Biochemical Diagnosis of Hypertensive Myocardial Fibrosis

A substantial increase in fibrillar collagen has been observed in the left cardiac ventricle of animals and humans with arterial hypertension. Hypertensive myocardial fibrosis is the result of both increased collagen types I and III due to the fact that its synthesis by fibroblasts and myofibroblasts is stimulated and its extracellular collagen degradation unchanged or decreased extracellular collagen degradation. Hemodynamic and non-hemodynamic factors may be involved in the disequilibrium between collagen synthesis and degradation that occurs in hypertension. As shown experimentally and clinically, an exaggerated rise in fibrilar collagen content promotes abnormalities of cardiac function, contributes to the decrease in coronary reserve and facilitates alterations in the electrical activity of the left ventricle. Although microscopic examination of cardiac biopsies is the most reliable method for documenting and measuring myocardial fibrosis, the development of non-invasive methods to indicate the presence of myocardial fibrosis in hypertensive patients would be useful. We have therefore applied a biochemical method based on the measurement of serum peptides derived from the tissue formation when synthesized and degradation of fibrillar collagens to monitor the turnover of these molecules in rats with spontaneous hypertension and patients with essential hypertension

Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure

The aim of this study was to investigate whether torasemide modifies collagen cross-linking in the failing human heart. We analyzed the degree of cross-linking and the expression of the enzyme lysyl oxidase, which regulates cross-linking, in the myocardium of patients with chronic heart failure at baseline and after 8 months of treatment with either torasemide or furosemide in addition to their standard heart failure therapy. Whereas lysyl oxidase protein expression was very scarce in normal hearts, it was highly expressed in failing hearts. Cross-linking was increased (P<0.001) in heart failure patients compared with normal hearts. These 2 parameters decreased (P=0.021 and P=0.034) in torasemide-treated patients and remained unchanged in furosemide-treated patients. In addition, more (P=0.009) patients showed normalization of left ventricular chamber stiffness in the torasemide subgroup than in the furosemide subgroup after treatment. Lysyl oxidase expression correlated with cross-linking (r=0.661; P<0.001), and cross-linking correlated with left ventricular chamber stiffness (r=0.452; P=0.002) in all patients. These findings show for the first time that lysyl oxidase overexpression is associated with enhanced collagen cross-linking in the failing human heart. In addition, we report that the ability of torasemide to correct both lysyl oxidase overexpression and enhanced collagen cross-linking results in normalization of left ventricular chamber stiffness in patients with heart failure. Lysyl oxidase may thus represent a target for reduction of stiff collagen and improvement of left ventricular mechanical properties in heart failure patients

Apoptosis in hypertensive heart disease: a clinical approach

PURPOSE OF REVIEW: It is widely accepted that there are two principal forms of cell death, namely, necrosis and apoptosis. According to the classical view, necrosis is the major mechanism of cardiomyocyte death in cardiac diseases. RECENT DEVELOPMENTS: In the past few years observations have been made showing that cardiomyocyte apoptosis occurs in diverse conditions including hypertensive heart disease, and that apoptosis may be a contributing cause of loss and functional abnormalities of cardiomyocytes in this condition. SUMMARY: This review will summarize recent evidence demonstrating the potential contribution of cardiomyocyte apoptosis to heart failure in hypertensive patients. In addition, some strategies aimed to detect and prevent apoptosis of cardiomyocytes will be considered

Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction

This study was designed to evaluate the association between circulating biomarkers of collagen metabolism and elevated left-sided filling pressures (FPs), as assessed from elevated estimated pulmonary capillary wedge pressure (ePCWP), in hypertensive patients with heart failure with normal ejection fraction. Echocardiography was performed and ePCWP was calculated from the formula ePCWP=1.90+1.24(maximum early transmitral flow velocity in diastole:tissue Doppler early mitral annulus velocity). The biomarkers of collagen synthesis (carboxy-terminal propeptide of procollagen type I) and degradation (matrix metalloproteinase [MMP] 1 and tissue inhibitor of MMP-1 [TIMP-1]) were analyzed by ELISA methods. Seventy-eight patients with normal FPs (ePCWP 15 mm Hg) were included. Compared with controls, the levels of the 3 biomarkers were increased in the 2 groups of patients. The MMP-1:TIMP-1 ratio, an index of MMP-1 activity, was increased in patients with normal FPs and unchanged in patients with elevated FPs. Patients with elevated FPs exhibited higher TIMP-1 levels and a lower MMP-1:TIMP-1 ratio than patients with normal FPs. ePCWP was independently associated with TIMP-1 (r=0.349; P<0.001) and the MMP-1:TIMP-1 ratio (r=-0.240; P<0.01) in all of the patients. Receiver operating characteristic curves showed that a cutoff value of TIMP-1 of 1557 ng/mL provided 64% sensitivity and 67% specificity for predicting elevated FPs with a relative risk of 3.71 (95% CI: 1.91 to 7.22). These findings suggest that, in hypertensive patients with heart failure with normal ejection fraction and elevated FPs, collagen synthesis predominates over degradation because of a relative excess of TIMP-1. This imbalance can facilitate myocardial fibrosis, which, in turn, may contribute to the elevation of FPs in these patients

