Vascular relaxation and cyclic guanosine monophosphate in a rat model of high output heart failure

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

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High-output heart failure in a newborn

BMJ Case Reports ◽

10.1136/bcr-2012-006289 ◽

2012 ◽

Vol 2012 (jul09 1) ◽

pp. bcr2012006289-bcr2012006289 ◽

Cited By ~ 2

Author(s):

M. I. Mascarenhas ◽

M. Moniz ◽

S. Ferreira ◽

A. Goulao ◽

R. Barroso

Keyword(s):

Heart Failure ◽

High Output Heart Failure ◽

High Output

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Delayed High Output Heart Failure due to Arteriovenous Fistula Complicated with Herniated Disc Surgery

Journal of Korean Medical Science ◽

10.3346/jkms.2016.31.12.2051 ◽

2016 ◽

Vol 31 (12) ◽

pp. 2051 ◽

Cited By ~ 3

Author(s):

Taeshik Park ◽

Sang-Ho Park ◽

Alok Arora

Keyword(s):

Heart Failure ◽

Arteriovenous Fistula ◽

Herniated Disc ◽

Disc Surgery ◽

High Output Heart Failure ◽

High Output

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Thyrotoxic High-Output Heart Failure in a Pregnant Woman with Anemia

10.1210/endo-meetings.2011.part3.p13.p2-705 ◽

2011 ◽

pp. P2-705-P2-705

Author(s):

Jennifer J Miranda ◽

Marc J Laufgraben ◽

Simonette Soler ◽

Athena Poppas ◽

Geetha Gopalakrishnan

Keyword(s):

Heart Failure ◽

Pregnant Woman ◽

High Output Heart Failure ◽

High Output

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Effects of Haima Duobian Pill in a Rat Model of Kidney Yang Deficiency Syndrome

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6696234 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yijia Zeng ◽

Tingna Li ◽

Xiaorui Zhang ◽

Yuanyuan Ren ◽

Qinwan Huang ◽

...

Keyword(s):

Rat Model ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Deficiency Syndrome ◽

Guanosine Monophosphate ◽

Network Pharmacology ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Effects ◽

Kidney Yang Deficiency

Objective. Modern research shows that Haima Duobian pill (HDP) can relieve the kidney yang deficiency syndrome (KYDS), but the mechanism is still unclear. The aim of this work was to study the effects of HDP in a rat model of KYDS. Materials and Methods. The network pharmacology methods were used to predict the therapeutic effects of Haima Duobian pill. Adenine was used to establish the rat model of kidney yang deficiency syndrome. The general physical signs of rats were observed after different doses of Haima Duobian pill (HDP) were given. Serum cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2), and gonadotropin-releasing hormone (GnRH) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Then, the histopathologic changes and sperm activity were detected. Results. HDP could improve the general signs of kidney yang deficiency syndrome rats. After the rats were treated with HDP, the expression of cGMP and E2 was significantly inhibited and the expression of cAMP and T was significantly increased. The pathological damage of testis, epididymis, and seminal vesicle was alleviated, and the sperm activity was improved. Conclusion. For adenine-induced kidney yang deficiency syndrome in rats, HDP had a significant therapeutic effect.

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Heart failure with preserved ejection fraction: controversies, challenges and future directions

Heart ◽

10.1136/heartjnl-2016-310790 ◽

2018 ◽

Vol 104 (5) ◽

pp. 377-384 ◽

Cited By ~ 37

Author(s):

Rosita Zakeri ◽

Martin R Cowie

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Management Strategies ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Protein Kinase G ◽

Preserved Ejection Fraction ◽

Future Directions ◽

Novel Treatments ◽

Inflammatory State

Heart failure with preserved ejection fraction (HFpEF) comprises almost half of the population burden of HF. Because HFpEF likely includes a range of cardiac and non-cardiac abnormalities, typically in elderly patients, obtaining an accurate diagnosis may be challenging, not least due to the existence of multiple HFpEF mimics and a newly identified subset of patients with HFpEF and normal plasma natriuretic peptide concentrations. The lack of effective treatment for these patients represents a major unmet clinical need. Heterogeneity within the patient population has triggered debate over the aetiology and pathophysiology of HFpEF, and the neutrality of randomised clinical trials suggests that we do not fully understand the syndrome(s). Dysregulated nitric oxide–cyclic guanosine monophosphate–protein kinase G signalling, driven by comorbidities and ageing, may be the fundamental abnormality in HFpEF, resulting in a systemic inflammatory state and microvascular endothelial dysfunction. Novel informatics platforms are also being used to classify HFpEF into subphenotypes, based on statistically clustered clinical and biological characteristics: whether such subclassification will lead to more targeted therapies remains to be seen. In this review, we summarise current concepts and controversies, and highlight the diagnostic and therapeutic challenges in clinical practice. Novel treatments and disease management strategies are discussed, and the large gaps in our knowledge identified.

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