scholarly journals Impaired Adenosine‐Mediated Coronary Vasodilation in Swine with Repetitive Pressure Overload‐Induced Heart Failure with Preserved Ejection Fraction

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Patrick Durkin ◽  
Beth Palka ◽  
John Canty ◽  
Brian Weil
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Pressure Overload ◽  
Preserved Ejection Fraction ◽  
Coronary Vasodilation

scholarly journals Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine

2018 ◽  
Vol 125 (1) ◽  
pp. 86-96 ◽  
Author(s):  
T. Dylan Olver ◽  
Jenna C. Edwards ◽  
Brian S. Ferguson ◽  
Jessica A. Hiemstra ◽  
Pamela K. Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Interval Exercise

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca2+-activated K+ (BKCa) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BKCa channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BKCa channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BKCa channel-mediated coronary vascular dysfunction, it did not change BKCa channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BKCa channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BKCa channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

scholarly journals A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Weijiang Tan ◽  
Xiang Li ◽  
Shuang Zheng ◽  
Xiaohui Li ◽  
Xiaoshen Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Pathological Examination ◽  
Type I ◽  
Preserved Ejection Fraction

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chronic pressure overload in the left ventricles of Tibetan minipigs for 12 weeks. Cardiac function, pathological and cellular changes, fibrotic signaling activation, and gene expression profiles were explored. The left ventricles developed concentric hypertrophy from weeks 4 to 6 and transition to dilation starting in week 10. Notably, the left ventricular ejection fraction was maintained at >50% in the DAC group during the 12-week period. Pathological examination, biochemical analyses, and gene profile analysis revealed evidence of inflammation, fibrosis, cell death, and myofilament dephosphorylation in the myocardium of HFpEF model animals, together with gene expression shifts promoting cardiac remodeling and downregulating metabolic pathways. Furthermore, we noted the activation of several signaling proteins that impact cardiac fibrosis and remodeling, including transforming growth factor-β/SMAD family members 2/3, type I/III/V collagens, phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, matrix metalloproteinases 2 and 9, tissue inhibitor of metalloproteinases 1 and 2, interleukins 6 and 1β, and inhibitor of κBα/nuclear factor-κB. Our findings demonstrate that this chronic pressure overload-induced porcine HFpEF model is a powerful tool to elucidate the mechanisms of this disease and translate preclinical findings.

scholarly journals Left atrial pressure overload and prognosis in elderly patients with heart failure and preserved ejection fraction: a prospective multicenter observational study

BMJ Open ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. e044605
Author(s):  
Shiro Hoshida ◽  
Koichi Tachibana ◽  
Yukinori Shinoda ◽  
Tomoko Minamisaka ◽  
Takahisa Yamada ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Elderly Patients ◽  
Sinus Rhythm ◽  
Left Atrial ◽  
Pressure Overload ◽  
Volume Index ◽  
Preserved Ejection Fraction ◽  
Patients With Heart Failure ◽  
All Cause Mortality

ObjectivesThe severity of diastolic dysfunction is assessed using a combination of several indices of left atrial (LA) volume overload and LA pressure overload. We aimed to clarify which overload is more associated with the prognosis in patients with heart failure and preserved ejection fraction (HFpEF).SettingA prospective, multicenter observational registry of collaborating hospitals in Osaka, Japan.ParticipantsWe enrolled hospitalised patients with HFpEF showing sinus rhythm (men, 79; women, 113). Blood tests and transthoracic echocardiography were performed before discharge. The ratio of diastolic elastance (Ed) to arterial elastance (Ea) was used as a relative index of LA pressure overload.Primary outcome measuresAll-cause mortality and admission for heart failure were evaluated at >1 year after discharge.ResultsIn the multivariable Cox regression analysis, Ed/Ea, but not LA volume index, was significantly associated with all-cause mortality or admission for heart failure (HR 2.034, 95% CI 1.059 to 3.907, p=0.032), independent of age, sex, and the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level. In patients with a higher NT-proBNP level, the effect of higher Ed/Ea on prognosis was prominent (p=0.015).ConclusionsEd/Ea, an index of LA pressure overload, was significantly associated with the prognosis in elderly patients with HFpEF showing sinus rhythm.Trial registration numberUMIN000021831.

