Jessica Regan | Virginia Commonwealth University (original) (raw)

Papers by Jessica Regan

Circulation, Nov 25, 2014

Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properti... more Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properties and promotes cardiovascular disease. Whether WD has direct effects on cardiac function is unknown. Hypothesis: We hypothesized that WD would negatively affect cardiac systolic and diastolic function in the mouse. Methods: CD1 8 week-old male mice were fed with standard chow diet with 17% fat content (N=8) or WD with 42.0% fat content (N=11) for 8 weeks. Food intake was measured daily. Mice underwent transthoracic echocardiography under mild sedation with pentobarbital at baseline, 4 weeks and 8 weeks to measure left ventricular end-diastolic diameter (LVEDD), ejection fraction (LVEF), mass (LVM), myocardial performance index (MPI) and isovolumetric relaxation time (IVRT). Left ventricular catheterization through retrograde right carotid artery approach was performed with a Millar catheter to measure peak systolic pressure (LVPSP) and end-diastolic pressure (LVEDP). An additional group of female mice (N=13) ...

Circulation, Nov 25, 2014

Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF... more Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents approximately 50% of all patients with HF, the mechanisms of disease are poorly understood, animal models of HFpEF not due pressure overload are lacking, and therapies for HFpEF are generally ineffective. Hypothesis: A continuous infusion of low dose of angiotensin II (ATII) may be sufficient to induce changes in left ventricular (LV) diastolic function without increasing blood pressure nor induce LV hypertrophy. Methods: Osmotic pumps were implanted subcutaneously in 8 week-old CD1 male mice randomly assigned to the ATII (200 ng/kg/day) or vehicle (N=8/group). Transthoracic echocardiography was performed at baseline and 4 weeks to measure LV dimensions, systolic and diastolic function. Aortic systolic and diastolic pressures (AoP), LV peak systolic and end-diastolic pressures (LVPSP, LVEDP) were measured at LV catheterization. Fibro...

Journal of the American College of Cardiology, Mar 1, 2017

Background: Ventilatory inefficiency, occurring to due ventilation/perfusion mismatch, independen... more Background: Ventilatory inefficiency, occurring to due ventilation/perfusion mismatch, independently predicts outcomes in systolic heart failure (SHF). However, the mechanism underlying this association is not understood. Increased afterload shifts the pressure-volume relationship rightward and impairs cardiac function during exercise. We hypothesize that increased arterial elastance (Ea), an afterload surrogate, correlates with worse ventilatory efficiency in patients with SHF. Methods: Sixty SHF outpatients underwent noninvasive hemodynamic assessment (ccNexfin, Edwards Lifesciences) and maximal treadmill cardiopulmonary exercise testing. Ea was calculated as 0.9 x systolic blood pressure (SBP) divided by stroke volume. Minute ventilation-carbon dioxide production slope (VE/VCO2) and oxygen uptake efficiency slope (OUES) were captured.

Circulation-heart Failure, Nov 1, 2017

Circulation, Nov 11, 2016

Background: Western diet (WD), rich in saturated fat and sugars, can induce cardiac dysfunction t... more Background: Western diet (WD), rich in saturated fat and sugars, can induce cardiac dysfunction through unknown mechanisms. Saturated fat and sugars can prime and activate the NLRP3 inflammasome that produces the cardiodepressant pro-inflammatory cytokine interleukin-18 (IL-18). Hypothesis: We hypothesize that IL-18 mediates WD-induced cardiac dysfunction, independent on the effects on glucose metabolism. Methods: Adult C57BL/6J (WT)(N=7) and IL-18 knock out (KO)(N=9) mice were randomly assigned to either standard mouse diet (SD, saturated fat 0.8%, sucrose 0%) or WD (saturated fat 12.8%, sucrose 30%) for 8 weeks. Transthoracic echocardiography was performed at baseline and at 8 weeks to measure LV fractional shortening (LVFS), isovolumetric relaxation time (IRT) and myocardial performance index (MPI). Food intake was measured daily, body weight weekly, and fasting glycemia at baseline and at 8 weeks. Results: After 8 weeks, WD-fed WT mice had significantly lower LVFS, higher IRT and MPI than WD-fed IL-18...

