Abstract 16307: Tofogliflozin Improves Pulmonary Hypertension With Heart Failure With Preserved Ejection Fraction Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yusuke Joki ◽  
Hakuoh Konishi ◽  
Kiyoshi Takasu ◽  
Tohru Minamino
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Beneficial Effect ◽  
Right Ventricular ◽  
Sglt2 Inhibitor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Urine Glucose

Introduction: Pulmonary hypertension (PH) is a syndrome of increased pulmonary artery pressure and often leads to death. Left heart diseases(LHD) are frequently complicated by PH (PH-LHD), classified group2. In particular, PH with heart failure with preserved LV ejection fraction (HFpEF) is higher prevalence metabolic syndrome and poor prognosis than LHD without PH. Tofogliflozin (TOFO) is SGLT2 inhibitor as a therapeutic agent for diabetes. Recent study revealed SGLT2 inhibitors have a beneficial effect on heart failure. However it has not been clarified that SGLT2 inhibitors affect PH-LHD. This study examined whether TOFO improved for PH-LHD. Hypothesis: We hypothesis TOFO has a protective effect for PH with HFpEF. Methods: We used two HFpEF mice models, induced by transverse aortic constriction (TAC) surgery and high fat diet (HFD). TAC model: C57BL/6J mice were subjected to TAC. Sham and TAC mice were treated with TOFO 3mg/kg in water by day or only water. After 4weeks, each mouse was measured physical data, Body weight (BW), Left ventricular weight (LV), Right ventricular weight (RV), right ventricular systolic pressure (RVSP), UCG, collected blood and urine glucose. HFD model: AKR/J mice fed a HFD for 20weeks. Regular diet and HFD mice were treated with TOHO 3mg/kg in water by day or only water. 20weeks later each mouse measured above data. Results and Conclusions: Mice treated with TOFO had significantly higher urine glucose concentrations. TAC induced left ventricular hypertrophy, increased HW/BW ratio and RVSP. However TAC+TOFO mice were reduced hypertrophy and LV/BW ratio than TAC group. Moreover TAC+TOFO mice were improved RV/LV ratio and RVSP (Figure). AKR/J+HFD groups substantially higher BW and occurred PH than RFD groups. In contrast with HFD, TOFO treated group ameliorated BW, RW/LW ratio, moreover normal RVSP. These results showed Tofogliflozin had a beneficial effect for PH with HFpEF.

scholarly journals Tofogliflozin improved pulmonary hypertension due to heart failure with preserved ejection fraction in mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
Y J Joki ◽  
H K Konishi ◽  
K T Takasu ◽  
T M Minamino
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Heart Diseases ◽  
Sglt2 Inhibitor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Chow Diet ◽  
Normal Chow

Abstract Introduction Pulmonary hypertension (PH) caused by left heart diseases is categorized as the group 2 (PH-LHD). PH-LHD due to heart failure with preserved LV ejection fraction (HFpEF) is more prevalent in patients with metabolic syndrome and shows poorer prognosis than LHD without PH. Tofogliflozin (TOFO) is an SGLT2 inhibitor utilized for diabetic treatment. Recent studies revealed that the SGLT2 inhibitor has a beneficial effect on heart failure; however, it remains unclear whether the SGLT2 inhibitor is effective for the treatment of PH-LHD. Hypothesis We hypothesized that TOFO has a protective effect on PH with HFpEF. Methods We generated two murine models for PH-LHD due to HFpEF, a transverse aortic constriction (TAC) model and a high fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg) for 4weeks. In another model, AKR/J mice were fed HFD or normal chow diet and treated with TOFO (3mg/kg in water) for 20 weeks. We then measured physical data including body weight (BW), left ventricular weight (LV), right ventricular weight (RV), and right ventricular systolic pressure (RVSP) and performed echocardiography. Results Mice treated with TOFO demonstrated increased urine glucose level. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RV/LV ratio and RVSP in TAC mice (Figure 1). HFD fed AKR/J mice demonstrated increased BW and PH as demonstrated by increased RV/LV ratio and RVSP compared with the normal chow group. TOFO treatment ameliorated the increases of BW, RV/LV ratio, and RVSP in HFD fed AKR/J mice (Figure 2). Conclusions TOFO treatment improved pulmonary hypertension in two models for PH-LHD due to HFpEF, suggesting that the SGLT2 inhibitor is effective for the treatment of this condition. FUNDunding Acknowledgement Type of funding sources: None. Figure 2. TOFO reduced RVSP caused by HFD