scholarly journals Right Ventricular and Right Atrial Function Are Less Compromised in Pulmonary Hypertension Secondary to Heart Failure With Preserved Ejection Fraction: A Comparison With Pulmonary Arterial Hypertension With Similar Pressure Overload

2021 ◽  
Author(s):  
Jessie van Wezenbeek ◽  
Azar Kianzad ◽  
Arno van de Bovenkamp ◽  
Jeroen Wessels ◽  
Sophia A. Mouratoglou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Ejection Fraction ◽  
Arterial Hypertension ◽  
Vena Cava ◽  
Pressure Overload ◽  
Right Atrial ◽  
Preserved Ejection Fraction ◽  
Pulmonary Arterial

Background: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and ventricular (RV) dysfunction are frequently observed. The question remains whether the PH with the associated RV/RA dysfunction in HFpEF are markers of disease severity. Methods: To obtain insight in the relative importance of pressure-overload and left-to-right interaction, we compared RA and RV function in 3 groups: 1. HFpEF (n=13); 2. HFpEF-PH (n=33), and; 3. pulmonary arterial hypertension (PAH) matched to pulmonary artery pressures of HFpEF-PH (PH limited to mPAP ≥30 and ≤50 mmHg) (n=47). Patients underwent right heart catheterization and cardiac magnetic resonance imaging. Results: The right ventricle in HFpEF-PH was less dilated and hypertrophied than in PAH. In addition, RV ejection fraction was more preserved (HFpEF-PH: 52±11 versus PAH: 36±12%). RV filling patterns differed: vena cava backflow during RA contraction was observed in PAH only. In HFpEF-PH, RA pressure was elevated throughout the cardiac cycle (HFpEF-PH: 10 [8–14] versus PAH: 7 [5–10] mm Hg), while RA volume was smaller, reflecting excessive RA stiffness (HFpEF-PH: 0.14 [0.10–0.17] versus PAH: 0.08 [0.06–0.11] mm Hg/mL). RA stiffness was associated with an increased eccentricity index (HFpEF-PH: 1.3±0.2 versus PAH: 1.2±0.1) and interatrial pressure gradient (9 [5 to 12] versus 2 [−2 to 5] mm Hg). Conclusions: RV/RA function was less compromised in HFpEF-PH than in PAH, despite similar pressure-overload. Increased RA pressure and stiffness in HFpEF-PH were explained by left atrial/RA-interaction. Therefore, our results indicate that increased RA pressure is not a sign of overt RV failure but rather a reflection of HFpEF-severity.

Abstract 87: Alterations to Cardiac Mechanics Do Not Preserve Normal Cardiac Function in a Novel Ossabaw Swine Model of Heart Failure with Preserved Ejection Fraction

