scholarly journals Novel antisense therapy targeting microRNA-132 in patients with heart failure

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J Taubel ◽  
W Hauke ◽  
S Rump ◽  
J Viereck ◽  
S Batkai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Private Company ◽  
Ventricular Ejection Fraction ◽  
Pharmacodynamic Effects ◽  
Amino Terminal ◽  
Patients With Heart Failure

Abstract Background Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. Purpose The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study. Methods Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. Results CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed median 23.3% NT-proBNP reduction, vs. 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and positive trends for cardiac fibrosis biomarkers. Conclusions This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. The indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Cardior Pharmaceuticals GmbH

scholarly journals Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study

2020 ◽  
Author(s):  
Jörg Täubel ◽  
Wilfried Hauke ◽  
Steffen Rump ◽  
Janika Viereck ◽  
Sandor Batkai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Controlled Study ◽  
Double Blind ◽  
Ventricular Ejection Fraction ◽  
Pharmacodynamic Effects ◽  
Amino Terminal ◽  
Patients With Heart Failure ◽  
Phase 1B

Abstract Aims Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study (NCT04045405). Methods and results Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed a median 23.3% NT-proBNP reduction, vs. a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraging positive trends for relevant cardiac fibrosis biomarkers. Conclusion This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. Although this study is limited by the small patient numbers, the indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF.

Right ventricular speckle tracking in patients with heart failure – a comparison of right ventricular measures

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
I.J Lundorff ◽  
M Sengeloev ◽  
S Pedersen ◽  
D Modin ◽  
N.E Bruun ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Right Ventricular ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Private Company ◽  
Ventricular Ejection Fraction ◽  
Risk Of Mortality ◽  
Patients With Heart Failure

Abstract Background RV dysfunction is associated with increased mortality and morbidity in patients with heart failure. Due to the complex shape and position of the RV, assessing RV function from echocardiographic images remains a challenge. Purpose We have previously found that global longitudinal strain from 2DSTE is superior to left ventricular ejection fraction (LVEF) in identifying HFrEF patients with high risk of mortality. In this study we wanted to examine RV 2DSTE in patients with HFrEF and compare its prognostic value to conventional RV measures. Methods and results Echocardiographic examinations were retrieved from 701 patients with HFrEF. RV estimates were analysed offline, and end point was all-cause mortality. During follow-up (median 39 months) 118 patients (16.8%) died. RV GLS and RV FWS remained associated with mortality after multivariable adjustment, independent of TAPSE (RV GLS: HR 1.07, 95% CI 1.02–1.13, p=0.010, per 1% decrease) (RV FWS: HR 1.05, 95% CI 1.01–1.09, p=0.010, per 1% decrease). This seemed to be caused by significant associations in men as TAPSE remained as the only independent prognosticator in women. All RV estimates provided prognostic information incremental to established risk factors and significantly increased C-statistics (TAPSE: 0.74 to 0.75; RVFAC: 0.74 to 0.75; RVFWS: 0.74 to 0.77; RVGLS: 0.74 to 0.77). Conclusions RV strain from 2DSTE was associated with mortality in patients with HFrEF, independent of TAPSE and established risk factors. Our results indicate that RV strain is particularly valuable in male patients, whereas in women TAPSE remains a stronger prognosticator. RV GLS and the risk of mortality Funding Acknowledgement Type of funding source: Private company. Main funding source(s): PGJ reports receiving lecture fee from Novo Nordisk.

scholarly journals Expression of serum microRNA-155 and its clinical importance in patients with heart failure after myocardial infarction

2019 ◽  
Vol 47 (12) ◽  
pp. 6294-6302
Author(s):  
Baojian Zhang ◽  
Biao Li ◽  
Fen Qin ◽  
Fan Bai ◽  
Chao Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Characteristic Curve ◽  
Clinical Importance ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Amino Terminal ◽  
Serum Mirna ◽  
Patients With Heart Failure

Objective This study was conducted to investigate the level of microRNA-155 (miRNA-155) in patients with heart failure (HF) after myocardial infarction (MI) and its clinical importance. Methods Serum miRNA-155 levels were measured using quantitative reverse transcription (qRT)-PCR. The left ventricular ejection fraction (LVEF), left ventricular posterior wall thickness, and left ventricular end-diastolic diameter were measured by echocardiography. Serum amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and other parameters were also analyzed. Results miRNA-155 levels in patients with HF were significantly higher than in control and MI groups. The area under the receiver operating characteristic curve of serum miRNA-155 in the diagnosis of HF after MI was 0.941, the cutoff value was 1.77, sensitivity was 92.73%, and specificity was 92.14%. NT-proBNP levels were significantly higher and LVEF was lower in patients with high versus low miRNA-155 expression. Conclusions Patients with HF after MI had elevated miRNA-155 levels and poor cardiac function, suggesting that determining miRNA-155 expression could be used to assess the severity of the disease.

