Advanced glycation end products accumulate in vascular smooth muscle and modify vascular but not ventricular properties in elderly hypertensive canines.

BACKGROUND: Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. METHODS AND RESULTS: Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure-volume analysis and aortic pressure-dimension and pressure-flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N(epsilon)-(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs. CONCLUSIONS: In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.

Titin isoforms, extracellular matrix, and global chamber remodeling in experimental dilated cardiomyopathy: functional implications and mechanistic insight.

BACKGROUND: Altered titin isoforms may modify cardiac function in heart failure (HF), but the nature of isoform switches and associated functional implications are not well defined. Limited studies have reported an increased compliant isoform (N2BA) expression in human systolic HF. Titin may also modulate stretch-regulated responses such as myocardial natriuretic peptide production. METHODS AND RESULTS: We characterized titin isoform expression and extracellular matrix in all 4 cardiac chambers and the left ventricular (LV) epicardium and endocardium in normal dogs (n=6) and those with HF (n=6) due to tachypacing and characterized functional implications at the LV myofiber and chamber level. Recognizing the potential for uncoupling of the extracellular matrix and cardiomyocyte in tachypacing, myocardial natriuretic peptide production, a molecular marker of stretch-regulated responses, was also assessed. All chambers were dilated in HF, but the extracellular matrix was not increased. HF dogs had markedly lower N2BA in the atria and right ventricle. In failing LVs, N2BA was decreased only in the epicardium, where myofiber passive stiffness was increased. However, LV chamber mechanics were driven by the marked LV dilatation, with no increase in LV diastolic stiffness. Natriuretic peptide concentrations increased markedly in the endocardium in relation to increases in LV wall stress. CONCLUSIONS: Tachypacing HF is characterized by decreases in compliant titin isoform expression in the atria, right ventricle, and LV epicardium. However, LV chamber mechanics are principally determined by geometric and extracellular matrix changes rather than titin-based myofiber stiffness in this model. Stretch-regulated myocardial responses (natriuretic peptide production) appeared intact, suggesting that the mechanotransduction role of titin was not impaired in HF.

Revisiting methods for assessing and comparing left ventricular diastolic stiffness: impact of relaxation, external forces, hypertrophy, and comparators.

Understanding diastolic function mandates feasible and accurate methods to construct and compare the diastolic pressure (P)-volume (V) relationship (PVR). This study compared the relaxation-corrected single beat (RC-SB) to the multiple-beat (MB) (vena cava occlusion) method for constructing the diastolic PVR in 26 young normal or old hypertensive dogs before and after increases in afterload (phenylephrine) or acute volume expansion in the presence (n = 14) or absence (n = 12) of the pericardium. The PVR data were fit to P = alphae(beta x V). Derived stiffness indexes compared included the stiffness coefficient (beta), curve-fitting constant (alpha), and the end-diastolic volume (EDV) at 10, 20, or 30 mmHg [EDV(x) = ln(P(x)/alpha)/beta] to account for covariance in alpha and beta. In pericardium-intact young normal and old hypertensive dogs studied over varying afterloads, the MB and RC-SB PVR appeared identical. The beta (r = 0.62) and alpha (r = 0.69) derived from the RC-SB vs. MB PVR showed moderate correlation but poor agreement. In contrast, the EDV(10-30) derived from RC-SB vs. MB PVR showed excellent correlation (r = 0.97) and agreement. The uncorrected SB method underestimated stiffness. As expected, after acute volume expansion, the RC-SB PVR was shifted upward from the MB PVR (decreased EDV(10-30); P < 0.05) in the pericardium-intact but not pericardium-absent dogs. The RC-SB method can substitute for the MB technique in construction of PVR in the absence of acute volume expansion. The concordance between these two methods was poorly reflected by comparing the derived alpha and beta but apparent when using EDV(10-30), which provides information regarding the position of the PVR in a single number.

Acute and chronic ventricular-arterial coupling in systole and diastole: insights from an elderly hypertensive model.

Aging and hypertension lead to arterial remodeling and tandem increases in arterial (Ea) and ventricular (LV) systolic stiffness (ventricular-arterial [VA] coupling). Age and hypertension also predispose to heart failure with normal ejection fraction (HFnlEF), where symptoms during hypertensive urgencies or exercise are common. We hypothesized that: (1) chronic VA coupling also occurs in diastole, (2) acute changes in Ea are coupled with shifts in the diastolic and systolic pressure-volume relationships (PVR), and (3) diastolic VA coupling reflects changes in LV diastolic stiffness rather than external forces or relaxation. Old chronically hypertensive (OHT, n=8) and young normal (YNL, n=7) dogs underwent assessment of PVR (caval occlusion) and of aortic pressure, dimension, and flow, at baseline and during changes in afterload and preload. Concomitant changes in the slope/position of PVR were accounted for by calculating systolic (ESV(200)) and diastolic (EDV(20)) volumes at common pressures (capacitance). OHT displayed marked vascular remodeling. Indices reflecting the pulsatile component of Ea (aortic stiffness and systemic arterial compliance) were more impaired in OHT at any distending pressure. In both groups, acute increases in Ea were associated with decreases in ESV(200) and EDV(20). However, at any load, OHT had lower ESV(200) and EDV(20), associated with LV remodeling and myocardial endothelin activation. Acute changes in EDV(20) were not mediated by changes in relaxation or external forces. These observations provide insight into the mechanisms whereby arterial remodeling and acute and chronic VA coupling in both systole and diastole may predispose to and interact with increases in load to cause HFnlEF.