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jenna C Edwards ◽  
Madeleine Dionne ◽  
T. D Olver ◽  
Jan R Ivey ◽  
Pamela K Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Strain Rate ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Volume Index ◽  
Lv Function ◽  
Swine Model ◽  
Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is clinically characterized by an increased incidence in females and many comorbidities including type 2 diabetes (T2D) and obesity. Animal models accurately representing clinical HFpEF are lacking; thus, the purpose of this study was to examine left ventricular (LV) mechanics in a novel Ossabaw swine model of chronic pressure-overload (aortic-banding; AB) and T2D (Western diet; WD) using two dimensional speckle tracking echocardiography (2D-STE). We hypothesized that global LV strain would be decreased primarily in the longitudinal direction in WD-AB animals. Methods: Female Ossabaws were randomly divided into 2 groups: CON (n=5) and WD-AB (n=5). LV function and strain were measured at 1 year of age after 6 mo. of AB and 9 mo. of WD via pressure-volume relations and 2D-STE. Significance was set at P < 0.05 using t-test vs. CON. Results: In the WD-AB group, ejection fraction (EF%) and end diastolic volume were normal (>50%), and observed in parallel with increased LV weight, lung weight, and LV diastolic wall thickness (i.e. concentric hypertrophy). WD-AB group had increased HOMA-IR and body surface area, two common features in T2D. In WD-AB animals, although global longitudinal systolic strain rate and end systolic displacement were increased, stroke volume index was decreased. Early diastolic rotation rate was decreased, while global longitudinal late diastolic strain rate was increased in the WD-AB group. These changes, considered in parallel with an increased end diastolic pressure-volume relationship in WD-AB animals, are consistent with diastolic dysfunction. In contrast, longitudinal, radial, and circumferential early diastolic strain rates increased in the WD-AB group. Conclusion: Contrary to our hypothesis, LV longitudinal strain was increased during both systole and diastole, and observed in parallel with decreased early diastolic untwisting in WD-AB animals. Our results suggest alterations to LV mechanics do not preserve normal systolic and diastolic cardiac function, despite normal resting EF%, in this novel translational model of pressure-overload HF with potential relevance to human HFpEF including associated clinical comorbidities (sex, obesity, and T2D).

P321A single factor related to left atrial pressure overload is useful for prognosis in elderly patients with heart failure with preserved ejection fraction: PURSUIT HFpEF study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Hoshida ◽  
T Watanabe ◽  
Y Shinoda ◽  
T Minamisaka ◽  
H Fukuoka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Elderly Patients ◽  
Left Atrial ◽  
Pressure Overload ◽  
Volume Index ◽  
Preserved Ejection Fraction ◽  
Single Factor ◽  
Cardiac Events ◽  
All Cause Mortality

Abstract Background E/e' and the ratio of diastolic elastance (Ed)/arterial elastance (Ea) = (E/e')/(0.9 × systolic blood pressure), indices of left atrial (LA) pressure overload, are elevated in elderly women with heart failure with preserved ejection fraction (HFpEF). The severity of diastolic dysfunction is assessed by a combination of several indices of LA volume and pressure overload. However, which overload is more important as a single factor for the prognosis of these patients remains undefined. Methods We enrolled patients with HFpEF showing sinus rhythm (n=145; left ventricular ejection fraction >50%; men/women, 56/89; mean age, 80.5 years). Blood examination and transthoracic echocardiography were performed before discharge. All-cause mortality and admission for cardiac events were evaluated after more than 1 year (mean, 370 days). Results The all-cause mortality rate was 11% (16/145). There were significant differences in age (p=0.005), serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level (p<0.001), LA volume index (p=0.018), E/e' (p=0.022), and Ed/Ea (p=0.016) between patients with and without all-cause mortality. When cutoff points for mortality by receiver operating characteristic curve analysis were examined, the area under the curve in LA volume index (0.564) was slightly smaller than that in age (0.734), NT-proBNP level (0.732), E/e' (0.695), and Ed/Ea (0.709). Kaplan-Meier survival analysis clearly showed that age >85 years (p<0.001), NT-proBNP level >888 pg/mL (p=0.003), E/e' >14.4 (p=0.020), and Ed/Ea >0.153 (p<0.001) were determinant factors for mortality. Cox hazard ratios were also significant in these indices (p=0.002, p=0.012, p=0.028, and p=0.001, respectively). In the case of all-cause mortality or admission for cardiac events, the results were nearly similar as those in the case of all-cause mortality. Ed/Ea exhibited a larger Cox hazard ratio for prognosis than E/e' in the multivariate analysis. Conclusions LA pressure overload compared to volume overload was a useful marker for prognosis in elderly patients with HFpEF. As a single index for LA pressure overload in noninvasive echocardiographic findings, Ed/Ea may be more suitable than E/e'.

