Experimental cardiac radiation exposure induces ventricular diastolic dysfunction with preserved ejection fraction

Hirofumi Saiki, Gilles Moulay, Adam J. Guenzel, Weibin Liu, Teresa D. Decklever, Kelly L. Classic, Linh Pham, Horng Haur Chen, John C Jr. Burnett, Stephen J Russell, Margaret May Redfield

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT (125I) measurement of cardiac iodine uptake allowed calculation of the131I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak ±dP/dt. Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. NEW & NOTEWORTHY Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.

Original languageEnglish (US)
Pages (from-to)H392-H407
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume313
Issue number2
DOIs
StatePublished - Aug 11 2017

Fingerprint

Ventricular Dysfunction
Heart Failure
Cardiac Myocytes
Oxidative Stress
Fibrosis
Radiotherapy
Inflammation
Radiation Dosage
Dependovirus
Radiation Effects
Left Ventricular Dysfunction
Left Ventricular Hypertrophy
Ventricular Pressure
Radiation Exposure
Left Ventricular Function
Iodine
Stroke Volume
Hypertrophy
Rodentia
Myocardium

Keywords

  • Animal model
  • Coronary microvasculature
  • Diastolic dysfunction
  • Heart failure with preserved ejection fraction
  • Radiation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Experimental cardiac radiation exposure induces ventricular diastolic dysfunction with preserved ejection fraction. / Saiki, Hirofumi; Moulay, Gilles; Guenzel, Adam J.; Liu, Weibin; Decklever, Teresa D.; Classic, Kelly L.; Pham, Linh; Chen, Horng Haur; Burnett, John C Jr.; Russell, Stephen J; Redfield, Margaret May.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 313, No. 2, 11.08.2017, p. H392-H407.

Research output: Contribution to journalArticle

@article{0049bad16a614e7f9d0096244595f3bf,
title = "Experimental cardiac radiation exposure induces ventricular diastolic dysfunction with preserved ejection fraction",
abstract = "Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT (125I) measurement of cardiac iodine uptake allowed calculation of the131I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak ±dP/dt. Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. NEW & NOTEWORTHY Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.",
keywords = "Animal model, Coronary microvasculature, Diastolic dysfunction, Heart failure with preserved ejection fraction, Radiation",
author = "Hirofumi Saiki and Gilles Moulay and Guenzel, {Adam J.} and Weibin Liu and Decklever, {Teresa D.} and Classic, {Kelly L.} and Linh Pham and Chen, {Horng Haur} and Burnett, {John C Jr.} and Russell, {Stephen J} and Redfield, {Margaret May}",
year = "2017",
month = "8",
day = "11",
doi = "10.1152/ajpheart.00124.2017",
language = "English (US)",
volume = "313",
pages = "H392--H407",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Experimental cardiac radiation exposure induces ventricular diastolic dysfunction with preserved ejection fraction

AU - Saiki, Hirofumi

AU - Moulay, Gilles

AU - Guenzel, Adam J.

AU - Liu, Weibin

AU - Decklever, Teresa D.

AU - Classic, Kelly L.

AU - Pham, Linh

AU - Chen, Horng Haur

AU - Burnett, John C Jr.

AU - Russell, Stephen J

AU - Redfield, Margaret May

PY - 2017/8/11

Y1 - 2017/8/11

N2 - Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT (125I) measurement of cardiac iodine uptake allowed calculation of the131I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak ±dP/dt. Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. NEW & NOTEWORTHY Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.

AB - Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT (125I) measurement of cardiac iodine uptake allowed calculation of the131I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak ±dP/dt. Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. NEW & NOTEWORTHY Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.

KW - Animal model

KW - Coronary microvasculature

KW - Diastolic dysfunction

KW - Heart failure with preserved ejection fraction

KW - Radiation

UR - http://www.scopus.com/inward/record.url?scp=85027250618&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027250618&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00124.2017

DO - 10.1152/ajpheart.00124.2017

M3 - Article

C2 - 28550173

AN - SCOPUS:85027250618

VL - 313

SP - H392-H407

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 2

ER -