The role of TGFβ1 and LRG1 in cardiac remodelling and heart failure.
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ABSTRACT:
SUBMITTER: Song W
PROVIDER: S-EPMC4322186 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Congestive heart failure remains a primary cause of cardiovascular-related events. Heart failure patients face two health care challenges. First, they are uncertain about their prognosis and second, they have an unpredictable clinical course with recurrent exacerbations of heart failure. The echocardiogram is an easily accessible bedside test without any associated procedural complications. Additionally, it provides a wealth of information about chamber size and function, valve integrity and the pericardial sac. In the present review, the most common echocardiographic predictors of impending cardiac events in congestive heart failure are described.
| S-EPMC2716263 | biostudies-other
Project description:AimsSurveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome.Methods and resultsA prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow-up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan-Meier analyses compared to those with no remodelling, log-rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction.ConclusionsCardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long-term outcomes whereas change in left ventricular ejection fraction did not.
| S-EPMC8712825 | biostudies-literature
Project description:AimsThis study aims to assess long-term changes in left ventricular ejection fraction (LVEF) together with echocardiographic markers of cardiac remodelling and their association with prognosis and patient-reported quality of life (QoL).Methods and resultsWe conducted a retrospective analysis of serial echocardiograms performed between January 2009 and December 2019 in 1089 patients (median age 63 years, 71.0% men) enrolled in the Mazankowski Heart Function Clinic Registry who had at least two echocardiograms separated by ≥12 months. We classified the patients into four subgroups by their baseline and LVEF trajectories: persistent heart failure with reduced ejection fraction (persistent HFrEF, n = 364), recovered ejection fraction (HFrecEF, n = 325), transient recovery in ejection fraction (HFtrecEF, n = 117), and preserved ejection fraction (HFpEF, n = 283); 4490 echocardiograms were included in the present analysis, with 4.1 ± 1.8 echocardiograms available per patient during follow-up. Reductions in echocardiographic markers of cardiac remodelling, including LVIDd [adjusted odds ratio (aOR): 2.22, 95% confidence interval (CI) 1.75-2.86], LVIDs (aOR: 2.44, 95% CI 2.00-2.94), left ventricular mass index (aOR: 1.15, 95% CI 1.09-1.22), E/e' ratio (aOR: 1.15, 95% CI 1.02-1.30), left atrial volume index (aOR: 1.10, 95% CI 1.03-1.16), along with an increase in the maximum recommended daily dose of renin-angiotensin system inhibitors (aOR: 1.04, 95% CI 1.01-1.07) and mineralocorticoid-receptor antagonists (aOR: 1.06, 95% CI 1.01-1.11) at 2 years, strongly predicted the HFrecEF classification, which was further sustained at 5 years of follow-up. However, changes in these parameters were mostly absent in patients experiencing only a transient recovery in LVEF (HFtrecEF), closely resembling patients with persistent HFrEF. In the multivariable analysis, HFrecEF patients had lower risk of all-cause mortality alone [adjusted hazard ratio (aHR): 0.46, 95% CI 0.23-0.93], and composite all-cause (aHR: 0.59, 95% CI 0.49-0.73), cardiovascular (aHR: 0.47, 95% CI 0.36-0.61), and heart failure (aHR: 0.50, 95% CI 0.35-0.70) related hospitalizations with mortality than patients with persistent HFrEF. QoL assessed through the shortened Kansas City Cardiomyopathy Questionnaire-12 at the end of follow-up was greater in patients with HFrecEF by 5.2, 12.4, and 9.4 points than persistent HFrEF, HFtrecEF, and HFpEF, respectively.ConclusionsPatients with HFrecEF experienced progressive normalization in echocardiographic markers of cardiac remodelling characterized by reductions in left ventricular dimensions and mass in tandem with reductions in left atrial volume and E/e' ratio, which is associated with better prognosis and QoL.
| S-EPMC8318501 | biostudies-literature
Project description:AimsCardiac hypertrophy and heart failure are associated with QT prolongation and lethal ventricular arrhythmias resulting from decreased K(+) current densities and impaired repolarization. Recent studies in mouse models of physiological cardiac hypertrophy revealed that increased phosphoinositide-3-kinase-α (PI3Kα) signalling results in the up-regulation of K(+) channels and the normalization of ventricular repolarization. The experiments here were undertaken to test the hypothesis that increased PI3Kα signalling will counteract the adverse electrophysiological remodelling associated with pathological hypertrophy and heart failure.Methods and resultsIn contrast to wild-type mice, left ventricular (LV) hypertrophy, induced by transverse aortic constriction (TAC), did not result in prolongation of ventricular action potentials or QT intervals in mice with cardiac-specific expression of constitutively active PI3Kα (caPI3Kα). Indeed, repolarizing K(+) currents and K(+) channel subunit transcripts were increased in caPI3Kα + TAC LV myocytes in proportion to the TAC-induced cellular hypertrophy. Congestive heart failure in a transgenic model of dilated cardiomyopathy model is accompanied by prolonged QT intervals and ventricular action potentials, reduced K(+) currents and K(+) channel transcripts. Increased PI3Kα signalling, but not renin-angiotensin system blockade, in this model also results in increased K(+) currents and improved ventricular repolarization.ConclusionIn the setting of pathological hypertrophy or heart failure, enhanced PI3Kα signalling results in the up-regulation of K(+) channel subunits, normalization of K(+) current densities and preserved ventricular function. Augmentation of PI3Kα signalling, therefore, may be a useful and unique strategy to protect against the increased risk of ventricular arrhythmias and sudden death associated with cardiomyopathy.