scholarly journals Chronic low-intensity exercise attenuates cardiomyocyte contractile dysfunction and impaired adrenergic responsiveness in aortic-banded mini-swine

2018 ◽  
Vol 124 (4) ◽  
pp. 1034-1044 ◽  
Author(s):  
Jessica A. Hiemstra ◽  
Adam B. Veteto ◽  
Michelle D. Lambert ◽  
T. Dylan Olver ◽  
Brian S. Ferguson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Pressure Overload ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction ◽  
Low Intensity ◽  
Low Intensity Exercise

Exercise improves clinical outcomes in patients diagnosed with heart failure with reduced ejection fraction (HFrEF), in part via beneficial effects on cardiomyocyte Ca2+ cycling during excitation-contraction coupling (ECC). However, limited data exist regarding the effects of exercise training on cardiomyocyte function in patients diagnosed with heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to investigate cardiomyocyte Ca2+ handling and contractile function following chronic low-intensity exercise training in aortic-banded miniature swine and test the hypothesis that low-intensity exercise improves cardiomyocyte function in a large animal model of pressure overload. Animals were divided into control (CON), aortic-banded sedentary (AB), and aortic-banded low-intensity trained (AB-LIT) groups. Left ventricular cardiomyocytes were electrically stimulated (0.5 Hz) to assess Ca2+ homeostasis (fura-2-AM) and unloaded shortening during ECC under conditions of baseline pacing and pacing with adrenergic stimulation using dobutamine (1 μM). Cardiomyocytes in AB animals exhibited depressed Ca2+ transient amplitude and cardiomyocyte shortening vs. CON under both conditions. Exercise training attenuated AB-induced decreases in cardiomyocyte Ca2+ transient amplitude but did not prevent impaired shortening vs. CON. With dobutamine, AB-LIT exhibited both Ca2+ transient and shortening amplitude similar to CON. Adrenergic sensitivity, assessed as the time to maximum inotropic response following dobutamine treatment, was depressed in the AB group but normal in AB-LIT animals. Taken together, our data suggest exercise training is beneficial for cardiomyocyte function via the effects on Ca2+ homeostasis and adrenergic sensitivity in a large animal model of pressure overload-induced heart failure. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show chronic low-intensity exercise training can prevent cardiomyocyte dysfunction and impaired adrenergic responsiveness in a translational large animal model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

scholarly journals Left atrial function in heart failure with preserved ejection fraction vs. aortic stenosis: evidence for atrial myopathy?

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
X Jin ◽  
JV Melle ◽  
AA Voors ◽  
DKL Sim ◽  
FR Jaufeerally ◽  
...  
Keyword(s):  
Heart Failure ◽  
Aortic Stenosis ◽  
Ejection Fraction ◽  
Left Atrial ◽  
Pressure Overload ◽  
Filling Pressure ◽  
Community Dwelling ◽  
Volume Index ◽  
Aortic Valve Area ◽  
Preserved Ejection Fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background and Aim Left atrial (LA) enlargement and impaired LA function are frequently found in patients with heart failure with preserved ejection fraction (HFpEF). Whether these structural and functional LA abnormalities are a consequence of increased LA pressure or whether HFpEF patients have an intrinsic LA myopathy is unknown. We compared LA pressure, size and function between patients with HFpEF and aortic stenosis, as a comparator with LA pressure overload, as well as community-dwelling control subjects. Methods Extensive echocardiographic assessments were performed in 219 patients with HFpEF (age 68 ± 11, 48% female), 173 patients with moderate to severe AS (age 69 ± 11, 55% female, aortic valve area index 0.55 ± 0.15 cm2/m2), and 219 controls (age 65 ± 9, 48% female, 42.2% hypertensive) Results Compared to controls, both patients with HFpEF and AS had larger LV and LA size and worse LV systolic, diastolic and LA function. Compared with AS patients, HFpEF patients had smaller LA volume index (40.2 ± 19.4 vs. 44.5 ± 11.9 ml/m2 p = 0.01) but similar LV filling pressure estimated by E/e’ (13.4 ± 4.8  13.4 ± 4.8 , p = 0.12). Despite smaller LA volume index and similar LV filling pressure, HFpEF patients had remarkably poorer LA function compared to AS [reservoir GLS, 22.6 ± 10% vs 31.4 ± 10.1 (p &lt; 0.001); contractile GLS, 15.8 ± 6.1% vs 17.5 ± 6.9 (p &lt; 0.05); LASrs, 0.92 ± 0.35% vs 1.27 ± 0.41 (p &lt; 0.001); LASre, -1.49 ± 0.65 vs -1.86 ± 0.67 (p &lt; 0.001)]. The differences in  LA reservoir GLS and LASrs remained significant  after adjustment for atrial fibrillation, diabetes, coronary artery disease, LV ejection fraction and LV mass index. Conclusion Patients with HFpEF had significantly worse LA function than patients with AS, despite similar LA pressure overload. These findings support the concept of an intrinsic LA myopathy in patients with HFpEF, beyond LA pressure overload. Abstract Figure.

