Technical considerations when intervening with coronary device catheters in the vicinity of previously deployed stents.

As stent use increases, interventional cardiologists are increasingly faced with patients that require procedures in the vicinity of previously deployed stents. We present two cases of side-branch interventions in the vicinity of previously deployed stents where devices were trapped by the stent. In each case, traction on the device resulted in stent dislodgment. The stents were successfully extracted and replaced without complications.

Regulation of cardiac adrenomedullin in heart failure.

Adrenomedullin (ADM), a potent natriuretic and vasorelaxing peptide with inotropic properties, is elevated in plasma in human and experimental congestive heart failure (CHF). Recent studies suggest that angiotensin II stimulates ADM production and secretion from cardiac myocytes and fibroblasts. In the present study, we investigated cardiac ADM in experimental CHF, and tested the hypothesis that angiotensin converting enzyme (ACE) inhibition modulates cardiac ADM in CHF. Cardiac tissue ADM immunoreactivity and gene expression were assessed by radioimmunoassay, immunohistochemistry, in situ hybridization and Northern blot analysis in normal and CHF dogs in the presence and absence of ACE inhibition. Experimental CHF was produced by progressive rapid ventricular pacing and characterized by increased ventricular ADM concentrations as well as increased ventricular ADM gene expression. ACE inhibition abolished the increases in ventricular ADM concentrations and ventricular ADM gene expression in CHF. Ventricular ADM gene expression was localized to ventricular myocytes and correlated with left ventricular mass index, suggesting that ventricular ADM is a marker for ventricular hypertrophy. In contrast, atrial ADM concentrations and gene expression did not change in CHF with or without ACE inhibition. Increased plasma ADM concentrations in CHF were also abolished with ACE inhibition. The present study demonstrates that circulating and ventricular ADM are activated in pacing-induced experimental CHF and that ACE inhibition reverses ventricular ADM activation in CHF. This study also indicates that cardiac ADM gene expression is differently regulated between atrium and ventricle in CHF.

Relationship between left ventricular wall stress and ANP gene expression during the evolution of rapid ventricular pacing-induced heart failure in the dog.

We have recently described a modified model of progressive rapid ventricular pacing-induced heart failure which evolves over a period of 38 days. To further characterize left ventricular remodeling during the progression of heart failure, we assessed left ventricular geometry, wall stress, and atrial natriuretic peptide (ANP) gene expression and protein content during control conditions, asymptomatic left ventricular dysfunction, and overt congestive heart failure (CHF). Although asymptomatic left ventricular dysfunction was characterized by a significant increase in systolic and diastolic left ventricular dimension (+30% and +6%, respectively, P<0.05 each) and a marked increase in left ventricular systolic wall stress (+68%, P<0.01), left ventricular ANP gene expression was unchanged as compared to control. In contrast, strong left ventricular ANP gene expression (+449%, P<0.05) was observed during overt CHF in the absence of further significant increases in left ventricular systolic wall stress. The onset of strong left ventricular ANP gene expression was associated with increased ANP content (+88%, P<0.05) and left ventricular mass index (+13%, P<0.05). In contrast, left atrial ANP gene expression and left ventricular diastolic wall stress increased progressively during asymptomatic left ventricular dysfunction (+39%, P=n.s. and +131%, P<0.01) and overt CHF (+76% and +336% vs. control, P<0.01 each). Progressive rapid ventricular pacing is associated with the induction of left ventricular ANP gene expression and protein synthesis exclusively during overt CHF. The current studies provide new insight into the temporal pattern of ANP-activation and the disparity between left ventricular systolic wall stress and ANP-activation in a large animal model of progressive CHF.

Subcutaneous administration of brain natriuretic peptide in experimental heart failure.

OBJECTIVES: The objective of this investigation was to define for the first time the cardiorenal and humoral actions of repeated short-term administration of subcutaneous (SQ) brain natriuretic peptide (BNP) administration during the evolution of experimental heart failure. BACKGROUND: The rationale of this study was based on BNP as a vasodilating, natriuretic, renin-inhibiting and lusitropic peptide of cardiac origin. METHODS: First, we defined the cardiorenal and humoral responses to acute low and high dose (5 microg/kg or 25 microg/kg) of SQBNP in experimental heart failure to establish the acute efficacy of an SQ delivery. Second, we characterized the response to 10 days of repeated short-term administration of BNP during the evolution of experimental heart failure produced by rapid ventricular pacing. RESULTS: Plasma BNP and 3',5'-cyclic guanosine monophosphate rapidly increased and peaked at 30 min after acute SQBNP administration with increases in urinary sodium excretion, urine flow and renal blood flow in association with reductions in cardiac filling pressures. After 10 days of repeated short-term administration of SQBNP, cardiac output was increased and systemic vascular resistance and pulmonary capillary wedge pressure were decreased, as compared with untreated dogs with heart failure. CONCLUSIONS: This study demonstrated for the first time that repeated short-term administration of SQ BNP administration for 10 days during the evolution of left ventricular dysfunction in a canine model results in an improvement in cardiovascular hemodynamics. This investigation supports a potential novel strategy for the chronic administration of BNP in the therapeutics of heart failure.

