scholarly journals Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

2020 ◽  
Vol 40 (6) ◽  
pp. 1543-1558 ◽  
Author(s):  
Longfei Wang ◽  
Gunner Halliday ◽  
Joshua R. Huot ◽  
Taijyu Satoh ◽  
Jeffrey J. Baust ◽  
...  
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Early Treatment ◽  
High Fat Diet ◽  
Combined Treatment ◽  
Preserved Ejection Fraction ◽  
High Fat ◽  
Prostacyclin Analog

Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. Conclusions: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

scholarly journals A Preclinical Rat Model of Heart Failure With Preserved Ejection Fraction With Multiple Comorbidities

2022 ◽  
Vol 8 ◽  
Author(s):  
Géraldine Hubesch ◽  
Aliénor Hanthazi ◽  
Angela Acheampong ◽  
Laura Chomette ◽  
Hélène Lasolle ◽  
...  
Keyword(s):  
Heart Failure ◽  
Metabolic Syndrome ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
High Fat Diet ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Preserved Ejection Fraction ◽  
High Fat

Heart failure with preserved ejection fraction (HFpEF) is a common complex clinical syndrome for which there are currently few evidence-based therapies. As patients with HFpEF very often present with comorbidities comprising the metabolic syndrome, we hypothesized, that metabolic syndrome could lead over time to the development of diastolic dysfunction and HFpEF. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 (the interleukin-1 receptor-like) markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

scholarly journals Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2011 ◽  
Vol 124 (2) ◽  
pp. 164-174 ◽  
Author(s):  
Marco Guazzi ◽  
Marco Vicenzi ◽  
Ross Arena ◽  
Maurizio D. Guazzi
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Preserved Ejection Fraction

scholarly journals Effect of Breathing Oxygen-Enriched Air on Exercise Performance in Patients With Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction: A Randomized, Placebo-Controlled, Crossover Trial

2021 ◽  
Vol 8 ◽  
Author(s):  
Julian Müller ◽  
Mona Lichtblau ◽  
Stéphanie Saxer ◽  
Luigi-Riccardo Calendo ◽  
Arcangelo F. Carta ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Exercise Performance ◽  
Minute Ventilation ◽  
Ambient Air ◽  
Work Rate ◽  
Blood Oxygenation ◽  
Preserved Ejection Fraction ◽  
Cycling Time

Objective: To evaluate the effects of breathing oxygen-enriched air (oxygen) on exercise performance in patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF).Methods: Ten patients with PH-HFpEF (five women, age 60 ± 9 y, mPAP 37 ± 14 mmHg, PAWP 18 ± 2 mmHg, PVR 3 ± 3 WU, resting SpO2 98 ± 2%) performed two-cycle incremental exercise tests (IET) and two constant-work-rate exercise test (CWRET) at 75% maximal work-rate (Wmax), each with ambient air (FiO2 0.21) and oxygen (FiO2 0.5) in a randomized, single-blinded, cross-over design. The main outcomes were the change in Wmax (IET) and cycling time (CWRET) with oxygen vs. air. Blood gases at rest and end-exercise, dyspnea by Borg CR10 score at end-exercise; continuous SpO2, minute ventilation (V'E), carbon dioxide output (V'CO2), and cerebral and quadricep muscle tissue oxygenation (CTO and QMTO) were measured.Results: With oxygen vs. air, Wmax (IET) increased from 94 ± 36 to 99 ± 36 W, mean difference (95% CI) 5.4 (0.9–9.8) W, p = 0.025, and cycling time (CWRET) from 532 ± 203 to 680 ± 76 s, +148 (31.8–264) s, p = 0.018. At end-exercise with oxygen, Borg dyspnea score and V'E/V'CO2 were lower, whereas PaO2 and end-tidal PaCO2 were higher. Other parameters were unchanged.Conclusion: Patients with PH-HFpEF not revealing resting hypoxemia significantly improved their exercise performance while breathing oxygen-enriched air along with less subjective dyspnea sensation, a better blood oxygenation, and an enhanced ventilatory efficiency. Future studies should investigate whether prolonged training with supplemental oxygen would increase the training effect and, potentially, daily activity for PH-HFpEF patients.Clinical Trial Registration: [clinicaltrials.gov], identifier [NCT04157660].