Journal of the American College of Cardiology, Mar 1, 2018

Canadian Journal of Cardiology, Oct 1, 2016

Circulation, Nov 10, 2015

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated l... more Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left ventricular (LV) filling pressures due to impaired LV diastolic function. Low-dose infusion of angiotensin 2 (AT2) in the mouse induces a HFpEF phenotype without increasing blood pressure. AT2 infusion induces expression of Interleukin-18 (IL-18) in the heart. We therefore tested whether IL-18 mediated AT2-induced LV diastolic dysfunction in this model. Methods: We infused subcutaneously AT2 (0.2 mg/Kg/day) or a matching volume of vehicle via osmotic pumps surgically implanted in the interscapular space in adult wild-type (WT) male mice and IL-18 knock-out mice (IL-18KO). We also treated WT mice with daily intraperitoneal injections of recombinant murine IL-18 binding protein (IL-18bp, a naturally occurring IL-18 blocker) at 3 different doses (0.1, 0.3 and 1.0 mg/kg) or vehicle for 25 days starting on day 3. We performed a Doppler-echocardiography study before implantation and at 28 days to measure LV dimensions, mass, and systolic and diastolic function in all mice. LV catheterization was performed prior to sacrifice to measure LV end-diastolic pressure (LVEDP) using a Millar catheter. Results: AT2 induces a significant increase in isovolumetric relaxation time (IRT) and myocardial performance index (MPI) at Doppler echocardiography and elevation of LVEDP at catheterization, indicative of impaired LV diastolic function, in absence of any measurable effects on systolic blood pressure nor LV dimensions, mass, or systolic function. Mice with genetic deletion of IL-18 (IL-18 KO) or WT mice treated with IL-18bp had no significant increase in IRT, MPI or LVEDP with AT2 infusion. Conclusion: Genetic or pharmacologic IL-18 blockade prevent diastolic dysfunction in a mouse model of HFpEF induced by low dose AT2 infusion, suggesting a critical role of IL-18 in the pathophysiology of HFpEF.

Circulation, Nov 25, 2014

Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF... more Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents approximately 50% of all patients with HF, the mechanisms of disease are poorly understood, animal models of HFpEF not due pressure overload are lacking, and therapies for HFpEF are generally ineffective. Hypothesis: A continuous infusion of low dose of angiotensin II (ATII) may be sufficient to induce changes in left ventricular (LV) diastolic function without increasing blood pressure nor induce LV hypertrophy. Methods: Osmotic pumps were implanted subcutaneously in 8 week-old CD1 male mice randomly assigned to the ATII (200 ng/kg/day) or vehicle (N=8/group). Transthoracic echocardiography was performed at baseline and 4 weeks to measure LV dimensions, systolic and diastolic function. Aortic systolic and diastolic pressures (AoP), LV peak systolic and end-diastolic pressures (LVPSP, LVEDP) were measured at LV catheterization. Fibro...

Circulation, Nov 25, 2014

Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properti... more Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properties and promotes cardiovascular disease. Whether WD has direct effects on cardiac function is unknown. Hypothesis: We hypothesized that WD would negatively affect cardiac systolic and diastolic function in the mouse. Methods: CD1 8 week-old male mice were fed with standard chow diet with 17% fat content (N=8) or WD with 42.0% fat content (N=11) for 8 weeks. Food intake was measured daily. Mice underwent transthoracic echocardiography under mild sedation with pentobarbital at baseline, 4 weeks and 8 weeks to measure left ventricular end-diastolic diameter (LVEDD), ejection fraction (LVEF), mass (LVM), myocardial performance index (MPI) and isovolumetric relaxation time (IVRT). Left ventricular catheterization through retrograde right carotid artery approach was performed with a Millar catheter to measure peak systolic pressure (LVPSP) and end-diastolic pressure (LVEDP). An additional group of female mice (N=13) ...