Modulation of functionally active endothelin-converting enzyme by chronic neutral endopeptidase inhibition in experimental atherosclerosis.

BACKGROUND: Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2 isoforms (ECE-1alpha and ECE-1beta), the result of alternative splicing of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides mediate antiproliferative and vasodilating actions. We sought to demonstrate the distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with atheroma formation. Our hypothesis was that chronic NEP-I, in association with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and associated atheroma formation. METHODS AND RESULTS: Cholesterol-fed New Zealand White rabbits (n=8, 1% cholesterol diet) and NEP-I-treated cholesterol-fed New Zealand White rabbits (n=8; candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1alpha and ECE-1beta immunoreactivity was present in the aortas of both groups. Compared with control values, plasma cGMP concentrations were increased (2.8+/-0.6 versus 8.4+/-1.2 pmol/mL, P<0.05), ECE-1 activity was attenuated (68+/-3% versus 32+/-8%, P<0. 05), aortic tissue ET-1 concentrations were reduced (4.6+/-0.5 versus 3.2+/-0.3 pg/mg protein, P<0.05), and atheroma formation was attenuated (62+/-6% versus 34+/-5%, P<0.01) by NEP-I. CONCLUSIONS: These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.

Vascular actions of brain natriuretic peptide: modulation by atherosclerosis and neutral endopeptidase inhibition.

OBJECTIVES: We sought to define the vascular actions of the cardiac hormone brain natriuretic peptide (BNP) on cellular proliferation and cyclic guanosine monophosphate (cGMP) in human aortic vascular smooth muscle cells (HAVSMCs). Secondly, we investigated BNP and acetylcholine (ACh) vasorelaxations in aortic rings from normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of neutral endopeptidase (NEP). BACKGROUND: The vascular actions of BNP are not well defined, despite the presence of its receptor in vascular smooth muscle and the upregulation of NEP, the ectoenzyme that degrades BNP, in the vascular wall in atherosclerosis. METHODS: HAVSMCs stimulated with fetal calf serum (FCS) were pulsed with bromodeoxyuridine (BrdU) with and without BNP. The HAVSMCs were incubated in the presence and absence of BNP to assess cGMP. Vasorelaxations to BNP and ACh were assessed in rings in normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of NEP, together with assessment of atheroma formation. RESULTS: FCS-stimulated BrdU uptake in HAVSMCs was suppressed with BNP. BNP potentiated cGMP in HAVSMCs. BNP resulted in potent vasorelaxation in normal isolated aortic rings, which were impaired in atherosclerotic versus normal rabbits and preserved with NEP inhibition, which also decreased atheroma formation. Relaxations to ACh, which were also impaired in atherosclerosis, were preserved with inhibition of NEP. CONCLUSIONS: We conclude that BNP potently inhibits vascular smooth muscle cell proliferation and potentiates the generation of cGMP. BNP potently relaxes the normal rabbit aorta, and this response is impaired in atherosclerosis but preserved with inhibition of NEP, together with a reduction in atheroma formation and preservation of relaxations to ACh.

The influence of abciximab use on clinical outcome after aortocoronary vein graft interventions.

OBJECTIVES: The purpose of this study was to evaluate the effect of abciximab use on clinical outcome in aortocoronary vein graft interventions. BACKGROUND: Although large randomized trials have demonstrated a significant benefit of abciximab use in the setting of percutaneous coronary interventions, there is relatively little data with respect to the use of this agent in percutaneous vein graft interventions. METHODS: Three hundred and forty-three patients were identified; 210 undergoing vein graft intervention without abciximab and 133 patients with abciximab. RESULTS: There were differences in baseline clinical and angiographic characteristics between the two groups; advanced age, unstable angina, older vein grafts and thrombus containing lesions were relatively common in both groups. Angiographic and procedural success rates were similar with or without the use of abciximab (89% vs. 92%, p = 0.15, and 85% vs. 91%, p = 0.12, respectively). The in-hospital composite end point of death/Q-wave myocardial infarction (QWMI)/repeat revascularization was similar between the two groups. Utilizing statistical modeling to adjust for baseline differences between the groups, abciximab use did not influence the cumulative long-term composite end point of death/MI/repeat revascularization. CONCLUSIONS: This study demonstrates that in this relatively high-risk population undergoing aortocoronary vein graft interventions, the administration of abciximab periprocedurally does not appear to reduce major adverse clinical events.