scholarly journals Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Tanaka ◽  
F Soga ◽  
K Tatsumi ◽  
Y Mochizuki ◽  
H Sano ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Function ◽  
Myocardial Function ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Prospective Multicenter Study ◽  
Lv Diastolic Function

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<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<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

scholarly journals Transitioning from Preclinical to Clinical Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach

2020 ◽  
Vol 9 (4) ◽  
pp. 1110 ◽  
Author(s):  
Antoni Bayes-Genis ◽  
Felipe Bisbal ◽  
Julio Núñez ◽  
Enrique Santas ◽  
Josep Lupón ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Left Atrial ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Preserved Ejection Fraction ◽  
Ventricular Ejection Fraction

To better understand heart failure with preserved ejection fraction (HFpEF), we need to better characterize the transition from asymptomatic pre-HFpEF to symptomatic HFpEF. The current emphasis on left ventricular diastolic dysfunction must be redirected to microvascular inflammation and endothelial dysfunction that leads to cardiomyocyte remodeling and enhanced interstitial collagen deposition. A pre-HFpEF patient lacks signs or symptoms of heart failure (HF), has preserved left ventricular ejection fraction (LVEF) with incipient structural changes similar to HFpEF, and possesses elevated biomarkers of cardiac dysfunction. The transition from pre-HFpEF to symptomatic HFpEF also involves left atrial failure, pulmonary hypertension and right ventricular dysfunction, and renal failure. This review focuses on the non-left ventricular mechanisms in this transition, involving the atria, right heart cavities, kidneys, and ultimately the currently accepted driver—systemic inflammation. Impaired atrial function may decrease ventricular hemodynamics and significantly increase left atrial and pulmonary pressure, leading to HF symptoms, irrespective of left ventricle (LV) systolic function. Pulmonary hypertension and low right-ventricular function are associated with the incidence of HF. Interstitial fibrosis in the heart, large arteries, and kidneys is key to the pathophysiology of the cardiorenal syndrome continuum. By understanding each of these processes, we may be able to halt disease progression and eventually extend the time a patient remains in the asymptomatic pre-HFpEF stage.

scholarly journals Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)

Circulation ◽  
2020 ◽  
Author(s):  
Matthew M. Y. Lee ◽  
Katriona J. M. Brooksbank ◽  
Kirsty Wetherall ◽  
Kenneth Mangion ◽  
Giles Roditi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Ejection Fraction ◽  
Global Longitudinal Strain ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Reduced Ejection Fraction ◽  
B Lines

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter randomized, double-blind, placebo-controlled trial to investigate the cardiac effects of empagliflozin in patients in NYHA functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomized 1:1 to empagliflozin 10 milligrams once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The co-primary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area (LVESVi) and LV global longitudinal strain (LV GLS) measured using cardiovascular magnetic resonance (CMR). Secondary efficacy outcomes included other CMR measures (LVEDVi, LVEF), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS)), 6-minute walk distance (6MWD), B-lines on lung ultrasound and biomarkers (including NT-proBNP). Results: From April 2018 to August 2019, 105 patients were randomized: 77 (73.3%) male, mean age 68.7 [SD 11.1] years, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% [9.8%], and 81 (77.1%) NYHA II and 24 (22.9%) NYHA III. Patients received standard treatment for HFrEF. Compared with placebo, empagliflozin reduced LVESVi by 6.0 (-10.8 to -1.2) ml/m 2 (p=0.015). There was no difference in LV GLS. Empagliflozin reduced LVEDVi by 8.2 (-13.7 to -2.6) ml/m 2 (p=0.0042) and reduced NT-proBNP by 28 (2 to 47) %, p=0.038. There were no between-group differences in other CMR measures, KCCQ-TSS, 6MWD or B-lines. Conclusions: The SGLT2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which SGLT2 inhibitors reduce HF hospitalization and mortality in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03485092.

