Results—Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT1 receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT1 and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT1 or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with th...
TL;DR: This study showed that the biosynthetic pathway of ET-1 is activated in LV myocardium in the failing heart, and the myocardial processing of big ET- 1 is highly specific for ECE-1.
TL;DR: The development of pacing‐induced CHF was associated with diminished brain perfusion under resting conditions and with treadmill exercise, and these perfusion abnormalities were pronounced in specific regions of the brain.
Abstract: OBJECTIVE Congestive heart failure (CHF) is associated with left ventricular (LV) failure, neurohormonal system activation, and diminished exercise capacity. Although alterations in systemic vascular resistive properties have been recognized to occur with CHF, whether and to what degree perfusion abnormalities occur within the brain after the development of CHF remain poorly understood. Accordingly, the present study measured brain blood flow patterns in pigs after the development of pacing-induced CHF at rest and after treadmill-induced exercise. MEASUREMENTS AND MAIN RESULTS Adult pigs (n = 6) were studied before and after the development of pacing-induced CHF (240 beats/min, 3 wks) at rest and with treadmill exercise (3 mph, 15 degrees incline, 10 mins). At rest, LV stroke volume was reduced nearly 45% with CHF compared with normal (20+/-2 vs. 36+/-3 mL; p<.05) and was associated with a more than four-fold increase in plasma catecholamines, renin activity, and endothelin concentration. At rest, global brain blood flow was reduced with CHF compared with the normal state (1.06+/-0.13 vs. 0.81+/-0.06 mL/min/g; p<.05). At rest, blood flow to the frontal lobe, cerebellum, and medullary regions was reduced by approximately 30% in the CHF group (p<.05). With treadmill exercise, LV stroke volume remained lower and neurohormonal concentrations remained higher in the pacing CHF state. Global brain blood flow increased significantly with treadmill exercise in both the normal and CHF states (4.58+/-1.36 and 2.01+/-0.29 mL/min/g; p<.05) but remained reduced in the CHF state compared with normal values (p<.05). In the CHF group, the relative increase in blood flow with exercise was significantly blunted in the parietal and occipital regions of the cerebrum and the suprapyramidal region of the medulla. CONCLUSIONS The development of pacing-induced CHF was associated with diminished brain perfusion under resting conditions and with treadmill exercise. These perfusion abnormalities with pacing CHF were pronounced in specific regions of the brain. The defects in brain perfusion with the development of CHF may contribute to abnormalities in centrally mediated processes of cardiovascular regulation.
TL;DR: Exposure of the left ventricular myocyte to endothelin during cardioplegic arrest directly contributed to contractile dysfunction after reperfusion, and alterations in intracellular calcium may play a role in potentiating the myocyte contractiles dysfunction associated with endothelins exposure duringCardiopleGic arrest.
Abstract: Transient left ventricular (LV) dysfunction can occur after cardioplegic arrest. The contributory mechanisms for this phenomenon are not completely understood. We tested the hypothesis that exposure of LV myocytes to endothelin (ET) during simulated cardioplegic arrest would have direct effects on contractile processes with subsequent reperfusion. LV porcine myocytes were randomly assigned to three groups: 1) CONTROL: normothermic (37 degrees C) cell media (n = 204); 2) Cardioplegia: simulated cardioplegic arrest (K(+) 24 mEq/L, 4 degrees C x 2 h) followed by reperfusion and rewarming with cell media (n = 164); and 3) Cardioplegia/ ET: simulated cardioplegic arrest in the presence of ET (200 pM) followed by reperfusion with cell media containing ET (n = 171). Myocyte contractility was measured by computer-assisted video microscopy. In a subset of experiments, myocyte intracellular calcium was determined after Fluo-3 (Molecular Probes, Eugene, OR) loading by digital fluorescence image analysis. Myocyte shortening velocity was reduced after cardioplegic arrest compared with controls (52 +/- 2 vs 84 +/- 3 microm/s, respectively; P < 0.05) and was further reduced with cardioplegic arrest and ET exposure (43 +/- 2 microm/s, P < 0.05). Intracellular calcium was significantly increased in myocytes exposed to cardioplegia compared with normothermic control myocytes and was further augmented by cardioplegia with ET supplementation (P < 0.05). Exposure of the LV myocyte to ET during cardioplegic arrest directly contributed to contractile dysfunction after reperfusion. Moreover, alterations in intracellular calcium may play a role in potentiating the myocyte contractile dysfunction associated with ET exposure during cardioplegic arrest.
TL;DR: Cardiopulmonary bypass and cardioplegic arrest induce temporal differences in endothelin 1 levels within the myocardial interstitium and systemic circulation, which, in turn, may influence left ventricular function in the postbypass period.
TL;DR: The conduct of and evaluation for cardiac transplantation has been well described previously and therefore will not be evaluated, but there has been recent progress in the genetic modification of animal organs for potential use in transplantation (xenografts) and if these developments come to fruition, then cardiac transplant/organ replacement may become a surgical option for a much greater number of CHF patients.
TL;DR: It is suggested that BK has a direct effect on LV myocyte contractility, and that this effect may be mediated by proteolysis of BK at the level of the LV myocytes sarcolemma.
Abstract: Background: Past studies have demonstrated that exogenous bradykinin (BK) causes vasodilation and increases coronary blood flow, effects that may be beneficial in the setting of cardiac disease sta...