Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental ...for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.
Extracellular matrix remodeling is extensive in several heart diseases and hampers cardiac filling, often leading to heart failure. Proteoglycans have over the last two decades emerged as molecules ...with important roles in matrix remodeling and fibrosis in the heart. Here we discuss and review current literature on proteoglycans that have been studied in cardiac remodeling. The small leucine rich proteoglycans (SLRPs) are located within the extracellular matrix and are organizers of the matrix structure. Membrane-bound proteoglycans, such as syndecans and glypicans, act as receptors and direct cardiac fibroblast signaling. Recent studies indicate that proteoglycans are promising as diagnostic biomarkers for cardiac fibrosis, and that they may provide new therapeutic strategies for cardiac disease.
•Extracellular matrix remodeling hampers cardiac filling, often leading to heart failure.•Proteoglycans have important roles in matrix remodeling and fibrosis in the heart.•The small leucine-rich proteoglycans are organizers of matrix structure.•Membrane-bound proteoglycans direct cardiac fibroblast signaling.•Proteoglycans are promising diagnostic biomarkers and targets for treatment of cardiac disease.
Abstract
Aims
Generation of reproducible cardiac disease phenotypes in mice is instrumental for investigating mechanisms leading to heart failure (HF). For decades, suture-based thoracic aortic ...constriction has been the preferred method for increasing left ventricular (LV) afterload in rodents, but the degree of stenosis resulting from this method is variable. In an effort to improve this methodology, we subjected mice to constriction of the ascending aorta using o-rings with fixed inner diameters (IDs).
Methods and results
Mice of C57BL/6J and FVB/N background were subjected to constriction of the ascending aorta using o-rings with fixed IDs of 0.71, 0.66, and 0.61 mm. O-ring aortic banding resulted in 98.7% survival 2 weeks post-surgery, with very low intra- and inter-surgeon variation. When using the narrowest o-ring (0.61 mm), mice developed hypertrophy within 1 week. Over 20 weeks, the mice gradually developed reduced LV ejection fraction (LVEF) and dilatation with increased left atrial dimensions and lung weight, indicating congestion. When using o-rings with IDs of 0.66 mm and 0.71 mm, the mice developed hypertrophy, but maintained a compensated state with stabilized LVEF 8-20 weeks post-surgery. The up-regulation of signature genes associated with HF, hypertrophy, fibrosis, and the level of activation of MAPK and NFAT signalling pathways corresponded to the degree of stenosis.
Conclusion
Here, we introduce a novel method for high precision aortic constriction in mice with high intra- and inter-surgeon reproducibility and low post-operative mortality that allows generation of specific cardiac disease phenotypes.
Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or ...reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.
The capacity for marine fishes to perform aerobically (aerobic scope) is predicted to control their thermal tolerance and, thus, the impact that rapid climate change will have on their populations. ...We tested the effect of increased water temperatures on the resting and maximum rates of oxygen consumption in five common coral reef fishes at Lizard Island on the northern Great Barrier Reef, Australia. All species exhibited a decline in aerobic capacity at elevated water temperatures (31, 32 or 33 °C) compared with controls (29 °C); however, the response was much stronger in two cardinalfishes, Ostorhinchus cyanosoma and O. doederleini, compared with three damselfishes, Dascyllus anuarus, Chromis atripectoralis and Acanthochromis polyacanthus. Aerobic scope of the two cardinalfishes was reduced by nearly half at 31 °C compared with 29 °C, and virtually all capacity for additional oxygen uptake was exhausted by 33 °C. In contrast, the three damselfishes retained over half their aerobic scope at 33 °C. Such differences in thermal tolerance between species, and possibly families, suggest that the community structure of reef fish assemblages might change significantly as ocean temperatures increase. Populations of thermally tolerant species are likely to persist at higher temperatures, but populations of thermally sensitive species could decline on low-latitude reefs if individual performance falls below levels needed to sustain viable populations.
Dysregulation of the extracellular matrix (ECM) occurs widely across cardiovascular pathologies. Recent work has revealed important roles for the «a disintegrin-like and metalloprotease domain with ...thrombospondin-type 1 motifs like” (ADAMTSL) family of secreted glycoproteins in cardiovascular tissues during development and disease. Key insights in this regard have come from naturally occurring gene mutations in humans and animals that result in severe diseases with cardiovascular manifestations or aortopathies. Expression of ADAMTSL genes is greatly increased in the myocardium during heart failure. Genetically modified mice recapitulate phenotypes of patients with ADAMTSL mutations and demonstrate important functions in the ECM. The novel functions thus disclosed are intriguing because, while these proteins are neither structural, nor proteases like the related ADAMTS proteases, they appear to act as regulatory, i.e., matricellular proteins. Evidence from genetic variants, genetically engineered mouse mutants, and in vitro investigations have revealed regulatory functions of ADAMTSLs related to fibrillin microfibrils and growth factor signaling. Interestingly, the ability to regulate transforming growth factor (TGF)β signaling may be a shared characteristic of some ADAMTSLs. TGFβ signaling is important in cardiovascular development, health and disease and a central driver of ECM remodeling and cardiac fibrosis. New strategies to target dysregulated TGFβ signaling are warranted in aortopathies and cardiac fibrosis. With their emerging roles in cardiovascular tissues, the ADAMTSL proteins may provide causative genes, diagnostic biomarkers and novel treatment targets in cardiovascular disease. Here, we discuss the relevance of ADAMTSLs to cardiovascular medicine.
When aortic valve replacement is needed, a biological valve is usually implanted in patients older than age 60 to 65 years. A large valvular opening area is important to avoid prosthesis–patient ...mismatch and facilitate reverse left ventricular remodeling. The Trifecta biological valve (St Jude Medical, St Paul, Minn) is, because of its design, believed to reduce transvalvular gradient compared with other biological valves, especially in smaller annuli. Several retrospective studies have compared transvalvular gradients of implanted valves prostheses using the respective manufacturers given size and not the actual annulus size measured by a metric sizer. This makes comparison of the hemodynamic properties of different valve brands and sizes difficult. We therefore performed a prospective randomized study, using the same metric sizer to measure annulus size, and compared hemodynamic profiles of the Trifecta to our standard Mosaic Ultra biological valve (Medtronic, Minneapolis, Minn).
Ninety elective patients with small to medium annulus diameter undergoing aortic valve replacement were randomized to either Trifecta or Mosaic Ultra. After native valve removal and decalcification, a Hegar-sizer was used to measure true annulus size. Then the largest possible valve of either brand was implanted according to the randomization protocol. Echocardiography was performed 6 months postoperatively.
Baseline parameters of the 2 cohorts were comparable. There were lower transvalvular gradients in the Trifecta compared with the Mosaic Ultra group for the given annulus sizes. Severe prosthesis–patient mismatch was present in 28% of patients in the Mosaic group and 3% of patients in the Trifecta group.
Trifecta showed lower transvalvular gradients and less severe prosthesis–patient mismatch compared with Mosaic Ultra for the given annulus sizes. ClinicalTrials.gov Protocol ID: 2011/2596/REK.
Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart ...failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction
and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti‐fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.
Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) ...patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.
This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.
T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions.
HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.
Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.
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The mechanisms by which truncating mutations in
(encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor relaxation in hypertrophic ...cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches, we explored how depletion of cMyBPC altered sarcomere function. We demonstrated that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM), normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation, enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with
mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across the cardiac cycle as the pathophysiologic mechanisms by which
truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in patients with DCM, whereas inhibiting myosin by MYK-461 should benefit the substantial proportion of patients with HCM with
mutations.
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