Interstitial fibrosis is an important component of diastolic, and systolic, dysfunction in heart failure (HF) and depends on activation and differentiation of fibroblasts into myofibroblasts (MyoFb). ...Recent clinical evidence suggests that in late-stage HF, fibrosis is not reversible.
The study aims to examine the degree of differentiation of cardiac MyoFb in end-stage HF and the potential for their phenotypic reversibility.
Fibroblasts were isolated from the left ventricle of the explanted hearts of transplant recipients (ischemic and dilated cardiomyopathy), and from nonused donor hearts. Fibroblasts were maintained in culture without passaging for 4 or 8 days (treatment studies). Phenotyping included functional testing, immunostaining, and expression studies for markers of differentiation. These data were complemented with immunohistology and expression studies in tissue samples.
Interstitial fibrosis with cross-linked collagen is prominent in HF hearts, with presence of activated MyoFbs. Tissue levels of transforming growth factor (TGF)-β1, lysyl oxidase, periostin, and osteopontin are elevated. Fibroblastic cells isolated from HF hearts are predominantly MyoFb, proliferative or nonproliferative, with mature α-smooth muscle actin stress fibers. HF MyoFb express high levels of profibrotic cytokines and the TGF-β1 pathway is activated. Inhibition of TGF-β1 receptor kinase in HF MyoFb promotes dedifferentiation of MyoFb with loss of α-smooth muscle actin and depolymerization of stress fibers, and reduces the expression of profibrotic genes and cytokines levels to non-HF levels.
MyoFb in end-stage HF have a variable degree of differentiation and retain the capacity to return to a less activated state, validating the potential for developing antifibrotic therapy targeting MyoFb.
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Abstract
Aims
The pathogenesis of endocarditis is not well understood resulting in unsuccessful attempts at prevention. Clinical observations suggest that Staphylococcus aureus infects either damaged ...or inflamed heart valves. Using a newly developed endocarditis mouse model, we therefore studied the initial adhesion of S. aureus in both risk states.
Methods and results
Using 3D confocal microscopy, we examined the adhesion of fluorescent S. aureus to murine aortic valves. To mimic different risk states we either damaged the valves with a surgically placed catheter or simulated valve inflammation by local endothelium activation. We used von Willebrand factor (VWF) gene-deficient mice, induced platelet and fibrinogen depletion and used several S. aureus mutant strains to investigate the contribution of both host and bacterial factors in early bacterial adhesion. Both cardiac valve damage and inflammation predisposed to endocarditis, but by distinct mechanisms. Following valve damage, S. aureus adhered directly to VWF and fibrin, deposited on the damaged valve. This was mediated by Sortase A-dependent adhesins such as VWF-binding protein and Clumping factor A. Platelets did not contribute. In contrast, upon cardiac valve inflammation, widespread endothelial activation led to endothelial cell-bound VWF release. This recruited large amounts of platelets, capturing S. aureus to the valve surface. Here, neither fibrinogen, nor Sortase A were essential.
Conclusion
Cardiac valve damage and inflammation predispose to S. aureus endocarditis via distinct mechanisms. These findings may have important implications for the development of new preventive strategies, as some interventions might be effective in one risk state, but not in the other.
Introduction: Obesity is a global health challenge, and pharmacologic options are emerging. Once daily subcutaneous administration of 3 mg liraglutide, a glucagon like peptide-1 analogue, has been ...shown to induce weight loss in clinical trials, but real-world effectiveness data are scarce. Methods: It is a single-centre retrospective cohort study of patients who were prescribed liraglutide on top of lifestyle adaptations after multidisciplinary evaluation. In Belgium, liraglutide is only indicated for weight management if the BMI is >30 kg/m 2 or ≥27 kg/m 2 with comorbidities such as dysglycaemia, dyslipidaemia, hypertension, or obstructive sleep apnoea. No indication is covered by the compulsory health care insurance. Liraglutide was started at 0.6 mg/day and uptitrated weekly until 3 mg/day or the maximum tolerated dose. Treatment status and body weight were evaluated at the 4-month routine visit. Results: Between June 2016 and January 2020, liraglutide was prescribed to 115 patients (77% female), with a median age of 47 (IQR 37.7–54.0) years, a median body weight of 98.4 (IQR 90.0–112.2) kg, a BMI of 34.8 (IQR 32.2–37.4) kg/m 2 , and an HbA1c level of 5.6%. Five (4%) patients did not actually initiate treatment, 9 (8%) stopped treatment, and 8 (7%) were lost to follow-up. At the 4-month visit, the median body weight had decreased significantly by 9.2% to 90.8 (IQR 82.0–103.5) kg (p < 0.001). Patients using 3.0 mg/day (n = 60) had lost 8.0 (IQR 5.8–10.4) kg. The weight loss was similar (p = 0.9622) in patients that used a lower daily dose because of intolerance: 7.4 (IQR 6.2–9.6) kg for 1.2 mg (n = 3), 7.8 (IQR 4.1–7.8) kg for 1.8 mg (n = 16), and 9.0 (IQR 4.8–10.7) kg for 2.4 mg/day (n = 14). Weight loss was minimal if liraglutide treatment was not started or stopped prematurely (median 3.0 IQR 0.3–4.8 kg, p < 0.001, vs. on treatment). Further analysis showed an additional weight reduction of 1.8 kg in the patients that had started metformin <3 months before the start of liraglutide (p < 0.001). The main reasons for liraglutide discontinuation were gastrointestinal complaints (n = 5/9) and drug cost (n = 2/9). Conclusion: In this selected group of patients, the majority complied with liraglutide treatment over the initial 4-month period and achieved a significant weight loss, irrespective of the maximally tolerated maintenance dose. Addition of metformin induced a small but significant additional weight loss.