ACCESSMENT OF RIGHT VENTRICULAR SYSTOLIC FUNCTION USING TAPSE

2011 ◽  
pp. 62-70
Author(s):  
Lien Nhut Nguyen ◽  
Anh Vu Nguyen
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Systolic Function ◽  
Systolic Heart Failure ◽  
Left Ventricular ◽  
Ventricular Ejection ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Background: The prognostic importance of right ventricular (RV) dysfunction has been suggested in patients with systolic heart failure (due to primary or secondary dilated cardiomyopathy - DCM). Tricuspid annular plane systolic excursion (TAPSE) is a simple, feasible, reality, non-invasive measurement by transthoracic echocardiography for evaluating RV systolic function. Objectives: To evaluate TAPSE in patients with primary or secondary DCM who have left ventricular ejection fraction ≤ 40% and to find the relation between TAPSE and LVEF, LVDd, RVDd, RVDd/LVDd, RA size, severity of TR and PAPs. Materials and Methods: 61 patients (36 males, 59%) mean age 58.6 ± 14.4 years old with clinical signs and symtomps of chronic heart failure which caused by primary or secondary DCM and LVEF ≤ 40% and 30 healthy subject (15 males, 50%) mean age 57.1 ± 16.8 were included in this study. All patients and controls were underwent echocardiographic examination by M-mode, two dimentional, convensional Dopler and TAPSE. Results: TAPSE is significant low in patients compare with the controls (13.93±2.78 mm vs 23.57± 1.60mm, p<0.001). TAPSE is linearly positive correlate with echocardiographic left ventricular ejection fraction (r= 0,43; p<0,001) and linearly negative correlate with RVDd (r= -0.39; p<0.01), RVDd/LVDd (r=-0.33; p<0.01), RA size (r=-0.35; p<0.01), TR (r=-0.26; p<0.05); however, no correlation was found with LVDd and PAPs. Conclusions: 1. Decreased RV systolic function as estimated by TAPSE in patients with systolic heart failure primary and secondary DCM) compare with controls. 2. TAPSE is linearly positive correlate with LVEF (r= 0.43; p<0.001) and linearly negative correlate with RVDd (r= -0.39; p<0.01), RVDd/LVDd (r=-0.33; p<0.01), RA size (r=-0.35; p<0.01), TR (r=-0.26; p<0.05); however, no correlation is found with LVDd and PAPs. 3. TAPSE should be used routinely as a simple, feasible, reality method of estimating RV function in the patients systolic heart failure DCM (primary and secondary).

Abstract 16574: Heart Failure Biomarkers (NT-proBNP, Gal-3, sST2) Correlate With Right Ventricular Systolic Pressure and Provide Insight to Poor CRT Response: A BIOCRT Substudy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Roderick C Deaño ◽  
Jackie Szymonifka ◽  
Qing Zhou ◽  
Jigar H Contractor ◽  
Zachary Lavender ◽  
...  
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Fold Increase ◽  
Left Ventricular ◽  
Cardiac Resynchronization ◽  
Cardiac Transplant ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Crt Response

Objective: Patients with heart failure (HF) and pulmonary hypertension (PH) have worse outcomes after cardiac resynchronization therapy (CRT). The relationship of circulating HF biomarkers and right ventricular systolic pressure (RVSP) may provide insight to the mechanism between PH and poor CRT response. Methods: In 90 patients (age 65 ± 13, 78% male, EF 26 ± 8%, RVSP 44 ± 12 mmHg) undergoing CRT, we measured baseline RVSP by echocardiography and obtained peripheral blood samples drawn at the time of device implantation. We measured levels of established and emerging HF biomarkers (Table 1). CRT non-response was defined as no improvement of adjudicated HF Clinical Composite Score at 6 months. Major adverse cardiac event (MACE) was defined as composite endpoint of death, cardiac transplant, left ventricular assist device, and HF hospitalization within 2 years. Results: There were 34% CRT non-responders and 27% had MACE. Per 1 unit increase in log-transformed RVSP, there was an 11-fold increase risk of having CRT non-response (odd ratio [OR] 11.0, p=0.01) and over 5-fold increase of developing 2-year MACE (hazard ratio [HR] 5.8, p=0.02). When comparing patients with severe PH (RVSP>60 mmHg) to those without PH (RVSP < 35 mmHg), there was an 8-fold increase in CRT nonresponse (OR 8.4, p=0.03) but no difference in MACE (p=NS). RVSP was correlated with increased biomarker levels of myocardial stretch and fibrosis, but not myocardial necrosis (Table 1). Conclusions: Higher RVSP is associated with greater rates of CRT non-response and adverse clinical outcomes. The mechanistic association between severe PH and CRT nonresponse may be explained by the biomarker profile reflective of myocardial wall stretch and fibrosis.