scholarly journals Characterization of NT-proBNP in Human Urine

2009 ◽  
Vol 55 (6) ◽  
pp. 1126-1134 ◽  
Author(s):  
Suetonia C Palmer ◽  
Zoltan H Endre ◽  
A Mark Richards ◽  
Timothy G Yandle
Keyword(s):  
Heart Failure ◽  
Healthy Subjects ◽  
Reversed Phase ◽  
Left Ventricular ◽  
Size Exclusion ◽  
Molecular Forms ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Amino Terminal ◽  
Patients With Heart Failure

Abstract Background: Urine amino-terminal probrain natriuretic peptide (NT-proBNP) concentrations may exclude the presence of heart failure and provide insight into renal clearance mechanisms for human NT-proBNP. We characterized the molecular forms of urine NT-proBNP detected by immunoassay. Methods: Urine from patients with heart failure was subjected to HPLC and analyzed using immunoassays specific toward different epitopes of NT-proBNP. We assessed urine NT-proBNP immunoreactivity in healthy subjects and patients with heart failure. Results: Size-exclusion chromatography of heart failure urine identified no NT-proBNP immunoreactivity coeluting with NT-proBNP(1–76); multiple immunoreactive NT-proBNP fragments were present. The absence of intact urinary NT-proBNP was supported by reversed-phase HPLC. Urine NT-proBNP immunoreactivity was higher in patients with acute [median 192 (interquartile range 108–1445) pg/mg creatinine] and chronic [52 (15–118) pg/mg creatinine] heart failure than in healthy subjects [4.2 (2.6–5.8) pg/mg creatinine] (P < 0.001). In 40 patients with heart failure, urine NT-proBNP immunoreactivity correlated with plasma NT-proBNP (r = 0.72, P < 0.001) and inversely with left ventricular ejection fraction (r = −0.33, P = 0.04). Conclusions: Our findings clarify previous reported relationships of urine NT-proBNP–like immunoreactivity with plasma NT-proBNP concentrations and the diagnosis of heart failure. As urine NT-proBNP immunoreactivity is not intact NT-proBNP(1–76), but rather reflects assorted metabolites, the diagnostic performance of NT-proBNP assays in urine may be assay specific, necessitating validation of biomarker performance on an assay-by-assay basis. .

scholarly journals A Randomized Controlled Trial to Study the Effect of Yoga Therapy on Cardiac Function and N Terminal Pro BNP in Heart Failure

2014 ◽  
Vol 9 ◽  
pp. IMI.S13939 ◽  
Author(s):  
Bandi Hari Krishna ◽  
Pravati Pal ◽  
G. K. Pal ◽  
J. Balachander ◽  
E. Jayasettiaseelon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Medical Therapy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Tei Index ◽  
Ventricular Ejection Fraction ◽  
Yoga Therapy ◽  
Standard Medical Therapy

Aims The purpose of this study was to evaluate whether yoga training in addition to standard medical therapy can improve cardiac function and reduce N terminal pro B-type natriuretic peptide (NT pro BNP) in heart failure (HF). Methods 130 patients were recruited and randomized into two groups: Control Group (CG) ( n = 65), Yoga Group (YG). In YG, 44 patients and in CG, 48 patients completed the study. Cardiac function using left ventricular ejection fraction (LVEF), myocardial performance index (Tei index), and NT pro BNP, a biomarker of HF, was assessed at baseline and after 12 weeks. Result Improvement in LVEF, Tei index, and NT pro BNP were statistically significant in both the groups. Furthermore, when the changes in before and after 12 weeks were in percentage, LVEF increased 36.88% in the YG and 16.9% in the CG, Tei index was reduced 27.87% in the YG and 2.79% in the CG, NT pro BNP was reduced 63.75% in the YG and 10.77% in the CG. The between group comparisons from pre to post 12 weeks were significant for YG improvements (LVEF, P < 0.01, Tei index, P < 0.01, NT pro BNP, P < 0.01). Conclusion These results indicate that the addition of yoga therapy to standard medical therapy for HF patients has a markedly better effect on cardiac function and reduced myocardial stress measured using NT pro BNP in patients with stable HF.

Sign in / Sign up

Export Citation Format

Share Document