Enhanced endothelin-converting enzyme immunoreactivity in early atherosclerosis.

Endothelin-1 (ET-1) is a 21-amino-acid local and circulating factor whose plasma concentrations are increased in advanced atherosclerosis. ET-1 is cleaved from a prohormone (big ET-1) by endothelin-converting enzymes (ECEs) into the biologically active mature form which mediates vasoconstriction and cell proliferation. This study was designed to test by immunohistochemistry the hypothesis that ECE is present locally in the neointima of atherosclerotic vessels. Two groups of rabbits, control (n = 6) and cholesterol-fed (1% cholesterol diet for 8 weeks; n = 6) were sacrificed. Aortas were excised and divided for determination of tissue ET-1 concentration by RIA and immunohistochemical analysis of ECE. Vascular wall ET-1 was increased in the atherosclerotic aorta (6.1 +/- 0.8 vs. 9.8 +/- 0.9 pg/mg protein; p < 0.05), whereas circulating ET-1 concentrations were similar in the two groups (3.8 +/- 0.4 vs. 2.4 +/- 1.4 pg/ml). Immunostaining revealed the presence of ECE in endothelial and vascular smooth-muscle cells of the control group. Enhanced ECE immunoreactivity was present in atherosclerotic aortas, particularly in the neointimal macrophages and smooth-muscle cells. We conclude that local vascular wall, but not circulating ET-1, is increased in early atherosclerosis. In addition, ECE immunoreactivity is increased in early atherosclerosis and may therefore contribute to the generation of local ET-1 in early experimental atherosclerosis. These studies provide important insights into the regulation of ET-1 in early atherosclerosis, which may contribute to the elucidation of factors involved in the progression of atherosclerosis.

Chronic oral endothelin type A receptor antagonism in experimental heart failure.

Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two distinct receptors, ET(A) and ET(B), resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ETA antagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing-induced CHF. These groups included a control untreated group (n = 6) and a group that received an orally active ET(A) receptor antagonist (A-127722, Abbott Pharmaceuticals, 5 mg/kg PO bid, n = 6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET(A) receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ET(A) receptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ET(A) receptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ET(A) receptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET-1 participates in the systemic and pulmonary vasoconstriction, the elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ET(A) receptor antagonism in CHF.

BNP: pathophysiological and potential therapeutic roles in acute congestive heart failure.

Controversy persists regarding the acute responsiveness of atrial (ANP) and brain (BNP) natriuretic peptides in pathophysiological conditions such as acute heart failure (AHF). This study was designed to test the hypothesis that AHF is characterized by selective activation of ANP, but not BNP. We also hypothesized that BNP replacement in AHF would reduce cardiac filling pressures, increase sodium excretion, and inhibit circulating renin. Two groups of anesthetized dogs underwent rapid left ventricular pacing to induce AHF. Group 1 (n = 7) served as control and group 2 (n = 7) received canine BNP (10 ng x kg(-1) x min(-1)). Cardiorenal parameters, circulating natriuretic peptides, 3',5'-cyclic guanosine monophosphate (cGMP), and plasma renin activity (PRA) were determined at baseline and during AHF in both groups. AHF was characterized by reductions in cardiac output (2.3 +/- 0.2 vs. 3.7 +/- 0.3 l/min, P < 0.05), pulmonary capillary wedge pressure (PCWP; 11.7 +/- 0.8 vs. 5.1 +/- 0.3 mmHg, P < 0.05), and selective activation of ANP (250 +/- 51 vs. 39 +/- 13 pg/ml, P < 0.05), with no increase in circulating BNP (49 +/- 15 vs. 60 +/- 16 pg/ml, P = not significant). Compared with control, exogenous supplemental BNP in AHF resulted in marked increases in circulating cGMP (65 +/- 6 vs. 18 +/- 5 pg/ml, P < 0.05), with reductions in PCWP (9.1 +/- 0.9 vs. 12.9 +/- 1.1 mmHg, P < 0.05) and increased urinary sodium excretion (120 +/- 36.8 vs. 24 +/- 6.3 microeq/min, P < 0.05) via reductions in distal tubular sodium reabsorption (94.3 +/- 1.8 vs. 98.0 +/- 0.4%, P < 0.05). Exogenous BNP prevented the increase in PRA that occurred in the control group. We conclude that AHF is characterized by a failure to increase circulating BNP underscoring differential physiological and pathophysiological roles for ANP and BNP in states of immediate cardiac overload. These studies also support a potential role for BNP in the therapeutics of AHF.