Recent studies showing an inverse association between estimated glomerular filtration rate (eGFR), a microvascular trait, and inactive desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) support ...the hypothesis that after vitamin K-dependent activation, matrix Gla protein (MGP) is renoprotective, but these were limited by their cross-sectional design.
In 1009 randomly recruited Flemish (50.6% women), we assessed the association between eGFR and plasma dp-ucMGP, using multivariable-adjusted analyses.
From baseline to follow-up 8.9 years later (median), dp-ucMGP increased by 23.0% whereas eGFR decreased by 4.05 mL/min/1.73 m2 (P < 0.001). In 938 participants with baseline eGFR ≥60 mL/min/1.73 m2, the incidence of eGFR <60 mL/min/1.73 m2 at follow-up was 8.0% versus 4.1% in the top versus the bottom halve of baseline dp-ucMGP. For a 5-fold higher plasma dp-ucMGP at baseline, eGFR at follow-up decreased by 3.15 mL/min/1.73 m2 95% confidence interval (CI) 1.26-5.05; P = 0.001. The hazard ratio expressing the risk of progression to eGFR <60 mL/min/1.73 m2 was 3.49 (95% CI 1.45-8.40; P = 0.005). The hazard ratio relating the presence of microalbuminuria at follow-up to baseline dp-ucMGP was 4.70 (95% CI 1.57-14.1; P = 0.006).
In conclusion, circulating inactive dp-ucMGP, a biomarker of poor vitamin K status, predicts renal dysfunction. Possible underlying mechanisms include protection by activated MGP against calcification and inhibition of the bone morphogenetic protein-signalling pathway.
Abstract
Background
Pulse pressure (PP) reflects the age-related stiffening of the central arteries, but no study addressed the management of the PP-related risk over the human lifespan.
Methods
In ...4,663 young (18–49 years) and 7,185 older adults (≥50 years), brachial PP was recorded over 24 hours. Total mortality and all major cardiovascular events (MACEs) combined were coprimary endpoints. Cardiovascular death, coronary events, and stroke were secondary endpoints.
Results
In young adults (median follow-up, 14.1 years; mean PP, 45.1 mm Hg), greater PP was not associated with absolute risk; the endpoint rates were ≤2.01 per 1,000 person-years. The adjusted hazard ratios expressed per 10-mm Hg PP increments were less than unity (P ≤ 0.027) for MACE (0.67; 95% confidence interval CI, 0.47–0.96) and cardiovascular death (0.33; 95% CI, 0.11–0.75). In older adults (median follow-up, 13.1 years; mean PP, 52.7 mm Hg), the endpoint rates, expressing absolute risk, ranged from 22.5 to 45.4 per 1,000 person-years and the adjusted hazard ratios, reflecting relative risk, from 1.09 to 1.54 (P < 0.0001). The PP-related relative risks of death, MACE, and stroke decreased >3-fold from age 55 to 75 years, whereas absolute risk rose by a factor 3.
Conclusions
From 50 years onwards, the PP-related relative risk decreases, whereas absolute risk increases. From a lifecourse perspective, young adulthood provides a window of opportunity to manage risk factors and prevent target organ damage as forerunner of premature death and MACE. In older adults, treatment should address absolute risk, thereby extending life in years and quality.
Graphical Abstract
Graphical Abstract
Muscular dystrophies (MDs) are often characterized by impairment of both skeletal and cardiac muscle. Regenerative strategies for both compartments therefore constitute a therapeutic avenue. ...Mesodermal iPSC-derived progenitors (MiPs) can regenerate both striated muscle types simultaneously in mice. Importantly, MiP myogenic propensity is influenced by somatic lineage retention. However, it is still unknown whether human MiPs have in vivo potential. Furthermore, methods to enhance the intrinsic myogenic properties of MiPs are likely needed, given the scope and need to correct large amounts of muscle in the MDs. Here, we document that human MiPs can successfully engraft into the skeletal muscle and hearts of dystrophic mice. Utilizing non-invasive live imaging and selectively induced apoptosis, we report evidence of striated muscle regeneration in vivo in mice by human MiPs. Finally, combining RNA-seq and miRNA-seq data, we define miRNA cocktails that promote the myogenic potential of human MiPs.