Abstract 19944: Targeted Therapy of Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: Safety and Efficacy in Comparison to IPAH in Compera

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Stephan Rosenkranz ◽  
Marius M Hoeper ◽  
Doerte Huscher ◽  
David Pittrow ◽  
Christian F Opitz
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Preserved Ejection Fraction ◽  
Evidence Based Treatment ◽  
Patients With Heart Failure ◽  
Venous Oxygen Saturation ◽  
Initial Ph ◽  
Pulmonary Arterial

Background: While targeted therapies are available for idiopathic pulmonary arterial hypertension (IPAH), evidence based treatment recommendations for pulmonary hypertension (PH) associated with heart failure and preserved ejection fraction (HFpEF) are lacking. Methods and Results: Out of 5,935 patients in the prospective COMPERA registry, we analyzed patients with “typical” IPAH (n=421, ≤2 of the following risk factors: BMI >30 kg/m2, hypertension, CAD, diabetes and atrial fibrillation at the time of diagnosis), “atypical” IPAH (n=139, >2 risk factors) or PH-HFpEF (n=226) who received targeted PH therapies. Patients with PH-HFpEF, when compared to “typical” and “atypical” IPAH were older (73±8 vs. 62±17 and 71±9 years), had a higher BMI (30 vs. 26 and 32 kg/m2), and more comorbidities (98% vs. 73% and 100%, all p<0.001), respectively. However, mean PAP (46±9 vs. 47±13 and 44±11 mmHg), cardiac index (2.2±0.7 vs. 2,3±0,8 and 2,2±0,8 l/min), and mixed venous oxygen saturation (62±7 vs. 62±10 and 63±9%, all ns) were almost identical. As compared to “typical” and “atypical” IPAH, PH-HFpEF patients had a higher PAWP (20±4 vs. 9±3 and 10±4 mmHg), resulting in a lower calculated PVR (559±270 vs. 861±477 and 784±844 dyn.s.cm-5). Survival at 1, 2 and 3 years post diagnosis was not different between groups. PDE-5 inhibitors were the most common form of initial PH treatment in PH-HFpEF (94%), and combination therapy was less common compared to “typical” or “atypical” IPAH at 1 year (7% vs. 44% and 26%). All 3 groups responded to targeted PH therapies at 12 months, while treatment effects were less pronounced in PH-HFpEF: Compared to baseline, the median increase of the 6MWD at 1 year was 29, 50, and 60 m, respectively. Treatment discontinuations occurred more frequently in patients with PH-HFpEF than in IPAH, either because of side effects or lack of improvement. Conclusions: Despite almost identical alterations of pulmonary artery pressure and cardiac output, patients with PH-HFpEF differed with respect to age, comorbidities and certain hemodynamic features when compared to “typical” or “atypical” IPAH. All groups responded to targeted PH therapy, however tolerability and efficacy of PH drugs were reduced in patients with PH-HFpEF while survival was not different.

Abstract 13487: Impact of the New Definition of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Fusako Sera ◽  
Tomohito Ohtani ◽  
kei nakamoto ◽  
Shungo Hikoso ◽  
Daisaku Nakatani ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Pulmonary Artery ◽  
Rank Test ◽  
Heart Catheterization ◽  
Preserved Ejection Fraction ◽  
Multicenter Observational Study ◽  
Definition Of ◽  
The Impact

Introduction: The proposed revision of hemodynamic definition of pulmonary hypertension (PH) adopts a lower threshold of mean pulmonary artery pressure (mPAP) > 20 mmHg. In addition, pulmonary vascular resistance (PVR) ≥ 3 Wood units (WU) is included as the definition of pre-capillary component of PH. Heart failure (HF) with preserved ejection fraction (HFpEF) can develop pre-capillary PH as well as post-capillary PH. We aimed to investigate the impact of the proposed definition of PH on clinical diagnosis of PH associated with HFpEF. Methods: From the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction) registry, 225 patients who were hospitalized with HF and underwent right heart catheterization were categorized according to the current guidelines and the proposed definition of PH: non-PH, isolated post-capillary PH (Ipc-PH), pre-capillary PH, and combined pre- and post-capillary PH (Cpc-PH). In the proposed definition, patients with mPAP > 20 mmHg, PVR < 3 WU, and pulmonary artery wedge pressure ≤ 15 mmHg do not meet criteria for any of the above categories and are categorized as “unclassified PH”. Results: Prevalence of PH was significantly increased in the proposed definition compared to that in the current definition (51% vs 29%, p<0.0001), with a doubled frequency of pre-capillary PH (Fig A). Furthermore, 24 patients (11%) were diagnosed as unclassified PH and accounted for 22% of those with PH by the proposed definition. Among the PH categories in the proposed definition, Cpc-PH category was significantly relevant for worse prognosis at 1 year after discharge in patients with HFpEF (p=0.03 vs non-PH by log-rank test with Bonferroni's correction) (Fig 2). Conclusions: The new definition of PH resulted in a remarkable increase of prevalence of PH in HFpEF with a quite a few patients with unclassified PH and doubled frequency of pre-capillary PH.

New Definition of Pulmonary Hypertension in Patients with Heart Failure with Preserved Ejection Fraction

2019 ◽  
Vol 200 (3) ◽  
pp. 386-388 ◽  
Author(s):  
Taiki Nishihara ◽  
Eiichiro Yamamoto ◽  
Takanori Tokitsu ◽  
Daisuke Sueta ◽  
Koichiro Fujisue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Preserved Ejection Fraction ◽  
Patients With Heart Failure ◽  
Definition Of
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