Association of cardiotrophin-1 with myocardial fibrosis in hypertensive patients with heart failure

Cardiotrophin-1 has been shown to be profibrogenic in experimental models. The aim of this study was to analyze whether cardiotrophin-1 is associated with left ventricular end-diastolic stress and myocardial fibrosis in hypertensive patients with heart failure. Endomyocardial biopsies from patients (n=31) and necropsies from 7 control subjects were studied. Myocardial cardiotrophin-1 protein and mRNA and the fraction of myocardial volume occupied by collagen were increased in patients compared with controls ( P <0.001). Cardiotrophin-1 overexpression in patients was localized in cardiomyocytes. Cardiotrophin-1 protein was correlated with collagen type I and III mRNAs ( r =0.653, P <0.001; r =0.541, P <0.01) and proteins ( r =0.588, P <0.001; r =0.556, P <0.005) in all subjects and with left ventricular end-diastolic wall stress ( r =0.450; P <0.05) in patients. Plasma cardiotrophin-1 and N-terminal pro-brain natriuretic peptide and serum biomarkers of myocardial fibrosis (carboxy-terminal propeptide of procollagen type I and amino-terminal propeptide of procollagen type III) were increased ( P <0.001) in patients compared with controls. Plasma cardiotrophin-1 was correlated with N-terminal pro-brain natriuretic peptide ( r =0.386; P <0.005), carboxy- terminal propeptide of procollagen type I ( r =0.550; P <0.001), and amino-terminal propeptide of procollagen type III ( r =0.267; P <0.05) in all subjects. In vitro, cardiotrophin-1 stimulated the differentiation of human cardiac fibroblast to myofibroblasts ( P <0.05) and the expression of procollagen type I ( P <0.05) and III ( P <0.01) mRNAs. These findings show that an excess of cardiotrophin-1 is associated with increased collagen in the myocardium of hypertensive patients with heart failure. It is proposed that exaggerated cardiomyocyte production of cardiotrophin-1 in response to increased left ventricular end-diastolic stress may contribute to fibrosis through stimulation of fibroblasts in heart failure of hypertensive origi

Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart disease

OBJECTIVE: To investigate whether cardiac expression of the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha) is altered in patients with hypertensive heart disease (HHD). METHODS: We studied endomyocardial septal biopsies from 24 patients with essential hypertension divided into three groups: 6 without left ventricular hypertrophy (LVH) (HT group), 10 with LVH (LVH group), and 8 with LVH and heart failure (HF) (HF group). The expression of two PPARalpha isoforms (the native active and the truncated inhibitory) was analyzed by Western blot and reverse transcription polymerase chain reaction (RT-PCR), and two PPARalpha target genes were evaluated by RT-PCR. Histomorphological features were evaluated in a second myocardial sample from LVH and HF groups. RESULTS: Whereas the expression of native PPARalpha protein was lower (p<0.05) in LVH and HF groups than in the HT group, truncated PPARalpha protein was overexpressed (p<0.001) in the HF group as compared with LVH and HT groups. The mRNA expression of native and truncated PPARalpha was similar in the three groups of hypertensives. In addition, a progressive decrease (p for trend<0.05) in the two PPARalpha target genes mRNA expression was observed among HT, LVH and HF groups. The amount of truncated PPARalpha protein correlates directly with cardiomyocytes apoptosis and inversely with cardiomyocytes density in patients with HHD. In addition, the expression of truncated PPARalpha protein was directly correlated with left ventricular volumes, and inversely with ejection fraction in all hypertensives. CONCLUSIONS: These findings suggest that post-transcriptional regulation of PPARalpha isoforms is altered in patients with HHD, namely in those developing HF. An excess of the truncated inhibitory isoform may be involved in hypertensive left ventricular failure and remodeling

Magnetic domain wall curvature induced by wire edge pinning

open14In this study, we report on the analysis of the magnetic domain wall (DW) curvature due to magnetic field induced motion in Ta/CoFeB/MgO and Pt/Co/Pt wires with perpendicular magnetic anisotropy. In wires of 20 mu m and 25 mu m, a large edge pinning potential produces the anchoring of the DW ends to the wire edges, which is evidenced as a significant curvature of the DW front as it propagates. As the driving magnetic field is increased, the curvature reduces as a result of the system moving away from the creep regime of DW motion, which implies a weaker dependence of the DW dynamics on the interaction between the DW and the wire edge defects. A simple model is derived to describe the dependence of the DW curvature on the driving magnetic field and allows us to extract the parameter sigma (E), which accounts for the strength of the edge pinning potential. The model describes well the systems with both weak and strong bulk pinning potentials like Ta/CoFeB/MgO and Pt/Co/Pt, respectively. This provides a means to quantify the effect of edge pinning induced DW curvature on magnetic DW dynamics.embargoed_20210815Herrera Diez, L.; Ummelen, F.; Jeudy, V.; Durin, G.; Lopez-Diaz, L.; Diaz-Pardo, R.; Casiraghi, A.; Agnus, G.; Bouville, D.; Langer, J.; Ocker, B.; Lavrijsen, R.; Swagten, H. J. M.; Ravelosona, D.Herrera Diez, L.; Ummelen, F.; Jeudy, V.; Durin, G.; Lopez-Diaz, L.; Diaz-Pardo, R.; Casiraghi, A.; Agnus, G.; Bouville, D.; Langer, J.; Ocker, B.; Lavrijsen, R.; Swagten, H. J. M.; Ravelosona, D

Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice

Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month- old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1–null mice was studied. Vascular smooth muscle cells were treated with CT-1 (10 −9 mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic modulus curve of old CT-1–null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1–null mice. CT-1–null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1–null mice displayed a 5-month increased median longevity compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging proces

Transition between Variscan and Alpine cycles in the Pyrenean-Cantabrian Mountains (N Spain): Geodynamic evolution of near-equator European Permian basins

In the northern Iberian Peninsula, the Pyrenean-Cantabrian orogenic belt extends E-W for ca. 1000 km between the Atlantic Ocean and Mediterranean Sea. This orogen developed from the collision between Iberia and Eurasia, mainly in Cenozoic times. Lower-middle Permian sediments crop out in small, elongated basins traditionally considered independent from each other due to misinterpretations on incomplete lithostratigraphic data and scarce radiometric ages. Here, we integrate detailed stratigraphic, sedimentary, tectonic, paleosol and magmatic data from well-dated lithostratigraphic units. Our data reveal a similar geodynamic evolution across the Pyrenean-Cantabrian Ranges at the end of the Variscan cycle. Lower-middle Permian basins started their development under an extensional regime related to the end of the Variscan Belt collapse, which stars in late Carboniferous times in the Variscan hinterland. This orogenic collapse transitioned to Pangea breakup at the middle Permian times in the study region. Sedimentation occurred as three main tectono-sedimentary extensional phases. A first phase (Asselian-Sakmarian), which may have even started at the end of the Carboniferous (Gzhelian) in some sections, is mainly represented by alluvial sedimentation associated with calc-alkaline magmatism. A second stage (late Artinskian-early Kungurian), represented by al-luvial, lacustrine and palustrine sediments with intercalations of calc-alkaline volcanic beds, shows a clear up-ward aridification trend probably related to the late Paleozoic icehouse-greenhouse transition. The third and final stage (Wordian-Capitanian) comprised of alluvial deposits with intercalations of alkaline and mafic beds, rarely deposited in the Cantabrian Mountains, and underwent significant pre-and Early Mesozoic erosion in some segments of the Pyrenees. This third stage can be related to a transition towards the Pangea Supercontinent breakup, not generalized until the Early/Middle Triassic at this latitude because the extensional process stopped about 10 Myr (Pyrenees) to 30 Myr (Cantabrian Mountains). When compared to other well-dated basins near the paleoequator, the tectono-sedimentary and climate evolution of lower-middle Permian basins in Western and Central Europe shows common features. Specifically, we identify coeval periods with magmatic activity, extensional tectonics, high subsidence rates and thick sedi-mentary record, as well as prolonged periods without sedimentation. This comparison also identifies some evolutionary differences between Permian basins that could be related to distinct locations in the hinterland or foreland of the Variscan orogen. Our data provide a better understanding of the major crustal re-equilibration and reorganization that took place near the equator in Western-Central Europe during the post-Variscan period

p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming

The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming holds great potential for modeling human diseases. However, the reprogramming process remains very inefficient and a better understanding of its basic biology is required. The mesenchymal-to-epithelial transition (MET) has been recognized as a crucial step for the successful reprogramming of fibroblasts into iPSCs. It has been reported that the p53 tumor suppressor gene acts as a barrier of this process, while its homolog p63 acts as an enabling factor. In this regard, the information concerning the role of the third homolog, p73, during cell reprogramming is limited. Here, we derive total Trp73 knockout mouse embryonic fibroblasts, with or without Trp53, and examine their reprogramming capacity. We show that p73 is required for effective reprogramming by the Yamanaka factors, even in the absence of p53. Lack of p73 affects the early stages of reprogramming, impairing the MET and resulting in altered maturation and stabilization phases. Accordingly, the obtained p73-deficient iPSCs have a defective epithelial phenotype and alterations in the expression of pluripotency markers. We demonstrate that p73 deficiency impairs the MET, at least in part, by hindering BMP pathway activation. We report that p73 is a positive modulator of the BMP circuit, enhancing its activation by DNp73 repression of the Smad6 promoter. Collectively, these findings provide mechanistic insight into the MET process, proposing p73 as an enhancer of MET during cellular reprogramming.Peer reviewe