Journal of Clinical Trials in Cardiology, 2015

Translational Medicine, 2013

Journal of cardiovascular pharmacology, 2018

Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart... more Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance. We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment. LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.0...

American Journal of Physiology - Heart and Circulatory Physiology, 2015

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms... more Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (ATII) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the ATII (0.2 mg·kg(-1)·day(-1)) or volume-matched vehicle (N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. ATII infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.

Biophysical Journal, 2014

American journal of physiology. Heart and circulatory physiology, Jan 15, 2015

The heart adapts to exercise stimuli in a sex-dimorphic manner when mice are fed the traditional ... more The heart adapts to exercise stimuli in a sex-dimorphic manner when mice are fed the traditional soy-based chow. Females undergo more voluntary exercise (4 wk) than males and exhibit more cardiac hypertrophy per kilometer run (18, 32). We have found that diet plays a critical role in cage wheel exercise and cardiac adaptation to the exercise stimulus in this sex dimorphism. Specifically, feeding male mice a casein-based, soy-free diet increases daily running distance over soy-fed counterparts to equal that of females. Moreover, casein-fed males have a greater capacity to increase their cardiac mass in response to exercise compared with soy-fed males. To further explore the biochemical mechanisms for these differences, we performed a candidate-based RT-PCR screen on genes previously implicated in diet- or exercise-based cardiac hypertrophy. Of the genes screened, many exhibit significant exercise, diet, or sex effects but only transforming growth factor-β1 shows a significant three-w...

Comparative medicine, 2013

The role of exercise in decreasing the risk of cardiovascular disease in postmenopausal women has... more The role of exercise in decreasing the risk of cardiovascular disease in postmenopausal women has not been studied sufficiently. Accordingly, we investigated the effect of voluntary wheel-running and forced treadmill exercise on cardiac adaptation in mice treated with 4-vinylcyclohexine diepoxide (VCD), which selectively accelerates the loss of primary and primordial follicles and results in a state that closely mimics human menopause. Two-month-old female C57BL/6 mice injected with VCD (160 mg/kg) for 20 consecutive days underwent ovarian failure by 60 to 90 d after injection. Responses to voluntary wheel running and treadmill exercise did not differ between VCD- and vehicle-treated 7-mo-old C57BL/6 or outbred B6C3F1 mice. Moreover, adaptive cardiac hypertrophy, hypertrophic marker expression, and skeletal muscle characteristics after voluntary cage-wheel exercise did not differ between VCD- and vehicle-treated mice. Because 5' AMP-activated protein kinase (AMPK) is a key compo...

Journal of visualized experiments : JoVE, 2014

The risk of cardiovascular disease (CVD) increases in post-menopausal women, yet, the role of exe... more The risk of cardiovascular disease (CVD) increases in post-menopausal women, yet, the role of exercise, as a preventative measure for CVD risk in post-menopausal women has not been adequately studied. Accordingly, we investigated the impact of voluntary cage-wheel exercise and forced treadmill exercise on cardiac adaptation in menopausal mice. The most commonly used inducible model for mimicking menopause in women is the ovariectomized (OVX) rodent. However, the OVX model has a few dissimilarities from menopause in humans. In this study, we administered 4-vinylcyclohexene diepoxide (VCD) to female mice, which accelerates ovarian failure as an alternative menopause model to study the impact of exercise in menopausal mice. VCD selectively accelerates the loss of primary and primordial follicles resulting in an endocrine state that closely mimics the natural progression from pre- to peri- to post-menopause in humans. To determine the impact of exercise on exercise capacity and cardiac ...

Frontiers in Physiology, 2013

† These authors have contributed equally to this work.