Abstract 13421: Ventricular and Arterial Elastance During Isometric Handgrip Exercise and Post-exercise Circulatory Arrest in Heart Failure With and Without Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Naoki Fujimoto ◽  
Keishi Moriwaki ◽  
Issei Kameda ◽  
Masaki Ishiyama ◽  
Taku Omori ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Heart Rate ◽  
Ejection Fraction ◽  
Circulatory Arrest ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Isometric Handgrip ◽  
Arterial Elastance ◽  
Post Exercise

Introduction: Isometric handgrip (IHG) training at 30% maximal voluntary contraction (MVC) lowers blood pressure in hypertensive patients. Impacts of IHG exercise and post-exercise circulatory arrest (PECA), which isolates metaboreflex control, have been unclear in heart failure (HF). Purpose: To investigate the impacts of IHG exercise and PECA on ventricular-arterial stiffness and left ventricular (LV) relaxation in HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods: We invasively obtained LV pressure-volume (PV) loops in 20 patients (10 HFpEF, 10 HFrEF) using conductance catheter with microtip-manometer during 3 minutes of IHG at 30%MVC and 3 minutes of PECA. Hemodynamics and LV-arterial function including LV end-systolic elastance (Ees) by the single-beat method, effective arterial elastance (Ea), and time constant of LV relaxation (Tau) were evaluated every minute. Results: At rest, HFpEF had higher LV end-systolic pressure (ESP) and lower heart rate than HFrEF with similar LV end-diastolic pressure (EDP). The coupling ratio (Ees/Ea) was greater in HFpEF than HFrEF (1.0±0.3 vs. 0.6±0.3, p<0.01). IHG for 3minutes similarly increased heart rate in HFpEF (by 10±8 bpm) and HFrEF (by 14±6 bpm). IHG also increased end-diastolic and LVESP (134±21 vs. 158±30 mmHg and 113±25 vs. 139±25 mmHg) in both groups (groupхtime effect p≥0.25). In HFpEF, Ees, Ea and Ees/Ea (1.0±0.3 vs. 1.1±0.4) were unaffected during IHG. In HFrEF, IHG induced variable increases in Ea. LV end-systolic volume and the ESPV volume-axis intercept were larger, and Ees at IHG 3 rd min was greater (1.30±0.7 vs. 3.1±2.1 mmHg/ml, p<0.01) than baseline, resulting in unchanged Ees/Ea at IHG 3 rd min (0.6±0.3 vs. 0.8±0.4, p≥0.37). Tau was prolonged only in HFrEF during IHG and was returned to the baseline value during PECA. During the first 2 minutes of PECA, LVESP was lower than that at IHG 3 rd min only in HFpEF, suggesting less metaboreflex control of blood pressure in HFpEF during IHG. Conclusions: IHG exercise at 30%MVC induced modest increases in LV end-systolic and end-diastolic pressures in HFpEF and HFrEF. Although the prolongation of LV relaxation was observed only in HFrEF, the ventricular and arterial coupling was maintained throughout the IHG exercise in both groups.

scholarly journals Echocardiography of right ventricular-arterial coupling predicts survival of elderly patients with heart failure and reduced to mid-range ejection fraction

