Abstract 13407: A Mouse Model of Heart Failure with Preserved Ejection Fraction (HFpEF) due to Chronic Infusion of a Low Subpressor Dose of Angiotensin II

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Stefano Toldo ◽  
Carlo Marchetti ◽  
Aysar Al Husseini ◽  
Salvatore Carbone ◽  
Jessica Regan ◽  
...  

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. Fibrosis was measured using Masson’s trichrome stain. The expression of Interleukin (IL)-18 mRNA levels, a cytokine associated with impaired cardiomyocyte relaxation, was measured at 4 weeks. Results: When compared to the baseline values or vehicle group, ATII infusion had no effects on AoP, LVPSP and HR, and had no effects on LV dimensions or mass, nor on LVEF (all P>0.2). ATII induced a significant impairment in LV diastolic function as measured by an increase (worsening) of the myocardial performance index (MPI), the LV isovolumetric relaxation time (IVRT) and of LVEDP (Figure). Cardiac expression of IL-18 mRNA was significantly increased 7-fold after ATII infusion (P<0.001), suggesting a potential mechanistic role of IL-18. Conclusion: Chronic infusion of low dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing blood pressure. The use of this mouse model may help understanding the mechanisms leading to HFpEF syndrome in patients.

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jessica A Regan ◽  
Adolofo G Mauro ◽  
Salvatore Carbone ◽  
Carlo Marchetti ◽  
Eleonora Mezzaroma ◽  
...  

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.


2015 ◽  
Vol 309 (5) ◽  
pp. H771-H778 ◽  
Author(s):  
Jessica A. Regan ◽  
Adolfo Gabriele Mauro ◽  
Salvatore Carbone ◽  
Carlo Marchetti ◽  
Rabia Gill ◽  
...  

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.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Tanaka ◽  
F Soga ◽  
K Tatsumi ◽  
Y Mochizuki ◽  
H Sano ◽  
...  

Abstract Background Type 2 diabetes mellitus (T2DM) has come to be considered an independent predictor of mortality, and also a contributor to the development of heart failure (HF) with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Left ventricular (LV) longitudinal myocardial dysfunction as assessed in terms of lower global longitudinal strain (GLS), has been identified even in T2DM patients with preserved LV ejection fraction (LVEF), and should be considered the first marker of a preclinical form of DM-related cardiac dysfunction, leading to HFpEF. Sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a new class of anti-hyperglycemic agents for T2DM, but the effect of SGLT2 inhibitors on LV longitudinal myocardial function in T2DM patients with HF remains uncertain. To examine this effect, as well as the association of LV longitudinal myocardial function with LV diastolic function after administration of SGLT2 inhibitor in T2DM patients with stable HF, we analyzed data from our previous prospective multicenter study, in which we investigated the effect of SGLT2 inhibitor on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Methods Our previous trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e' annular velocities (E/e'). LV longitudinal myocardial function was assessed as GLS based on the current guidelines. Results E/e' significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p=0.020) as previously described, while GLS showed significant improvement from 15.5±3.5% to 16.9±4.1% (p&lt;0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HFpEF patients was more significant from 17.0±1.9% to 18.7±2.0% (p&lt;0.001), compared to that in HFrEF patients from 11.3±3.8% to 11.8±4.6% (p=0.13). It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameter for the change in E/e' after administration of dapagliflozin. Conclusion Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF. Representative case Funding Acknowledgement Type of funding source: None


2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Piercarlo Ballo ◽  
Irene Betti ◽  
Giuseppe Mangialavori ◽  
Leandro Chiodi ◽  
Gherardo Rapisardi ◽  
...  

Management of patients with peripartum cardiomyopathy (PPCM) is still a major clinical problem, as only half of them or slightly more show complete recovery of left ventricular (LV) function despite conventional evidence-based treatment for heart failure. Recent observations suggested that bromocriptine might favor recovery of LV systolic function in patients with PPCM. However, no evidence exists regarding its effect on LV diastolic dysfunction, which is commonly observed in these patients. Tissue Doppler (TD) is an echocardiographic technique that provides unique information on LV diastolic performance. We report the case of a 37-year-old white woman with heart failure (NYHA class II), moderate LV systolic dysfunction (ejection fraction 35%), and severe LV diastolic dysfunction secondary to PPCM, who showed no improvement after 2 weeks of treatment with ramipril, bisoprolol, and furosemide. At 6-week followup after addition of bromocriptine, despite persistence of LV systolic dysfunction, normalization of LV diastolic function was shown by TD, together with improvement in functional status (NYHA I). At 18-month followup, the improvement in LV diastolic function was maintained, and normalization of systolic function was observed. This paper might support the clinical utility of bromocriptine in patients with PPCM by suggesting a potential benefit on LV diastolic dysfunction.


2021 ◽  
Vol 9 ◽  
Author(s):  
Miao Hou ◽  
Lei Cao ◽  
Yueyue Ding ◽  
Ye Chen ◽  
Bo Wang ◽  
...  