Ventricular structure and function in aged dogs with renal hypertension: a model of experimental diastolic heart failure.

BACKGROUND: Heart failure (HF) with normal ejection fraction (diastolic HF [DHF]) usually occurs in elderly patients with hypertension. The presence and significance of altered systolic and diastolic ventricular function in DHF is increasingly controversial. Our objective was to develop a clinically relevant large-animal model to better understand the pathophysiology of DHF. METHODS AND RESULTS: Ventricular structure and function were characterized in young control (YC group; n=6), old control (OC group; n=7), and old dogs made hypertensive by renal wrapping (experimental DHF [ExDHF] group; n=8). The ExDHF group was associated with normal left ventricular (LV) volume, increased LV mass, and myocardial fibrosis. LV relaxation was impaired in ExDHF (tau=53+/-6 ms) compared with OC (tau=35+/-3 ms; P<0.05) and YC (tau=33+/-6 ms; P<0.05) dogs. The percent diastole at which relaxation is complete was increased in ExDHF (116+/-30%) compared with OC (69+/-8%; P<0.05) and YC (35+/-5%; P<0.05) dogs. The coefficient of LV diastolic stiffness was similar in OC, YC, and ExDHF dogs. Diastolic pressures increased dramatically in response to increases in blood pressure. End-systolic LV stiffness was enhanced in ExDHF dogs and after load enhancement of myocardial performance was maintained. Arterial stiffness was increased in ExDHF dogs. CONCLUSIONS: Aged dogs with chronic hypertension exhibit LV hypertrophy and fibrosis with impaired LV relaxation but no increase in the coefficient of LV diastolic stiffness. LV systolic and arterial stiffness are increased, which may exacerbate load-dependent impairment of relaxation and contribute to increased filling pressures with hypertensive episodes. This model mimics many of the structural and functional characteristics described in the limited studies of human DHF and provides insight into the pathogenesis of DHF.

Acute and chronic reduction of functional mitral regurgitation in experimental heart failure by percutaneous mitral annuloplasty.

OBJECTIVES: We sought to determine acute and chronic efficacy of a percutaneous mitral annuloplasty (PMA) device in experimental heart failure (HF). Further, we evaluated the potential for adverse effects on left ventricular (LV) function and coronary perfusion. BACKGROUND: Reduction of mitral annular dimension with a PMA device in the coronary sinus may reduce functional mitral regurgitation (MR) in advanced HF. METHODS: Study 1: a PMA device was placed acutely in anesthetized open-chest dogs with rapid pacing-induced HF (n = 6) instrumented for pressure volume analysis. Study 2: in 12 anesthetized dogs with HF, fluoroscopic-guided PMA was performed, and dogs were followed for four weeks with continuing rapid pacing. RESULTS: Study 1: percutaneous mitral annuloplasty reduced annular dimension and severity of MR at baseline and with phenylephrine infusion to increase afterload (MR jet/left atrial [LA] area 26 +/- 1% to 7 +/- 2%, p < 0.05). Pressure volume analysis demonstrated no acute impairment of LV function. Study 2: no device was placed in two dogs because of prototype size limitations. Attempted PMA impaired coronary flow in three dogs. Percutaneous mitral annuloplasty (n = 7) acutely reduced MR (MR jet/LA area 43 +/- 4% to 8 +/- 5%, p < 0.0001), regurgitant volume (14.7 +/- 2.1 ml to 3.1 +/- 0.5 ml, p < 0.05), effective regurgitant orifice area (0.130 +/- 0.010 cm(2) to 0.040 +/- 0.003 cm(2), p < 0.05), and angiographic MR grade (2.8 +/- 0.3 device to 1.0 +/- 0.3 device, p < 0.001). In the conscious state, MR was reduced at four weeks after PMA (MR jet/LA area 33 +/- 3% HF baseline vs. 11 +/- 4% four weeks after device, p < 0.05) CONCLUSIONS: Percutaneous mitral annuloplasty results in acute and chronic reduction of functional MR in experimental HF.

3-D model of a total hip replacement in vivo providing hydrodynamic pressure and film thickness for walking and bicycling.