| S-EPMC3258651 | biostudies-literature
Project description:We investigated whether ?(2) -adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart.We explored the angiogenic effects of ?(2) -adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated ?(2) -adrenoceptor overexpression was obtained via direct intramyocardial injection 4-weeks post-MI. Adenovirus(Ad)-GFP and saline injected rats served as controls. Furthermore, we extended our observation to ?(2) -adrenoceptor -/- mice undergoing MI.Transgenes were robustly expressed in the LV at 2 weeks post-gene therapy, whereas their expression was minimal at 4-weeks post-gene delivery. In HF rats, cardiac ?(2) -adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad-?(2) -adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, ?(2) -adrenoceptor overexpression was associated with a markedly increased capillary and arteriolar length density and enhanced in vivo myocardial blood flow and coronary reserve. At the molecular level, cardiac ?(2) -adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In ?(2) -adrenoceptor-/- mice, we found a ~25% reduction in cardiac capillary density compared with ?(2) -adrenoceptor+/+ mice. The lack of ?(2) -adrenoceptors was associated with a higher mortality rate at 30 days and LV dilatation, and a worse global cardiac contractility compared with controls.?(2) -Adrenoceptors play an important role in the regulation of the angiogenic response in HF. The activation of VEGF/PKB/eNOS pathway seems to be strongly involved in this mechanism.
| S-EPMC3448898 | biostudies-other
Project description:Background and purposeThe synthetic vitamin D3 analogue paricalcitol acts as a selective activator of the vitamin D receptor (VDR). While there is evidence for cardioprotective effects of paricalcitol associated with the VDR pathway, less information is available about the structural and functional cardiac effects of paricalcitol on established heart failure (HF) and particularly its effects on associated electrophysiological or Ca2+ handling remodelling.Experimental approachWe used a murine model of transverse aortic constriction (TAC) to study the effect of paricalcitol on established HF. Treatment was initiated 4 weeks after surgery over five consecutive weeks, and mice were sacrificed 9 weeks after surgery. Cardiac MRI (CMRI) was performed 4 and 9 weeks after surgery. Hearts were used for biochemical and histological studies and to isolate ventricular myocytes for electrophysiological and calcium imaging studies.Key resultsCMRI analysis revealed that, compared with vehicle, paricalcitol treatment prevented the progression of ventricular dilation and hypertrophy after TAC and halted the corresponding decline in ejection fraction. These beneficial effects were related to the attenuation of intracellular Ca2+ mishandling remodelling, antifibrotic and antihypertrophic effects and potentially antiarrhythmic effects by preventing the reduction of K+ current density and the long QT, JT and TpTe intervals observed in HF animals.Conclusion and implicationsThe results suggest that paricalcitol treatment in established HF hampers disease progression and improves adverse electrophysiological and Ca2+ handling remodelling, attenuating the vulnerability to HF-associated ventricular arrhythmias. Paricalcitol may emerge as a potential therapeutic option in the treatment of HF.
| S-EPMC7312271 | biostudies-literature
Project description:AimsEchocardiographic response after cardiac resynchronization therapy (CRT) is often lesser in ischaemic cardiomyopathy (ICM) than non-ischaemic dilated cardiomyopathy (NIDCM) patients. We assessed the association of heart failure aetiology on the amount of reverse remodelling and outcome of CRT.Methods and resultsNine hundred twenty-eight CRT patients were retrospectively included. Reverse remodelling and endpoint occurrence (all-cause mortality, heart transplantation, or left ventricular assist device implantation) was assessed. Two response definitions [≥15% reduction left ventricular end systolic volume (LVESV) and ≥5% improvement left ventricular ejection fraction] and the most accurate cut-off for the amount of reverse remodelling that predicted endpoint freedom were assessed. Mean follow-up was 3.8 ± 2.4 years. ICM was present in 47%. ICM patients who were older (69 ± 7 vs. 63 ± 11), more often men (83% vs. 58%), exhibited less LVESV reduction (13 ± 31% vs. 23 ± 32%) and less left ventricular ejection fraction improvement (5 ± 11% vs. 10 ± 12%) than NIDCM patients (all P < 0.001). Nevertheless, every 1% LVESV reduction was associated with a relative reduction in endpoint occurrence: NIDCM 1.3%, ICM 0.9%, and absolute risk reduction was similar (0.4%). The most accurate cut-off of LVESV reduction that predicted endpoint freedom was 17.1% in NIDCM and 13.2% in ICM.ConclusionsICM patients achieve less reverse remodelling than NIDCM, but the prognostic gain in terms of survival time is the same for every single percentage of reverse remodelling that does occur. The assessment and expected magnitude of reverse remodelling should take this effect of heart failure aetiology into account.