Circulation, Nov 25, 2014

Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properti... more Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properties and promotes cardiovascular disease. Whether WD has direct effects on cardiac function is unknown. Hypothesis: We hypothesized that WD would negatively affect cardiac systolic and diastolic function in the mouse. Methods: CD1 8 week-old male mice were fed with standard chow diet with 17% fat content (N=8) or WD with 42.0% fat content (N=11) for 8 weeks. Food intake was measured daily. Mice underwent transthoracic echocardiography under mild sedation with pentobarbital at baseline, 4 weeks and 8 weeks to measure left ventricular end-diastolic diameter (LVEDD), ejection fraction (LVEF), mass (LVM), myocardial performance index (MPI) and isovolumetric relaxation time (IVRT). Left ventricular catheterization through retrograde right carotid artery approach was performed with a Millar catheter to measure peak systolic pressure (LVPSP) and end-diastolic pressure (LVEDP). An additional group of female mice (N=13) ...

Circulation, Nov 25, 2014

Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF... more Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents approximately 50% of all patients with HF, the mechanisms of disease are poorly understood, animal models of HFpEF not due pressure overload are lacking, and therapies for HFpEF are generally ineffective. Hypothesis: A continuous infusion of low dose of angiotensin II (ATII) may be sufficient to induce changes in left ventricular (LV) diastolic function without increasing blood pressure nor induce LV hypertrophy. Methods: Osmotic pumps were implanted subcutaneously in 8 week-old CD1 male mice randomly assigned to the ATII (200 ng/kg/day) or vehicle (N=8/group). Transthoracic echocardiography was performed at baseline and 4 weeks to measure LV dimensions, systolic and diastolic function. Aortic systolic and diastolic pressures (AoP), LV peak systolic and end-diastolic pressures (LVPSP, LVEDP) were measured at LV catheterization. Fibro...

Journal of the American College of Cardiology, Mar 1, 2017

Background: Ventilatory inefficiency, occurring to due ventilation/perfusion mismatch, independen... more Background: Ventilatory inefficiency, occurring to due ventilation/perfusion mismatch, independently predicts outcomes in systolic heart failure (SHF). However, the mechanism underlying this association is not understood. Increased afterload shifts the pressure-volume relationship rightward and impairs cardiac function during exercise. We hypothesize that increased arterial elastance (Ea), an afterload surrogate, correlates with worse ventilatory efficiency in patients with SHF. Methods: Sixty SHF outpatients underwent noninvasive hemodynamic assessment (ccNexfin, Edwards Lifesciences) and maximal treadmill cardiopulmonary exercise testing. Ea was calculated as 0.9 x systolic blood pressure (SBP) divided by stroke volume. Minute ventilation-carbon dioxide production slope (VE/VCO2) and oxygen uptake efficiency slope (OUES) were captured.

Circulation-heart Failure, Nov 1, 2017

Circulation, Nov 11, 2016

Background: Western diet (WD), rich in saturated fat and sugars, can induce cardiac dysfunction t... more Background: Western diet (WD), rich in saturated fat and sugars, can induce cardiac dysfunction through unknown mechanisms. Saturated fat and sugars can prime and activate the NLRP3 inflammasome that produces the cardiodepressant pro-inflammatory cytokine interleukin-18 (IL-18). Hypothesis: We hypothesize that IL-18 mediates WD-induced cardiac dysfunction, independent on the effects on glucose metabolism. Methods: Adult C57BL/6J (WT)(N=7) and IL-18 knock out (KO)(N=9) mice were randomly assigned to either standard mouse diet (SD, saturated fat 0.8%, sucrose 0%) or WD (saturated fat 12.8%, sucrose 30%) for 8 weeks. Transthoracic echocardiography was performed at baseline and at 8 weeks to measure LV fractional shortening (LVFS), isovolumetric relaxation time (IRT) and myocardial performance index (MPI). Food intake was measured daily, body weight weekly, and fasting glycemia at baseline and at 8 weeks. Results: After 8 weeks, WD-fed WT mice had significantly lower LVFS, higher IRT and MPI than WD-fed IL-18...