Aim: Hypertension is associated with cardiac structural and functional changes, including left ventricular hypertrophy (LVH) and LV systolic dysfunction diastolic dysfunction. Neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker associated with cardiovascular diseases. The current study aimed to evaluate NLR in children with newly diagnosed essential hypertension and its relationship between blood pressure and cardiac changes.Methods and Subjects: Sixty-five children with newly diagnosed essential hypertension and 54 healthy children were included. Clinical characteristics, blood cell counts, and biochemical parameters were collected. LVH was assessed by calculation of LV mass index (LVMI), and LV systolic function was evaluated by measuring LV ejection fraction and fractional shortening. LV diastolic function was primarily assessed with E/E′ ratio by Doppler and echocardiography.Results: The hypertension children had significantly higher LVMI and E/E′ ratio than the controls, whereas there was no difference in LV systolic function between the two groups. The NLR was significantly higher in the hypertension group than the control group. Moreover, NLR was positively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels in the hypertension group. Additionally, a significantly positive correlation between NLR and E/E′ ratio was found in the hypertension group. However, NLR was not related to LVH and LV systolic function indicators in hypertension children.Conclusion: NLR is elevated in hypertension children, and it is associated positively with office blood pressure levels. Moreover, NLR may help assess LV diastolic function in hypertension children.


2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
K Nakamura ◽  
A Yamada ◽  
S Jinno ◽  
M Kato ◽  
A Takahashi ◽  
...  

Abstract Background It remains to be clarified whether clinical significance of left ventricular (LV) diastolic function differs depending on the severity of LV systolic dysfunction in patients with acute heart failure (AHF). The aim of this study was to examine the prognostic role of LV diastolic function in AHF patients with various systolic dysfunction.Methods: We studied consecutive hospitalized AHF patients with LV ejection fraction (LVEF) &lt;50%. The exclusion criteria were as follows: atrial fibrillation, severe mitral regurgitation, and inadequate echo image quality. They underwent echocardiography on admission. The eligible patients (n = 289, 165 males, 76 ± 10 years) were divided into 4 groups based on LVEF and left atrial pressure (LAP) grade estimated as in the ESC guidelines: Group I (LVEF 40-49% (mildly reduced LVEF)/normal LAP, n = 28), II (mildly reduced EF/increased LAP, n = 38), III (LVEF &lt;40% (severely reduced LVEF)/normal LAP, n = 110), and IV (severely reduced LVEF/increased LAP, n = 113). Cardiac death was examined up to 60 months.Results: In total, 58 patients (20%) died because of cardiac events during the follow-up (mean 20 ± 19 months). In patients with mildly reduced LVEF, Group I showed significantly less cardiac death ratio than II (n = 1 vs 10, Group I vs II, p = 0.03). On the other hand, in patients with severely reduced LVEF, there was no significant difference in cardiac death ratio between Group III and IV (n = 23 vs 24, Group III vs IV, p = 0.80). That is, LAP grade was a prognostic marker when the patients had mild LV systolic dysfunction, whereas it did not contribute to the prediction of cardiac mortality when patients showed severely reduced LV systolic function. Group I showed significantly better prognosis than those with severe LV systolic dysfunction regardless of LAP grade (Group III, IV) (Group I vs III, p = 0.04; Group I vs IV, p = 0.04).Conclusions: LV diastolic function may have a different clinical significance depending on the severity of LV systolic dysfunction in AHF patients.


2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
F Soga ◽  
H Tanaka ◽  
K Tatsumi ◽  
Y Mochizuki ◽  
H Sano ◽  
...  