Clinical and treatment perspectives for heart failure with preserved ejection fraction

2016 ◽  
Author(s):  
◽  
Jessica Ann Hiemstra
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Contractile Function ◽  
Pressure Overload ◽  
The United States ◽  
Calcium Handling ◽  
Swine Model ◽  
Preserved Ejection Fraction ◽  
Novel Treatment ◽  
Hormone Status

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Heart failure with preserved ejection fraction (HFpEF) currently represents half of the ~6 million heart failure patients in the United States, and is increasing at a rate of ~1% per year. Conventional treatments commonly used for heart failure with reduced ejection fraction (HFrEF) patients have proven ineffective for HFpEF, highlighting the critical need for development of novel treatment options for this HF sub-population. Further, population studies have repeatedly found HFpEF to disproportionally effect women 2:1 over the age of sixty-five compared to men. Therefore the purpose of my dissertation was two-fold: (1) To examine novel treatment perspectives testing pharmacological interventions for treatment of heart failure with preserved ejection fraction; and (2) A clinical perspective examining mechanisms responsible for the increased prevalence of HFpEF in women. A novel miniature swine model displaying key characteristics of HFpEF was used to assess both of these aims. Aim one evaluated the efficacy of three different pharmacological treatments. The first drug cyclospsorine, aimed at inhibiting cylophilin D and preventing mitochondria permeability transition and the second drug tadalafil, aimed at inhibiting phosphodiesterase 5 and preserving cyclic guanine monophosphate (cGMP) both were ineffective in treating HFpEF. However, the third drug tested, saxagliptin; a dipeptidyl-peptidase 4 inhibitor, aimed at preserving cGMP, improved both cellular and functional cardiovascular outcomes in our mini-swine HFpEF model. This study highlighted the potential benefit of saxagliptin's for treatment of HFpEF, which currently lacks any viable therapeutic options. The purpose of the second aim was to evaluate HFpEF from a clinical prospective, in effort to uncover what mechanisms actually lead to the development of HFpEF. We hypothesized female sex hormones would protect against pressure overload-induced cardiomyocyte calcium handling and contractile abnormalities, thus preserving overall cardiomyocyte function. In contrast to our hypothesis, our results found regardless of hormone status, compromised cardiomyocyte excitation-contraction coupling (ECC) was evident by impaired calcium release and reuptake in parallel with diminished contractile function. Cardiomyocyte dysfunction was associated with distinct alterations to the protein levels and phosphorylation state of important calcium handling and contractile proteins. Our results show impaired cardiomyocyte function contributes to pressure-overload HF regardless of hormone status in a translational model with potential relevance to human HFpEF. While important advances have been made in our understanding of the haemodynamic and cellular pathophysiology HFpEF as well as contributing mechanisms associated with the disease, further research is urgently required to determine how to better target these abnormalities to reduce the substantial burden of morbidity and mortality in this form of HF, which is reaching epidemic proportions.

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