Journal of the American College of Cardiology, Mar 1, 2018

Canadian Journal of Cardiology, Oct 1, 2016

Circulation, Nov 10, 2015

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated l... more Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left ventricular (LV) filling pressures due to impaired LV diastolic function. Low-dose infusion of angiotensin 2 (AT2) in the mouse induces a HFpEF phenotype without increasing blood pressure. AT2 infusion induces expression of Interleukin-18 (IL-18) in the heart. We therefore tested whether IL-18 mediated AT2-induced LV diastolic dysfunction in this model. Methods: We infused subcutaneously AT2 (0.2 mg/Kg/day) or a matching volume of vehicle via osmotic pumps surgically implanted in the interscapular space in adult wild-type (WT) male mice and IL-18 knock-out mice (IL-18KO). We also treated WT mice with daily intraperitoneal injections of recombinant murine IL-18 binding protein (IL-18bp, a naturally occurring IL-18 blocker) at 3 different doses (0.1, 0.3 and 1.0 mg/kg) or vehicle for 25 days starting on day 3. We performed a Doppler-echocardiography study before implantation and at 28 days to measure LV dimensions, mass, and systolic and diastolic function in all mice. LV catheterization was performed prior to sacrifice to measure LV end-diastolic pressure (LVEDP) using a Millar catheter. Results: AT2 induces a significant increase in isovolumetric relaxation time (IRT) and myocardial performance index (MPI) at Doppler echocardiography and elevation of LVEDP at catheterization, indicative of impaired LV diastolic function, in absence of any measurable effects on systolic blood pressure nor LV dimensions, mass, or systolic function. Mice with genetic deletion of IL-18 (IL-18 KO) or WT mice treated with IL-18bp had no significant increase in IRT, MPI or LVEDP with AT2 infusion. Conclusion: Genetic or pharmacologic IL-18 blockade prevent diastolic dysfunction in a mouse model of HFpEF induced by low dose AT2 infusion, suggesting a critical role of IL-18 in the pathophysiology of HFpEF.

Circulation, Nov 25, 2014

Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF... more Introduction: Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents approximately 50% of all patients with HF, the mechanisms of disease are poorly understood, animal models of HFpEF not due pressure overload are lacking, and therapies for HFpEF are generally ineffective. Hypothesis: A continuous infusion of low dose of angiotensin II (ATII) may be sufficient to induce changes in left ventricular (LV) diastolic function without increasing blood pressure nor induce LV hypertrophy. Methods: Osmotic pumps were implanted subcutaneously in 8 week-old CD1 male mice randomly assigned to the ATII (200 ng/kg/day) or vehicle (N=8/group). Transthoracic echocardiography was performed at baseline and 4 weeks to measure LV dimensions, systolic and diastolic function. Aortic systolic and diastolic pressures (AoP), LV peak systolic and end-diastolic pressures (LVPSP, LVEDP) were measured at LV catheterization. Fibro...

Circulation, Nov 25, 2014

Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properti... more Introduction: Western diet (WD), rich in saturated fat and sucrose, has pro-inflammatory properties and promotes cardiovascular disease. Whether WD has direct effects on cardiac function is unknown. Hypothesis: We hypothesized that WD would negatively affect cardiac systolic and diastolic function in the mouse. Methods: CD1 8 week-old male mice were fed with standard chow diet with 17% fat content (N=8) or WD with 42.0% fat content (N=11) for 8 weeks. Food intake was measured daily. Mice underwent transthoracic echocardiography under mild sedation with pentobarbital at baseline, 4 weeks and 8 weeks to measure left ventricular end-diastolic diameter (LVEDD), ejection fraction (LVEF), mass (LVM), myocardial performance index (MPI) and isovolumetric relaxation time (IVRT). Left ventricular catheterization through retrograde right carotid artery approach was performed with a Millar catheter to measure peak systolic pressure (LVPSP) and end-diastolic pressure (LVEDP). An additional group of female mice (N=13) ...