Fluorescein transport in isolated proximal tubules in vitro: epifluorometric analysis.

An epifluorometric method was used to quantify the bidirectional fluxes of fluorescein across the basolateral surfaces of nonperfused rabbit tubule segments in vitro. Proximal S2 segments, but not cortical collecting tubules or cortical thick ascending limbs, accumulated fluorescein to levels in cytoplasm over 100-fold greater than in the external medium. The rate of intracellular fluorescein accumulation was dependent on the concentration of the ligand in the external bath. The apparent Km was 10 microM and the Vmax was 623 x 10(-6) mol.min-1.l-1. Probenecid and ouabain inhibited fluorescein accumulation. We conclude that fluorescein is transported into the cytoplasm of proximal tubules by basolateral mechanisms that share features in common with the classical organic anion system. This fluorescent compound offers some unique advantages for the study of the organic anion transport system in intact cells.

Effect of amiloride on the compensatory renal growth that follows uninephrectomy in mice.

The increase in contralateral kidney mass that follows the removal of one kidney is caused primarily by the hypertrophy and, to a lesser extent, the hyperplasia of tubule cells. Amiloride inhibits the proliferation of cells in tissue culture environments and diminishes compensatory hyperplasia of liver cells after partial hepatectomy. In the current study, we determined the extent to which amiloride diminished the compensatory increase in contralateral kidney weight and protein content after uninephrectomy. Caworth Farms mice, 3 to 4 months of age, received amiloride by daily intraperitoneal injection for 7 days before the left kidney was removed and for an additional 4 days after nephrectomy. Four days after uninephrectomy, compensatory hypertrophy was quantified by the increase in weight and protein content of the right kidney in comparison with the left (R - L divided by L x 100; [weight] +24.7% +/- 2.9% and [protein] +20.6% +/- 4.4%). Treatment with amiloride reversibly reduced the compensatory increase in kidney weight and protein content (dose required to achieve 50% inhibition, 11.4 and 2.4 mg/kg/day, respectively). Hexamethylene amiloride, an analog with weak affinity for conductive Na+ channels and high affinity for Na+-H+ exchangers, had no effect on compensatory hypertrophy. Spironolactone, a natriuretic and antikaliuretic agent of potency similar to that of amiloride, but with a different cellular mechanism of action, had no effect on compensatory hypertrophy. We conclude that amiloride reversibly blunts the compensatory renal hypertrophy after uninephrectomy in mice by mechanisms that appear to be separate from the drug's effects to block Na+-H+ exchange and transepithelial Na+ and K+ transport.

Chemical modification of cell proliferation and fluid secretion in renal cysts.

We used an in vitro model, MDCK cyst, to determine the extent to which pharmacologic compounds known to inhibit plasma membrane solute transport mechanisms could alter the enlargement of renal epithelial cysts. Solitary MDCK cells cultured within collagen gel undergo clonal growth to form true epithelial cysts in which a single layer of polarized cells (apex toward lumen) encloses a fluid-filled cavity. Repeated observations by light microscopy were used to quantitate the rate of cyst growth in diameter, and demonstrated that cyst enlargement involved an increase in cell number (proliferation) and a net increase in intracystic volume (fluid secretion). Intracyst pressure was greater than the interstitium (6.7 mm H2O +/- 3.1 SD), indicating that fluid entry was secondary to net solute accumulation. Amiloride and seven amiloride analogs that inhibited to different degrees conductive Na+ transport, Na+-dependent H+ transport and Na+-dependent Ca++ transport reversibly decreased the rate of cyst enlargement. The effectiveness of these agents to retard cyst enlargement correlated with their relative potencies to inhibit Na+-dependent Ca++ transport. Morphologic examination indicated that amiloride and amiloride analogs decreased cell proliferation and fluid secretion to the same degree. Ouabain and vanadate (Na+K,ATPase inhibitors), and L-645,695 (Na+-dependent Cl-/HCO3- inhibitor) potently slowed cyst expansion. In contrast to amiloride and amiloride analogs, these agents caused an unusual degree of cellular stratification within the cyst walls, a finding consistent with the notion that fluid secretion was inhibited to a greater extent then cellular proliferation. We conclude that chemical inhibitors of primary and secondary active solute transport can diminish or halt the enlargement of epithelial cysts in vitro by decreasing the rate of cellular proliferation and/or net fluid secretion.