Formulation of a 3-D lubrication simulation of a total hip replacement in vivo is presented using a finite difference approach. The goal is to determine if hydrodynamic lubrication is taking place, how thick the joint fluid film is and over what percentage of two gait cycles, (walking and bicycling), the hydrodynamic lubricating action is occurring, if at all. The assumption of rigid surfaces is made, which is conservative in the sense that pure hydrodynamic lubrication is well known to predict thinner films than elasto-hydrodynamic lubrication (EHL) for the same loading. The simulation method includes addressing the angular velocity direction changes and accurate geometry configuration for the acetabular cup and femoral head components and provides a range of results for material combinations of CoCrMo-on-UHMWPE, CoCrMo-on-CoCrMo, and alumina-on-alumina components. Results are in the form of the joint fluid film pressure distributions, load components and film thicknesses of the joint fluid, for the gait cycles of walking and bicycling. Results show hydrodynamic action occurs in only about 10% of a walking gait cycle and throughout nearly 90% of a bicycling gait. During the 10% of the walking cycle that develops hydrodynamic lubrication, the minimum fluid film thicknesses are determined to be between 0.05 micron and 1.1 microns, while the range of film thicknesses for bicycling is between 0.1 micron and 1.4 microns, and occurs over 90% of the bicycling gait. Pressure distributions for these same periods are in the range of 2 MPa to 870 MPa for walking and 1 MPa to 24 MPa for bicycling.

Hemodynamic and humoral effects of vasopeptidase inhibition in canine hypertension.

Vasopeptidase inhibitors are potent new antihypertensive agents. The dual inhibition of ACE and neutral endopeptidase may result in synergistic humoral effects with unique hemodynamic actions. We investigated the hemodynamic and neurohumoral effects of vasopeptidase inhibition in conscious dogs made hypertensive by bilateral renal wrapping and subsequently instrumented for long-term assessment of left ventricular pressure and volume (n=8). Intravenous vasopeptidase inhibition (omapatrilat, 30 micromol/kg over 10 minutes) reduced peak left ventricular pressure (171+/-6 versus 130+/-6 mm Hg immediately after infusion, P<0.01) through arterial vasodilation (arterial elastance, 9.8+/-0.8 to 5.8+/-1.6 mm Hg/mL, P<0.01) and preload reduction (left ventricular end-diastolic volume, 51.1+/-6.8 to 46.0+/-6.9 mL, P<0.01). At 60 minutes, preload decreased further (40.5+/-5.9 mL, P<0.01 versus baseline). Vasopeptidase inhibition increased plasma levels of adrenomedullin (41.2+/-9.6 versus 72.3+/-15 pg/mL, P<0.01), whereas levels of the natriuretic peptides and cGMP were unchanged. Similar hemodynamic and humoral effects were observed with long-term therapy. Neither an equimolar dose of an ACE inhibitor (fosinopril) nor exogenous adrenomedullin had as potent of a hypotensive effect, and neither reduced preload. In summary, the potent short-term and long-term hypotensive effects of vasopeptidase inhibition were prominently mediated by preload reduction, an effect not reproduced by ACE inhibition nor adrenomedullin augmentation and not associated with enhanced natriuretic peptide levels. Combined arterial vasodilation and preload reduction may confer additional potency as well as unique cardioprotective effects. Synergistic effects on humoral and probably endothelial vasodilatory factors appear to be important in mediating the unique hemodynamic profile of vasopeptidase inhibition in this form of experimental hypertension.

Actions of a novel synthetic natriuretic peptide on hemodynamics and ventricular function in the dog.

Dendroaspis natriuretic peptide (DNP) is a recently discovered peptide with structural similarity to known natriuretic peptides. DNP has been shown to possess potent renal actions. Our objectives were to define the acute hemodynamic actions of DNP in normal anesthetized dogs and the acute effects of DNP on left ventricular (LV) function in conscious chronically instrumented dogs. In anesthetized dogs, DNP, but not placebo, decreased mean arterial pressure (141 +/- 6 to 109 +/- 7 mmHg, P < 0.05) and pulmonary capillary wedge pressure (5.8 +/- 0.3 to 3.4 +/- 0.2 mmHg, P < 0.05). Cardiac output decreased and systemic vascular resistance increased with DNP and placebo. DNP-like immunoreactivity and guanosine 3',5'-cyclic monophosphate concentration increased without changes in other natriuretic peptides. In conscious dogs, DNP decreased LV end-systolic pressure (120 +/- 7 to 102 +/- 6 mmHg, P < 0.05) and volume (32 +/- 6 to 28 +/- 6 ml, P < 0.05) and LV end-diastolic volume (38 +/- 5 to 31 +/- 4 ml, P < 0.05) but not arterial elastance. LV end-systolic elastance increased (6.1 +/- 0.7 to 7.4 +/- 0.6 mmHg/ml, P < 0.05), and Tau decreased (31 +/- 2 to 27 +/- 1 ms, P < 0.05). The effects on hemodynamics, LV function, and second messenger generation suggest synthetic DNP may have a role as a cardiac unloading and lusitropic peptide.