Haemodynamic factors influence all forms of vascular growth (vasculogenesis, angiogenesis, arteriogenesis). Because of its prominent role in atherosclerosis, shear stress has gained particular ...attention, but other factors such as circumferential stretch are equally important to maintain the integrity and to (re)model the vascular network. While these haemodynamic forces are crucial determinants of the appearance and the structure of the vasculature, they are in turn subjected to structural changes in the blood vessels, such as an increased arterial stiffness in chronic arterial hypertension and ageing. This results in an interplay between the various forces (biomechanical forces) and the involved vascular elements. Although many molecular mediators of biomechanical forces still need to be identified, there is plenty of evidence for the causal role of these forces in vascular growth processes, which will be summarized in this review. In addition, we will discuss the effects of concomitant diseases and disorders on these processes by altering either the biomechanics or their transduction into biological signals. Particularly endothelial dysfunction, diabetes, hypercholesterolaemia, and age affect mechanosensing and -transduction of flow signals, thereby underpinning their influence on cardiovascular health. Finally, current approaches to modify biomechanical forces to therapeutically modulate vascular growth in humans will be described.
The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that ...the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease.
Mice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb postnatally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers.
This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Submitted 7 April 2006
; accepted in final form 22 May 2006
We characterized hemodynamics and systolic and ...diastolic right ventricular (RV) function in relation to structural changes in the rat model of monocrotaline (MCT)-induced pulmonary hypertension. Rats were treated with MCT at 30 mg/kg body wt (MCT30, n = 15) and 80 mg/kg body wt (MCT80, n = 16) to induce compensated RV hypertrophy and RV failure, respectively. Saline-treated rats served as control (Cont, n = 13). After 4 wk, a pressure-conductance catheter was introduced into the RV to assess pressure-volume relations. Subsequently, rats were killed, hearts and lungs were rapidly dissected, and RV, left ventricle (LV), and interventricular septum (IVS) were weighed and analyzed histochemically. RV-to-(LV + IVS) weight ratio was 0.29 ± 0.05 in Cont, 0.35 ± 0.05 in MCT30, and 0.49 ± 0.10 in MCT80 ( P < 0.001 vs. Cont and MCT30) rats, confirming MCT-induced RV hypertrophy. RV ejection fraction was 49 ± 6% in Cont, 40 ± 12% in MCT30 ( P < 0.05 vs. Cont), and 26 ± 6% in MCT80 ( P < 0.05 vs. Cont and MCT30) rats. In MCT30 rats, cardiac output was maintained, but RV volumes and filling pressures were significantly increased compared with Cont (all P < 0.05), indicating RV remodeling. In MCT80 rats, RV systolic pressure, volumes, and peak wall stress were further increased, and cardiac output was significantly decreased (all P < 0.05). However, RV end-systolic and end-diastolic stiffness were unchanged, consistent with the absence of interstitial fibrosis. MCT-induced pressure overload was associated with a dose-dependent development of RV hypertrophy. The most pronounced response to MCT was an overload-dependent increase of RV end-systolic and end-diastolic volumes, even under nonfailing conditions.
right ventricular hypertrophy; right ventricular failure; pressure-volume relations
Address for reprint requests and other correspondence: P. Steendijk, Dept. of Cardiology, C5-P, Leiden Univ. Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands (e-mail: p.steendijk{at}lumc.nl )
Background:
In heart failure patients, cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling.
Aim:
The aim of this study was to evaluate whether changes in levels of ...circulating biomarkers of extracellular matrix metabolism correlate with the response to CRT.
Methods and results:
Clinical parameters, left ventricular (LV) volumes, and circulating levels of tenascin-C (TNC), matrix metalloproteinase-2 (MMP-2), MMP-9, and amino-terminal propeptide of brain natriuretic peptide (NT-proBNP) were assessed in 64 patients at baseline and 6 months follow-up. The majority of patients (72%) showed a >10% reduction in LV end-systolic volume at follow-up, and were classified as responders to CRT. The remaining patients were classified as non-responders. In responders, a significant decrease in circulating levels of TNC (from 60±40ng/mL to 47±30ng/mL, p<0.01), MMP-9 (from 55±30 AU to 44±27 AU, p<0.01), and NT-proBNP (from 2106±1805pg/mL to 1132±1289pg/mL, p<0.001) were observed at follow-up; MMP-2 levels were unchanged. In non-responders TNC, NT-proBNP, MMP-9 and MMP-2 levels remained unchanged.
Conclusion:
At 6months follow-up, CRT was associated with reverse LV remodelling, and a significant decrease in TNC, MMP-9, and NT-proBNP levels. This suggests an important role of ECM modulation in the process of reverse ventricular remodelling in patients responding to CRT.
