Closing the Loop: Modelling of Heart Failure Progression from Health to End-Stage Using a Meta-Analysis of Left Ventricular Pressure-Volume Loops

Abstract Background Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3. Methods Firstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-β1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry. Results HDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and −dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined. Conclusion Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.

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The use of bolus intravenous nitroglycerin to alter load on a beat-by-beat basis to generate left ventricular pressure-volume relationships in patients with congestive heart failure

Journal of the American College of Cardiology ◽

10.1016/0735-1097(91)91301-t ◽

1991 ◽

Vol 17 (2) ◽

pp. A84 ◽

Cited By ~ 2

Author(s):

Howard L. Haber ◽

Eric Powers ◽

Christopher L. Simek ◽

Stewart Pollock ◽

Alberto Sadun ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Ventricular Pressure ◽

Intravenous Nitroglycerin

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Synthesis and Biological Activity of the Pyridine-Hexacyclic-Steroid Derivative on a Heart Failure Model

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523021666211222125403 ◽

2021 ◽

Vol 21 ◽

Author(s):

Figueroa-Valverde Lauro ◽

López-Ramos Maria ◽

Díaz-Cedillo Francisco ◽

Rosas-Nexticapa Marcela ◽

Mateu-Armad Maria Virginia ◽

...

Keyword(s):

Heart Failure ◽

Biological Activity ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Ventricular Pressure ◽

Pyridine Derivative ◽

Dependent Manner ◽

Inotropic Activity ◽

Heart Failure Model ◽

Chemical Strategies

Background: Several drugs with inotropic activity have been synthesized; however, there is very little information on biological activity exerted by steroid derivatives in the cardiovascular system. Objective: The aim of this research was to prepare a steroid-pyridine derivative to evaluate the effect it exerts on left ventricular pressure and characterize its molecular interaction. Methods: The first stage was carried out through the synthesis of a steroid-pyridine derivative using some chemical strategies. The second stage involved the evaluation of the biological activity of the steroid-pyridine derivative on left ventricular pressure using a model of heart failure in the absence or presence of the drugs, such as flutamide, tamoxifen, prazosin, metoprolol, indomethacin, and nifedipine. Results: The results showed that steroid-pyridine derivative increased left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These results indicate that positive inotropic activity produced by the steroid-pyridine derivative was via calcium channel activation. Furthermore, the biological activity exerted by the steroid-pyridine derivative on the left ventricle produces changes in cAMP concentration. Conclusion: It is noteworthy that positive inotropic activity produced by this steroid-pyridine derivative involves a different molecular mechanism compared to other positive inotropic drugs. Therefore, this steroid could be a good candidate for the treatment of heart failure.

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Time delay to peak left ventricular pressure rise identifies the substrate for dyssynchronous heart failure and detects disease modification with resynchronization- an observational clinical study

EP Europace ◽

10.1093/europace/euab116.456 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

H Odland ◽

T Holm ◽

S Ross ◽

LO Gammelsrud ◽

R Cornelussen ◽

...

Keyword(s):

Heart Failure ◽

Nyha Class ◽

Pressure Rise ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Ventricular Pressure ◽

Cardiac Resynchronization ◽

Disease Modification ◽

Volumetric Response

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian South East Health Authorities Introduction Identification of disease modification prior to implantation of Cardiac Resynchronization Therapy may help select the right patients, increase responder-rates and promote the utilization of CRT. We tested the hypothesis that shortening of time-to-peak left ventricular pressure rise (Td) with CRT is useful to predict long-term volumetric response (End-systolic volume (ESV) decrease >15%) to CRT. Methods Forty-five heart failure patients admitted for CRT implantation with a class I/IIa indication according to current ESC/AHA guidelines were included in the study. Td was measured from onset QRS at baseline and from onset of pacing with CRT. Results Baseline characteristics were mean age 63 ± 10 years , 71% males, NYHA class 2.5, 87% LBBB, QRS duration 173 ± 15ms, EF biplane 31 ± 1%, ESV 144 ± 12mL and end-diastolic volume 2044 ± 14mL. At 6-months follow-up six patients increased ESV by 5 ± 8%, while 37 responders (85%) had a mean ESV decrease of 40 ± 2%. Responders presented with a higher Td at baseline compared to non-responders (163 ± 4ms vs 119 ± 9ms, p < 0.01). Td decreased to 156 ± 4ms (p = 0.02) with CRT in responders, while in non-responders Td increased to 147 ± 10ms (p < 0.01) with CRT. A decrease in Td of less than +3.5ms from baseline accurately identified responders to therapy (AUC 0.98, p < 0.01, sensitivity 97%, specificity 100%). AUC was 0.92 for baseline Td and a cut-off at 120ms yielded a sensitivity of 100% and specificity of 80% to identify volumetric responders. A linear relationship between the change in Td from baseline and ESV decrease on long term was found (β=-61, R = 0.58, P < 0.01). Conclusions Td at baseline and the shortening of Td with CRT accurately identifies responders to CRT, with incremental value on top of current guidelines, in a population with already high response rates. Td carries the potential to become the marker for prediction of long-term volumetric response in CRT candidates. Abstract Figure.

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