Abstract Funding Acknowledgements Type of funding sources: None. Background Type 2 diabetes mellitus (T2DM) is a well-known risk factor for heart failure (HF), even in patients without a structural heart disease or a symptom of HF. Diabetes-related cardiomyopathy is presented as an left ventricular (LV) diastolic dysfunction, which, like cardiovascular disease, is a contributor of the development of HF in both patients with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Furthermore, comorbid factors other than T2DM also have been identified as high risk factors for of progression to HF. Dapagliflozin is a sodium glucose cotransporter type 2 (SGLT2) inhibitor, and represents a new class of anti-hyperglycemic agents for T2DM. A result from a recent large clinical trial showed that dapagliflozin reduced risk of worsening HF or death from cardiovascular causes for patients with HFrEF compared to those who received a placebo, regardless of the presence or absence of T2DM. However, the effect of SGLT2 inhibitors on LV diastolic function in T2DM patients with HF who had cardiovascular risk factors other than T2DM remains uncertain. Purpose Our purpose was to investigate the impact of dapagliflozin on LV diastolic function in T2DM patients with stable HF complicating cardiovascular risk factors. Methods We analyzed data from our previous prospective multicenter study, which investigate the effect of dapagliflozin on LV diastolic function of 53 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitor started the administration of dapagliflozin. Cardiovascular risk factors other than T2DM was determined as age, gender, hypertension, dyslipidemia, history of cardiovascular events and overweight. Results E/e′ significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p = 0.020) as previously described. Multivariate logistic regression analysis showed that dyslipidemia was the only independent determinant of an improvement of E/e’ among cardiovascular risk factors. Furthermore, relative changes in E/e’ from baseline to 6 months after administration of dapagliflozin seen in HFpEF patients with dyslipidemia were significantly larger than those in HFpEF patients without dyslipidemia (-15.2% vs. 29.6%, p = 0.014), but such a difference was not observed in non-HFpEF patients. In addition, relative changes in high-density lipoprotein cholesterol (HDL-C) from baseline to 6 months after administration of dapagliflozin had significant correlation with those in E/e’ (r=-0.300, p = 0.038). However, such correlations were not observed in low-density lipoprotein cholesterol (LDL-C) and triglyceride (r = 0.05, p = 0.72 and r = 0.05, p = 0.73). Conclusion: Dapagliflozin was more beneficial effect on LV diastolic function for T2DM patients with stable HF, especially those with complicating dyslipidemia. Our findings may thus offer a new insight into the management of T2DM patients with HF. Abstract Figure.


2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Antonella De Angelis ◽  
Donato Cappetta ◽  
Marialucia Telesca ◽  
Gabriella Bellocchio ◽  
Konrad Urbanek ◽  
...  

Abstract Aims The majority of elderly patients with heart failure has a preserved ejection fraction (HFpEF) that constitutes a syndrome characterized by frequent hospitalizations and high mortality. Despite the growing social burden of HFpEF, the comprehension of its pathophysiology is incomplete, and treatment remains largely undefined. Ageing itself may contribute independently to deterioration of diastolic function. Methods and results An 18-month-old female Fischer 344 rats were treated with oral administration of either sacubitril/valsartan (60 mg/kg/die, 1:1 ratio) or valsartan alone (30 mg/kg/die) for 12 weeks. Tail-cuff method was used to monitor blood pressure weekly. Echocardiography and left ventricle catheterization were employed to assess systolic and diastolic function, at baseline, and before sacrifice. Cardiac tissue was used for molecular biology and histochemistry assays. Tail-cuff analysis indicated a comparable decrease in blood pressure between treatments. Hypertrophy also showed a significant reduction with both treatments. On the contrary, myocardial function analysis demonstrated that no treatment was efficacy on diastolic dysfunction. The lack of improvement of cardiac function could be attributed to the inability of the treatments to counteract the accumulation of fibrotic tissue in the left ventricle, which, in turn, is attributable to the failure to reduce the inflammatory process and oxidative stress, and to the inability to modulate angiotensin II pathway. Conclusions Our results evidenced that both sacubitril/valsartan or valsartan treatment was able to improve diastolic function and pro-fibrotic remodelling, partly due to a lack of effect on classical and non-classical pathways of angiotensin II.


Author(s):  
Akio Ishida ◽  
Akihiro Isotani ◽  
Michiko Fujisawa ◽  
Eva Garcia del Saz ◽  
Kiyohito Okumiya ◽  
...  

Background A sodium‐restricted diet represents a potential non‐pharmacological strategy for improving blood pressure, arterial stiffness, and left ventricular (LV) diastolic function. We investigated age‐related differences in LV structure and function and the relationship between LV function and central hemodynamics in an indigenous Papuan population, who maintain a traditional lifestyle, including a low‐salt and high‐potassium diet. Methods and Results We measured LV dimensions, transmitral blood flow, and mitral annular tissue velocities through echocardiography and Doppler imaging. Blood pressure and brachial‐ankle pulse wave velocity were measured using an automatic device (Omron). Central blood pressure and wave reflection parameters were estimated via oscillometry (Mobil‐O‐Graph, using European calibrations). A total of 82 native Papuans (median age, 42 years; 38 women; no blood pressure treatment) were enrolled. Age‐related difference in brachial systolic pressure was modest but significant, and brachial‐ankle pulse wave velocity significantly increased with age; however, LV mass index remained unchanged. LV ejection fraction and global longitudinal strain were preserved; mitral A‐wave velocity and average E/e´ increased; and e´ and E/A decreased with age. Brachial‐ankle pulse wave velocity and spot urine Na/K were positively and independently correlated with E/e´. Age and heart rate were inversely associated with E/A. In conclusion, LV systolic function was preserved; however, LV diastolic function decreased with age in Papuans. Moreover, age‐related arterial stiffening, but not wave reflections, was inversely related to LV diastolic function. Conclusions Our results suggest that arterial and LV stiffness may not be altered by sodium restriction. Longitudinal studies are warranted to elucidate the effects of diet on arterial and LV function.


Sign in / Sign up

Export Citation Format

Share Document