Abstract MRI using targeted contrast agents (CA) has emerged as a promising technique to study atherothrombotic disease in vivo. Particularly, the use of targeted Gd and lipid-based nanoparticles has ...enabled detailed in vivo imaging of various molecular markers of atherosclerotic plaque pathophysiology. For validation purposes, it is crucial that nanoparticle accumulation in the plaque, cellular association and localization can be assessed by ex vivo immuno-histology or fluorescence microscopy of tissue sections. In this review we discuss the various methods that are available for histological evaluation of targeted MRI contrast agents such as lipid-based nanoparticles and iron oxide particles. We discuss the detection of these contrast agents in paraffin-embedded and in cryopreserved tissue sections of atherosclerotic plaques. During the embedding procedure in paraffin, most components of targeted lipid-based nanoparticles are generally washed out, though the actual targeting moieties may be retained in the embedded sections. Therefore staining of the antibody–antigen complex provides a suitable way to visualize the presence of the nanoparticle in the plaque. In cryosections, the localization of nanoparticles can be assessed directly by measuring the fluorescence of an incorporated fluorophore or by secondary stainings of the Gd-containing DTPA lipids or the iron oxide particles. With certain secondary stainings, be it for the contrast agent or for co-localization with the target, the contrast agent itself may interfere with standard histological protocols, yielding false positive results. The here presented techniques enable proper visualization of MR contrast agent accumulation and localization in atherosclerotic plaque, which will provide the validation necessary to advance these lipid-based nanoparticles to the clinic.
Recent advances in molecular resonance imaging of atherosclerosis enable to visualize atherosclerotic plaques in vivo using molecular targeted contrast agents. This offers opportunities to study ...atherosclerosis development and plaque vulnerability noninvasively. In this review, we discuss MRI contrast agents targeted toward atherosclerotic plaques and illustrate how these new imaging platforms could assist in our understanding of atherogenesis and atheroprogression. In particular, we highlight the challenges and limitations of the different contrast agents and hurdles for clinical application. We describe the most promising existing compounds to detect atherosclerosis and plaque vulnerability. Of particular interest are the fibrin-targeted compounds that detect thrombi and, furthermore, the contrast agents targeted to integrins that allow to visualize plaque neovascularization. Moreover, vascular cell adhesion molecule 1–targeted iron oxides seem promising for early detection of atherosclerosis. These targeted MRI contrast agents, however promising and well characterized in (pre)clinical models, lack specificity for plaque vulnerability.
High-resolution contrast-enhanced imaging of the murine atherosclerotic vessel wall is difficult due to unpredictable flow artifacts, motion of the thin artery wall and problems with flow suppression ...in the presence of a circulating contrast agent.
We applied a 2D-FLASH retrospective-gated CINE MRI method at 9.4T to characterize atherosclerotic plaques and vessel wall distensibility in the aortic arch of aged ApoE(-/-) mice after injection of a contrast agent. The method enabled detection of contrast enhancement in atherosclerotic plaques in the aortic arch after I.V. injection of micelles and iron oxides resulting in reproducible plaque enhancement. Both contrast agents were taken up in the plaque, which was confirmed by histology. Additionally, the retrospective-gated CINE method provided images of the aortic wall throughout the cardiac cycle, from which the vessel wall distensibility could be calculated. Reduction in plaque size by statin treatment resulted in lower contrast enhancement and reduced wall stiffness.
The retrospective-gated CINE MRI provides a robust and simple way to detect and quantify contrast enhancement in atherosclerotic plaques in the aortic wall of ApoE(-/-) mice. From the same scan, plaque-related changes in stiffness of the aortic wall can be determined. In this mouse model, a correlation between vessel wall stiffness and atherosclerotic lesions was found.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
In patients with heart failure cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling.
Aim:
To evaluate whether myocardial collagen metabolism in patients with ...heart failure is implicated in adverse ventricular remodelling and response to CRT.
Methods:
Collagen synthesis and degradation were assessed from the concentrations of aminoterminal propeptides of type I and type III collagen (PINP and PIIINP) and carboxyterminal telopeptide of type I collagen (ICTP), respectively, in serum of 64 patients with heart failure before and after 6 months of CRT. Forty-six patients (72%) showed a > 10% reduction in LV end-systolic volume at follow-up and were classified as responders to CRT, the other 18 patients (28%) were classified as non-responders.
Results:
Responders demonstrated a mean (±SEM) increase of serum PINP and PIIINP during follow-up, from 32.9±2.2 to 46.7±4.0 μg/L (p<0.001) and from 4.59±0.24 to 5.13±0.36 μg/L (p<0.05), respectively. In non-responders, serum PINP and PIIINP remained unchanged during follow-up. At baseline, responders had significantly lower serum PINP than non-responders (32.9±2.2 vs. 41.8±4.3 μg/L; p<0.05).
ICTP levels of responders at baseline tended to be higher than in non-responders (3.54±0.56 vs. 2.08±0.37 μg/L, p=ns), and in both groups ICTP levels did not change upon CRT.
Conclusion:
Reverse LV remodelling following CRT is associated with increased collagen synthesis rate in the first 6 months of follow-up.
Abstract Lack of dystrophin results in skeletal muscle dystrophy and dilated cardiomyopathy in humans and animal models. To achieve a basic understanding of the natural development of cardiomyopathy ...in different dystrophinopathy mouse models, left and right ventricular heart function was assessed at different ages in three dystrophinopathy mouse models ( mdx , mdx / utrn+/− model and mdx / utrn−/− ) using magnetic resonance imaging. Left ventricular function was significantly decreased, already at 2 months in the most severely affected mdx / utrn−/− mice. Furthermore, whereas heart function was stable in wild-type mice over time, both mdx and mdx / utrn+/− showed a clear decrease at 10 months of age, most prominently in the right ventricle. Therefore magnetic resonance imaging is an adequate technique to determine heart function in dystrophinopathy mouse models and can be used to assess the effect of potential therapies.
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