Inhibition of Hypertrophy Is a Good Therapeutic Strategy in Ventricular Pressure Overload

Schiattarella, Gabriele Giacomo; Hill, Joseph A.

doi:10.1161/circulationaha.115.013894

Cited by 202 publications

(127 citation statements)

References 151 publications

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“…9, 12 Aortic stiffness increases with age and leads to elevated systolic blood and pulse pressures, which impose systolic overload, because of augmented wave reflection, on the LV, resulting in diastolic dysfunction 13-17 and concentric remodeling/hypertrophy with increased wall thickness and relatively little change in volume. [15][16][17][18][19][20] In the present study, the HFpEF patients had lower LVDd and LVMI but higher RWT, displaying predominantly concentric remodeling/hypertrophy with a similar increase in E/e' or LV end-diastolic pressure as compared with HFrEF patients. LV diastolic wall stress, which is proportional to pressure and cavity radius and inverse to wall thickness according to the Laplace law, 15 is therefore considered to be lower in patients with HFpEF because of the presence of concentric remodeling/hypertrophy compared with HFrEF patients who are predominantly associated with eccentric hypertrophy.…”

Section: Study Limitationssupporting

confidence: 49%

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

Harada¹,

Mizuno²,

Kugimiya³

et al. 2017

Circ J

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Section: Study Limitationssupporting

confidence: 49%

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

Harada¹,

Mizuno²,

Kugimiya³

et al. 2017

Circ J

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“…31,33,34 In this study, we demonstrated that Bsg is a novel signaling that promotes cardiac hypertrophy, fibrosis, and heart failure in response to pressure overload. These responses were accompanied by significant upregulation of inflammatory cytokines/chemokines and growth factors by Bsg in CFs and cardiomyocytes.…”

Section: Bsg In Cardiac Tissues Promotes Hypertrophy Fibrosis and Hmentioning

confidence: 65%

Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice

Suzuki

Satoh

Ikeda

et al. 2016

ATVB

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Objective— Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinases and promotes inflammation. However, the role of Bsg in the pathogenesis of cardiac hypertrophy and failure remains to be elucidated. We examined the role of Bsg in cardiac hypertrophy and failure in mice and humans. Approach and Results— We performed transverse aortic constriction in Bsg +/– and in wild-type mice. Bsg +/– mice showed significantly less heart and lung weight and cardiac interstitial fibrosis compared with littermate controls after transverse aortic constriction. Both matrix metalloproteinase activities and oxidative stress in loaded left ventricle were significantly less in Bsg +/– mice compared with controls. Echocardiography showed that Bsg +/– mice showed less hypertrophy, less left ventricular dilatation, and preserved left ventricular fractional shortening compared with littermate controls after transverse aortic constriction. Consistently, Bsg +/– mice showed a significantly improved long-term survival after transverse aortic constriction compared with Bsg +/+ mice, regardless of the source of bone marrow ( Bsg +/+ or Bsg +/– ). Conversely, cardiac-specific Bsg-overexpressing mice showed significantly poor survival compared with littermate controls. Next, we isolated cardiac fibroblasts and examined their responses to angiotensin II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion, and extracellular signal–regulated kinase/Akt/JNK activities in Bsg +/+ cardiac fibroblasts, all of which were significantly less in Bsg +/– cardiac fibroblasts. Consistently, extracellular and intracellular Bsg significantly promoted cardiac fibroblast proliferation. Finally, serum levels of Bsg were significantly elevated in patients with heart failure and predicted poor prognosis. Conclusions— These results indicate the crucial roles of intracellular and extracellular Bsg in the pathogenesis of cardiac hypertrophy, fibrosis, and failure in mice and humans.

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“…Less is known about cardiac signal transduction in large mammals, despite the significant differences between large and small mammalian hearts including include life span, heart rate, Ca 2+ handling, tolerance for myocardial injury, and rate of progression of cardiac remodeling 43. The differences in cardiac biology between small and large mammals are not purely academic.…”

Section: Discussionmentioning

confidence: 99%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

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Inhibition of Hypertrophy Is a Good Therapeutic Strategy in Ventricular Pressure Overload

Cited by 202 publications

References 151 publications

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

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Inhibition of Hypertrophy Is a Good Therapeutic Strategy in Ventricular Pressure Overload

Cited by 202 publications

References 151 publications

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction ― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction ― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

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Product

Resources

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B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　― Relevance to Age-Related Left Ventricular Modeling in Japanese ―