| S-EPMC7160473 | biostudies-literature
Project description:Cardiac troponin (cTn) is the primary biomarker for the diagnosis of myocardial necrosis in an acute coronary syndrome (ACS). cTn levels can also be elevated in many other conditions, including heart failure, with significant prognostic value. An elevated cTn level can be found in both acute and chronic heart failure and its presence is believed to be due to multiple different pathophysiological processes. In acute decompensated heart failure (AHF), an elevated cTn level has been repeatedly shown to correlate with increased short- and long-term mortality and, to a lesser extent, readmission rates. These associations have been demonstrated with both I and T isoforms of cTn, as well as when troponin is measured with conventional assays or new high-sense assays. In multimarker models, cTn has repeatedly been found to be an independent predictive variable enhancing prognostic ability of the model. cTn is therefore an important biomarker for prognosis in AHF.
| S-EPMC5491037 | biostudies-other
Project description:AimsWe investigate the role of mitochondrial oxidative stress in mitochondrial proteome remodelling using mouse models of heart failure induced by pressure overload.Methods and resultsWe demonstrate that mice overexpressing catalase targeted to mitochondria (mCAT) attenuate pressure overload-induced heart failure. An improved method of label-free unbiased analysis of the mitochondrial proteome was applied to the mouse model of heart failure induced by transverse aortic constriction (TAC). A total of 425 mitochondrial proteins were compared between wild-type and mCAT mice receiving TAC or sham surgery. The changes in the mitochondrial proteome in heart failure included decreased abundance of proteins involved in fatty acid metabolism, an increased abundance of proteins in glycolysis, apoptosis, mitochondrial unfolded protein response and proteolysis, transcription and translational control, and developmental processes as well as responses to stimuli. Overexpression of mCAT better preserved proteins involved in fatty acid metabolism and attenuated the increases in apoptotic and proteolytic enzymes. Interestingly, gene ontology analysis also showed that monosaccharide metabolic processes and protein folding/proteolysis were only overrepresented in mCAT but not in wild-type mice in response to TAC.ConclusionThis is the first study to demonstrate that scavenging mitochondrial reactive oxygen species (ROS) by mCAT not only attenuates most of the mitochondrial proteome changes in heart failure, but also induces a subset of unique alterations. These changes represent processes that are adaptive to the increased work and metabolic requirements of pressure overload, but which are normally inhibited by overproduction of mitochondrial ROS.
| S-EPMC3243039 | biostudies-literature
Project description:AimsImmunomodulation in heart failure (HF) has been studied in several randomized controlled trials (RCTs) with variable effects on cardiac structure, function, and outcomes. We sought to determine the effect of immunomodulation on left ventricular ejection fraction (LVEF), LV end-diastolic dimension (LVEDD), and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF) through meta-analyses and trial sequential analyses (TSAs) of RCTs.Methods and resultsPubMed, Embase®, Cochrane CENTRAL, and ClinicalTrials.gov were systematically reviewed to identify RCTs that studied the effects of immunomodulation in patients with HFrEF. The primary endpoint in this analysis was change in LVEF. Secondary outcomes were changes in LVEDD and all-cause mortality. TSA was used to quantify the statistical reliability of data in the cumulative meta-analyses. Nineteen RCTs with 1341 HFrEF subjects were eligible for analyses. The aetiology of HF, specific immunomodulation strategy, and treatment duration were variable across trials. Immunomodulation led to a greater improvement in LVEF [mean difference: +5.7% 95% confidence interval (CI): 3.0-8.5%, P < 0.001] and reduction in LVEDD (mean difference: -3.7 mm, 95% CI: -7.0 to -0.4 mm, P = 0.028) than no immunomodulation in meta-analyses and TSAs. We observed a non-significant decrease in all-cause mortality among those on immumomodulation (risk ratio: 0.7, 95% CI: 0.4-1.3, P = 0.234), but the Z-curve for cumulative treatment effect of immunomodulation in the TSA did not cross the boundary of futility.ConclusionsImmunomodulation led to improved cardiac structure and function in patients with HFrEF. While these benefits did not translate into a significant improvement in mortality, our analysis suggests that larger studies of targeted immunomodulation are needed to understand the true benefits.
| S-EPMC7261557 | biostudies-literature