Functional effects of losartan in hypertrophic cardiomyopathy—a randomised clinical trial

Axelsson, Anna; Iversen, Kasper; Vejlstrup, Niels; Ho, Carolyn Y.; Havndrup, Ole; Kofoed, Klaus F.; Norsk, Jakob; Jensen, Morten Kvistholm; Bundgaard, Henning

doi:10.1136/heartjnl-2015-308343

Cited by 31 publications

(23 citation statements)

References 33 publications

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“…Although ARBs are used widely in the treatment of CVD, meta-analyses of randomized clinical trials suggest that ARBs are not as effective as expected in preventing pathologic remodeling, fibrosis and cardiomyopathy ( Axelsson et al, 2015 , 2016 ). Despite the potential of AT2R to promote cardiovascular repair, to date there are no approved AT2R agonists to treat CVD or its co-morbidities.…”

Section: Introductionmentioning

confidence: 99%

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Toedebusch¹,

Belenchia²,

Pulakat³

2018

Front. Pharmacol.

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Cardiovascular disease incidence continues to rise and new treatment paradigms are warranted. We reported previously that activation of Angiotensin II receptor (encoded by the X-linked Agtr2 gene) by a new peptide agonist, NP-6A4, was more effective in protecting mouse cardiomyocyte HL-1 cells and human coronary artery vascular smooth muscle cells (hCAVSMCs) from acute nutrient deficiency than other drugs tested. To elucidate further the protective effects of NP-6A4 in human cells, we studied the effects of NP-6A4 treatment on functions of human coronary artery endothelial cells (hCAECs), and hCAVSMCs. In hCAVSMCs, NP-6A4 (1 μM) increased Agtr2 mRNA (sixfold, p < 0.05) after 12-h exposure, whereas in hCAECs, significant increase in Agtr2 mRNA (hCAECs: eightfold) was observed after prolonged exposure. Interestingly, NP-6A4 treatment (1 μM, 12 h) increased AT2R protein levels in all human cells tested. Pre-treatment with AT2R-antagonist PD123319 (20 μM) and anti-AT2R siRNA (1 μM) suppressed this effect. Thus, NP-6A4 activates a positive feedback loop for AT2R expression and signaling in hCAVSMCs and hCAECs. NP-6A4 (1–20 μM) increased cell index (CI) of hCAVSMCs as determined by real time cell analyzer (RTCA), indicating that high concentrations of NP-6A4 were not cytotoxic for hCAVSMCs, rather promoting better cell attachment and growth. Seahorse Extracellular Flux Assay revealed that NP-6A4 (1 μM) treatment for 7 days increased whole cell-based mitochondrial parameters of hCAVSMCs, specifically maximal respiration (p < 0.05), spare respiratory capacity (p < 0.05) and ATP production (p < 0.05). NP-6A4 (1 μM; 7 days) also suppressed Reactive Oxygen Species (ROS) in hCAVSMCs. Exposure to Doxorubicin (DOXO) (1 μM) increased ROS in hCAVSMCs and this effect was suppressed by NP-6A4 (1 μM). In hCAECs grown in complete medium, NP-6A4 (1 μM) and Ang II (1 μM) exerted similar changes in CI. Additionally, NP-6A4 (5 μM: 12 h) increased expression of eNOS (sixfold, p < 0.05) and generation of nitric oxide (1.3-fold, p < 0.05) in hCAECs and pre-treatment with PD123319 (20 μM) suppressed this effect partially (65%). Finally, NP-6A4 decreased phosphorylation of Jun-N-terminal kinase, implicated in apoptosis of ECs in atherosclerotic sites. Taken together, NP-6A4, through its ability to increase AT2R expression and signaling, exerts different cell-specific protective effects in human VSMCs and ECs.

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Section: Introductionmentioning

confidence: 99%

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Toedebusch¹,

Belenchia²,

Pulakat³

2018

Front. Pharmacol.

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“…This has prompted the testing of L-type Ca 2+ channel blockers (e.g., diltiazem) (22,23), angiotensin II receptor antagonists (e.g., losartan) (24), antioxidants (e.g., N-acetylcysteine) (21,25,26), and metabolic modulators (perhexiline) (27) with success in preventing hypertrophy, fibrosis, and adverse cardiac remodeling in animal models. However, neither diltiazem (28), nor losartan (29,30), nor perhexiline (31) is able to prevent development of the cardiac phenotype in HCM patients. One possible reason for the difference in outcomes between mouse and human studies could be inclusion of patients with a variety of causal HCM mutations in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

Vakrou

Fukunaga²,

Foster

et al. 2018

JCI Insight

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“…In a small pilot study of losartan in noHCM (NCT01150461), there was a trend towards improvement in LV mass and an improvement in late gadolinium enhancement on magnetic resonance imaging compared to placebo . A larger single‐centre randomized trial (INHERIT, NCT01447654) of losartan in obstructive and non‐obstructive patients, however, failed to demonstrate a beneficial effect on LV mass, measures of diastolic function, or exercise capacity . A phase II placebo‐controlled trial of valsartan (VANISH, NCT01912534) is currently underway in HCM mutation carriers with asymptomatic or early/mild disease.…”

Section: Novel Pharmacotherapies For Hypertrophic Cardiomyopathymentioning

confidence: 99%

Hypertrophic cardiomyopathy: the future of treatment

Tuohy

Kaul

Song

et al. 2020

European J of Heart Fail

132

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Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic disorder most often caused by sarcomeric mutations resulting in left ventricular hypertrophy, fibrosis, hypercontractility, and reduced compliance. It is the most common inherited monogenic cardiac condition, affecting 0.2% of the population. Whereas currently available therapies for HCM have been effective in reducing morbidity, there remain important unmet needs in the treatment of both the obstructive and non‐obstructive phenotypes. Novel pharmacotherapies directly target the molecular underpinnings of HCM, while innovative procedural techniques may soon offer minimally‐invasive alternatives to current septal reduction therapy. With the advent of embryonic gene editing, there now exists the potential to correct underlying genetic mutations that may result in disease. This article details the recent developments in the treatment of HCM including pharmacotherapy, septal reduction procedures, mitral valve manipulation, and gene‐based therapies.

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Functional effects of losartan in hypertrophic cardiomyopathy—a randomised clinical trial

Abstract: NCT01447654-results.

Cited by 31 publications

References 33 publications

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Cell-Specific Protective Signaling Induced by the Novel AT2R-Agonist NP-6A4 on Human Endothelial and Smooth Muscle Cells

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

Hypertrophic cardiomyopathy: the future of treatment

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