Chronic pressure overload predisposes to heart failure, but the pathogenic role of microvascular endothelial cells (MiVEC) remains unknown. We characterized transcriptional, metabolic, and functional ...adaptation of cardiac MiVEC to pressure overload in mice and patients with aortic stenosis (AS).
In
mice subjected to transverse aortic constriction or sham surgery, we performed RNA sequencing of isolated cardiac
-MiVEC and validated the signature in freshly isolated MiVEC from left ventricle outflow tract and right atrium of patients with AS. We next compared their angiogenic and metabolic profiles and finally correlated molecular and pathological signatures with clinical phenotypes of 42 patients with AS (50% women).
In mice, transverse aortic constriction induced progressive systolic dysfunction, fibrosis, and reduced microvascular density. After 10 weeks, 25 genes predominantly involved in matrix-regulation were >2-fold upregulated in isolated MiVEC. Increased transcript levels of
(
),
,
, and
were confirmed by quantitative reverse transcription polymerase chain reaction and recapitulated in left ventricle outflow tract-derived MiVEC of AS (
<0.05 versus right atrium-MiVEC). Fatty acid oxidation increased >2-fold in left ventricle outflow tract-MiVEC, proline content by 130% (median, IQR, 58%-474%;
=0.008) and procollagen secretion by 85% (mean 95% CI, 16%-154%;
<0.05 versus right atrium-MiVEC for all). The altered transcriptome in left ventricle outflow tract-MiVEC was associated with impaired 2-dimensional-vascular network formation and 3-dimensional-spheroid sprouting (
<0.05 versus right atrium-MiVEC), profibrotic ultrastructural changes, and impaired diastolic left ventricle function, capillary density and functional status, especially in female AS.
Pressure overload induces major transcriptional and metabolic adaptations in cardiac MiVEC resulting in excess interstitial fibrosis and impaired angiogenesis. Molecular rewiring of MiVEC is worse in women, compromises functional status, and identifies novel targets for intervention.
The loss of endogenous cardiac regenerative capacity within the first week of postnatal life has intensified clinical trials to induce cardiac regeneration in the adult mammalian heart using ...different progenitor cell types. We hypothesized that donor age-related phenotypic and functional characteristics of cardiac progenitor cells (CPC) account for mixed results of cell-based cardiac repair. We compared expression profiles and cell turnover rates of human heart-derived c-kit
progenitors (c-kit
CPC) and cardiosphere-derived cells (CDC) from young and adult donor origin and studied their in vitro angiogenic and cardiac differentiation potential, which can be relevant for cardiac repair. We report that 3-dimensional CDC expansion recapitulates a conducive environment for growth factor and cytokine release from adult donor cells (aCDC) that optimally supports vascular tube formation and vessel sprouting. Transdifferentiation capacity of c-kit
CPCs and CDCs towards cardiomyocyte-like cells was modest, however, most notable in young c-kit
cells and adult CDCs. Progenitors isolated with different methods thus show cell- and donor-specific characteristics that may account for variable contributions in functional myocardial recovery.
Cardiac resynchronization therapy (CRT) has evolved into an established therapy for patients with chronic heart failure and a wide QRS complex. Data on long-term outcomes over time are scarce and the ...criteria for implantation remain a subject of investigation.
An international, multicenter, retrospective registry includes 2275 patients who received CRT between 30 November 2000 and 31 December 2019, with a mean follow-up of 3.6 ± 2.7 years. Four time periods were defined, based on landmark trials and guidelines. The combined endpoint was a composite of all-cause mortality, heart transplantation, or left ventricular assist device implantation.
The composite endpoint occurred in 656 patients (29.2%). The mean annual implantation rate tripled from 31.5 ± 17.4/year in the first period to 107.4 ± 62.4/year in the last period. In the adjusted Cox regression analysis, the hazard ratio for the composite endpoint was not statistically different between time periods. When compared to sinus rhythm with left bundle branch block (LBBB), a non-LBBB conduction pattern (sinus rhythm: HR 1.51, 95% CI 1.12-2.03; atrial fibrillation: HR 2.08, 95% CI 1.30-3.33) and a QRS duration below 130 ms (HR 1.64, 95% CI 1.29-2.09) were associated with a higher hazard ratio.
Despite innovations, an adjusted regression analysis revealed stable overall survival over time, which can at least partially be explained by a shift in patient characteristics.
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