[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: gly96/IEX 1 is a growth- and apoptosis-regulating, immediate early gene that is widely expressed in epithelial and vascular tissues. In vascular tissues, expression of the gene is induced by mechanical stretch, and overexpression of the gene prevents injury-induced vascular smooth muscle hypertrophy and neointimal hyperplasia. We now show that deletion of the gly96/IEX-1 gene in mice is associated with development of elevated blood pressure, cardiac hypertrophy, and diminished fractional shortening of the left ventricle. Systolic blood pressure in conscious male gly96/IEX-1-/- mice is 20-25 mmHg higher than in gly96/IEX-1+/+ mice. Serum and/or urine concentrations of sodium, potassium, creatinine, angiotensin II, corticosterone, aldosterone, epinephrine, norepinephrine, prostaglandin E2, thromboxane B2, prostaglandin-6-keto-1alpha, nitrites and nitrates, cAMP, and cGMP are normal in gly96/IEX-1-/- mice. Alterations in dietary sodium intake do not alter blood pressure in gly96/IEX-1-/- mice. Aortic mRNAs for endothelial nitric oxide synthase, guanylate cyclase-alpha, and cGMP kinase-1 are increased in gly96/IEX-1-/- mice. Treatment with Nomega-nitro-L-arginine methyl ester or L-arginine does not alter blood pressure in gly96/IEX-1-/- mice. Gly96/IEX-1-/- mice respond to infused sodium nitroprusside with decrements in blood pressure similar to those seen in wild-type littermate mice. In contrast to gly96/IEX-1 transgenic mice that have abnormalities in immune function, gly96/IEX-1-/- mice have normal lymphoid tissue architecture and a normal complement of T and B cells in lymphoid tissues. Ablation of the gly96/IEX-1 gene results in hypertension and cardiac hypertrophy, suggesting a novel role for this gene in cardiovascular physiology.
Journal of Applied Physiology 03/2006; 100(2):707-16. · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial (ANP) and brain (BNP) natriuretic peptides are hormones of myocardial cell origin. These hormones bind to the natriuretic peptide A receptor (NPRA) throughout the body, stimulating cGMP production and playing a key role in blood pressure control. Because NPRA receptors are present on cardiomyocytes, we hypothesized that natriuretic peptides may have direct autocrine or paracrine effects on cardiomyocytes or adjacent cardiac cells. Because both natriuretic peptides and NPRA gene expression are upregulated in states of pressure overload, we speculated that the effects of the natriuretic peptides on cardiac structure and function would be most apparent after pressure overload. To attenuate cardiomyocyte NPRA activity, transgenic mice with cardiac specific expression of a dominant-negative (DN-NPRA) mutation (HCAT D 893A) in the NPRA receptor were created. Cardiac structure and function were assessed (avertin anesthesia) in the absence and presence of pressure overload produced by suprarenal aortic banding. In the absence of pressure overload, basal and BNP-stimulated guanylyl cyclase activity assessed in cardiac membrane fractions was reduced. However, systolic blood pressure, myocardial cGMP, log plasma ANP levels, and ventricular structure and function were similar in wild-type (WT-NPRA) and DN-NPRA mice. In the presence of pressure overload, myocardial cGMP levels were reduced, and ventricular hypertrophy, fibrosis, filling pressures, and mortality were increased in DN-NPRA compared with WT-NPRA mice. In addition to their hormonal effects, endogenous natriuretic peptides exert physiologically relevant autocrine and paracrine effects via cardiomyocyte NPRA receptors to modulate cardiac hypertrophy and fibrosis in response to pressure overload.
[Show abstract][Hide abstract] ABSTRACT: 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.
Reduction of mitral annular dimension with a PMA device in the coronary sinus may reduce functional mitral regurgitation (MR) in advanced HF.
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.
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)
Percutaneous mitral annuloplasty results in acute and chronic reduction of functional MR in experimental HF.
Journal of the American College of Cardiology 11/2004; 44(8):1652-61. · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mitral regurgitation (MR) may develop in patients with advanced systolic congestive heart failure (CHF) without organic mitral valve disease and contribute to worsening symptoms and survival. Surgical mitral annuloplasty improves symptoms in patients with advanced CHF, and percutaneous approaches to mitral annuloplasty are being developed. Our objective was to define the prevalence, clinical correlates, and prognostic implications of functional MR and the use of mitral annuloplasty in patients with advanced systolic CHF evaluated in a heart failure clinic.
We reviewed clinical, echocardiographic, and survival data from all patients with advanced systolic CHF (New York Heart Association class III or IV; ejection fraction </=35%) resulting from ischemic or idiopathic cardiomyopathy who were evaluated at our heart failure clinic between January 1996 and September 2001. Of 716 patients with advanced CHF, 558 had satisfactory baseline echocardiograms performed at our institution. Among these patients, MR was severe in 24 (4.3%), moderate-severe in 70 (12.5%), moderate in 122 (21.9%), mild-moderate in 66 (11.8%), mild in 218 (39.1%), and absent or present as only a trace in 58 (10.4%). The severity of MR was confirmed by quantitative analysis in 72% of patients with hemodynamically significant MR (more than moderate). The severity of MR correlated with the severity of systolic dysfunction (P <.001), ventricular dilatation (P <.03), atrial dilatation (P <.001), diastolic dysfunction (P <.001), and pulmonary hypertension (P <.001). Coexistent severe or moderate-severe tricuspid regurgitation was present in 25% of patients with hemodynamically significant MR. Patients with hemodynamically significant MR had higher mortality (P=.03) but not when controlling for age, sex, cause, New York Heart Association class, and ejection fraction (P=.95). Only 3 patients subsequently underwent mitral valve repair.
Among patients with advanced CHF, hemodynamically significant MR is common. The severity of MR did not provide independent prognostic information in this group recognized to have uniformly high mortality.
Journal of Cardiac Failure 09/2004; 10(4):285-91. · 3.32 Impact Factor