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1.
JACC Heart Fail ; 11(8 Pt 2): 1103-1117, 2023 08.
Article in English | MEDLINE | ID: mdl-36939661

ABSTRACT

BACKGROUND: Many patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure. OBJECTIVES: This study sought to characterize patients with normal resting LA pressure (pulmonary capillary wedge pressure [PCWP] <15 mm Hg) but exercise-induced left atrial hypertension (EILAH). METHODS: The REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH). RESULTS: Patients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e', and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU) and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present. CONCLUSIONS: Patients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033).


Subject(s)
Atrial Fibrillation , Heart Failure , Hypertension , Humans , Atrial Fibrillation/complications , Atrial Fibrillation/therapy , Cardiac Catheterization , Heart Failure/complications , Heart Failure/therapy , Heart Failure/diagnosis , Stroke Volume/physiology , Ventricular Function, Left
4.
Arterioscler Thromb Vasc Biol ; 30(3): 477-82, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20056912

ABSTRACT

OBJECTIVE: In a previous study we identified metallothionein (MT) as a candidate gene potentially influencing collaterogenesis. In this investigation, we determined the effect of MT on collaterogenesis and examined the mechanisms contributing to the effects we found. METHODS AND RESULTS: Collateral blood flow recovery was assessed using laser Doppler perfusion imaging, and angiogenesis was measured using a Matrigel plug assay. Smooth muscle cells were isolated from MT knockout (KO) mice for functional assays. Gene expression of matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, and Fat cadherin in smooth muscle cells was measured by real-time polymerase chain reaction, and protein levels of vascular endothelial growth factor and matrix metalloproteinase-9 were determined using enzyme-linked immunosorbent assay and Western blot. CD11b(+) macrophages were tested for invasiveness using a real-time impedance assay. Both flow recovery and angiogenesis were impaired in MT KO mice. Proliferation, migration, and invasion were decreased in MT KO smooth muscle cells, and matrix metalloproteinase-9, platelet-derived growth factor, and vascular endothelial growth factor expression were also decreased, whereas FAT-1 cadherin expression was elevated. MT KO CD11b(+) cells were more invasive than wild-type cells. CONCLUSIONS: MT plays an important role in collateral flow recovery and angiogenesis, an activity that appears to be mediated, in part, by the effects of MT on the functionality of 3 cell types essential for these processes: endothelial cells, smooth muscle cells, and macrophages.


Subject(s)
Arteries/growth & development , Macrophages/physiology , Metallothionein/physiology , Muscle, Smooth, Vascular/physiology , Neovascularization, Physiologic/physiology , Animals , Arteries/cytology , Cell Movement/physiology , Cell Proliferation , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/physiology , Hindlimb/blood supply , Macrophages/cytology , Male , Metallothionein/genetics , Mice , Mice, Knockout , Models, Animal , Muscle, Smooth, Vascular/cytology , Regional Blood Flow/physiology
6.
Am J Physiol Heart Circ Physiol ; 292(4): H1891-7, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17189353

ABSTRACT

Despite numerous animal trials reporting that cell therapy promotes collateral flow, clinical trials have not convincingly shown benefit. Patient-related risk factors are often used to explain these discrepancies. However, during the course of our own angiogenesis studies using mice, we noted large anatomical variability in collateral vessels. The purpose of the present investigation was to define how important this factor might be in determining intervention outcomes. Hindlimb ischemia was induced in BALB/c mice by ligating the superficial femoral artery. After 24 h, animals were treated by injecting the adductor muscle with either control media or cultured mesenchymal stem cells (MSCs). Blood flow recovery was measured using laser-Doppler [laser-Doppler perfusion imaging (LDPI) ratio]. In a second experiment, mice were stratified 24 h after arterial ligation before treatment by using a simple clinical score of the ligated leg: 1, able to flex, mild discoloration; 2, no flexion, mild discoloration; 3, severe discoloration; and 4, any necrosis. Without stratification, blood flow recovery significantly increased in the MSC-treated group (P < 0.05, n = 6 MSC group, n = 7 media group). In the experiment employing stratification, all differences between the groups disappeared (n = 11 MSC group, n = 10 media group; P = 0.3). Furthermore, we found a striking inverse correlation between clinical score on day 1 and the LDPI ratio on day 28 (P < 0.0001; n = 79). Anatomical confirmation of the disparity in preexisting collaterals was found in two different mouse strains using microscopic computed tomography. In conclusion, there is substantial interanimal variability in preexisting collateral flow, and this variability can importantly influence outcome. To overcome this, either animals must be stratified before treatment, the number of animals must be increased substantially, or, preferably, both.


Subject(s)
Collateral Circulation/physiology , Disease Models, Animal , Ischemia/physiopathology , Ischemia/therapy , Mesenchymal Stem Cell Transplantation , Mice, Inbred BALB C , Animals , Corrosion Casting , Femoral Artery , Hindlimb/blood supply , Ischemia/pathology , Laser-Doppler Flowmetry , Ligation , Mice , Mice, Inbred C57BL , Necrosis , Predictive Value of Tests , Regional Blood Flow , Sensitivity and Specificity
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