Journal of Clinical Trials in Cardiology, 2015

Translational Medicine, 2013

Journal of cardiovascular pharmacology, 2018

Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart... more Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance. We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment. LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.0...

American Journal of Physiology - Heart and Circulatory Physiology, 2015

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms... more Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (ATII) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the ATII (0.2 mg·kg(-1)·day(-1)) or volume-matched vehicle (N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. ATII infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.

Biophysical Journal, 2014

American journal of physiology. Heart and circulatory physiology, Jan 15, 2015

The heart adapts to exercise stimuli in a sex-dimorphic manner when mice are fed the traditional ... more The heart adapts to exercise stimuli in a sex-dimorphic manner when mice are fed the traditional soy-based chow. Females undergo more voluntary exercise (4 wk) than males and exhibit more cardiac hypertrophy per kilometer run (18, 32). We have found that diet plays a critical role in cage wheel exercise and cardiac adaptation to the exercise stimulus in this sex dimorphism. Specifically, feeding male mice a casein-based, soy-free diet increases daily running distance over soy-fed counterparts to equal that of females. Moreover, casein-fed males have a greater capacity to increase their cardiac mass in response to exercise compared with soy-fed males. To further explore the biochemical mechanisms for these differences, we performed a candidate-based RT-PCR screen on genes previously implicated in diet- or exercise-based cardiac hypertrophy. Of the genes screened, many exhibit significant exercise, diet, or sex effects but only transforming growth factor-β1 shows a significant three-w...

Comparative medicine, 2013

The role of exercise in decreasing the risk of cardiovascular disease in postmenopausal women has... more The role of exercise in decreasing the risk of cardiovascular disease in postmenopausal women has not been studied sufficiently. Accordingly, we investigated the effect of voluntary wheel-running and forced treadmill exercise on cardiac adaptation in mice treated with 4-vinylcyclohexine diepoxide (VCD), which selectively accelerates the loss of primary and primordial follicles and results in a state that closely mimics human menopause. Two-month-old female C57BL/6 mice injected with VCD (160 mg/kg) for 20 consecutive days underwent ovarian failure by 60 to 90 d after injection. Responses to voluntary wheel running and treadmill exercise did not differ between VCD- and vehicle-treated 7-mo-old C57BL/6 or outbred B6C3F1 mice. Moreover, adaptive cardiac hypertrophy, hypertrophic marker expression, and skeletal muscle characteristics after voluntary cage-wheel exercise did not differ between VCD- and vehicle-treated mice. Because 5' AMP-activated protein kinase (AMPK) is a key compo...

Journal of visualized experiments : JoVE, 2014

The risk of cardiovascular disease (CVD) increases in post-menopausal women, yet, the role of exe... more The risk of cardiovascular disease (CVD) increases in post-menopausal women, yet, the role of exercise, as a preventative measure for CVD risk in post-menopausal women has not been adequately studied. Accordingly, we investigated the impact of voluntary cage-wheel exercise and forced treadmill exercise on cardiac adaptation in menopausal mice. The most commonly used inducible model for mimicking menopause in women is the ovariectomized (OVX) rodent. However, the OVX model has a few dissimilarities from menopause in humans. In this study, we administered 4-vinylcyclohexene diepoxide (VCD) to female mice, which accelerates ovarian failure as an alternative menopause model to study the impact of exercise in menopausal mice. VCD selectively accelerates the loss of primary and primordial follicles resulting in an endocrine state that closely mimics the natural progression from pre- to peri- to post-menopause in humans. To determine the impact of exercise on exercise capacity and cardiac ...

Frontiers in Physiology, 2013

† These authors have contributed equally to this work.