2020 ◽  
Vol 90 (2) ◽  
Author(s):  
Gian Marco Rosa ◽  
Andreina D'Agostino ◽  
Stefano Giovinazzo ◽  
Giovanni La Malfa ◽  
Paolo Fontanive ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Right Ventricular ◽  
Ace Inhibitor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Volume Index ◽  
Systolic Volume ◽  
End Systolic Volume ◽  
And Gender ◽  
The Impact

Echocardiography of right ventricular (RV)-arterial coupling obtained by the estimation of the ratio of the longitudinal annular systolic excursion of the tricuspid annular plane and pulmonary artery systolic pressure (TAPSE/PASP) has been found to be a remarkable prognostic indicator in patients with HF. Our aim was to evaluate the impact of TAPSE, PASP and their ratio in the prognostic stratification of outpatients with HF aged ≥70 years and reduced to mid-range ejection fraction (EF). A complete echocardiographic examination was performed in 400 outpatients with chronic HF and left ventricular (LV) EF ≤50% who averaged 77 years in age. During a median follow-up period of 25 months (interquartile range: 8-46), there were 135 cardiovascular deaths. Two different Cox regression models were evaluated, one including TAPSE and PASP, separately, and the other with TAPSE/PASP. In the first model, LV end-systolic volume index, age, no angiotensin converting enzyme (ACE) inhibitor use, TAPSE, PASP and gender were found to be independently associated with the outcome after adjustment for demographics, clinical, biochemical, echocardiographic data. In the second model, TAPSE/PASP resulted the most important independent predictor of outcome (hazard ratio [HR]:0.07, p<0.0001) followed by LV end-systolic volume index, no ACE inhibitor use, age and gender. The use of the variable TASPE/PASP improved the predictive value of the new multivariable model (area under the curve [AUC] of 0.74 vs AUC of 0.71; p<0.05). TASPE/PASP improved the net reclassification (NRI = 14.7%; p<0.01) and the integrated discrimination (IDI = 0.04; p<0.01). In conclusion, the study findings showed that assessment of RV-arterial coupling by TAPSE/PASP was of major importance to assess the prognosis of patients with chronic HF and LV EF ≤50% aged ≥70 years.

1409Use of phenomapping to determine response of treatment by sacubitril/valsartan in patients with heart failure with reduced ejection fraction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Godet ◽  
O Raitiere ◽  
H Chopra ◽  
P Guignant ◽  
C Fauvel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Heat Map ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background Treatment by sacubitril/valsartan decreases mortality, improves KCCQ score and ejection fraction in patients with heart failure with reduced ejection fraction (HF REF), but there is currently no data to predict response to treatment. Purpose The purpose of our work was to assess whether unbiased clustering analysis, using dense phenotypic data, could identify phenotypically distinct HF-REF subtypes with good or no response after 6 months of sacubitril/valsartan administration. Methods A total of 78 patients in NYHA functional class 2–3 and treated by ACE inhibitor or AAR2, were prospectively assigned to equimolar sacubitril/valsartan replacement. We collected demographic, clinical, biological and imaging continuous variables. Phenotypic domains were imputed with 5 eigenvectors for missing value, then filtered if the Pearson correlation coefficient was >0.6 and standardized to mean±SD of 0±1. Thereafter, we used agglomerative hierarchical clustering for grouping phenotypic variables and patients, then generate a heat map (figure 1). Subsequently, participants were categorized using Penalized Model-Based Clustering. P<0,05 was considered significant. Results Mean age was 60.4±13.4 yo and 79.0% patients were males. Mean ejection fraction was 29.3±7.0%. Overall, 16 phenotypic domains were isolated (figure 1) and 3 phenogroups were identified (Table 1). Phenogroup 1 was remarkable by isolated left ventricular involvement (LVTDD 64.3±5.9mm vs 73.9±8.7 in group 2 and 63.8±5.7 in group3, p<0.001) with moderate diastolic dysfunction (DD), no mitral regurgitation (MR) and no pulmonary hypertension (PH). Phenogroups 2 and 3 corresponded to patients with severe PH (TRMV: 2.93±0.47m/s in group 2 and 3.15±0.61m/s in groupe 3 vs 2.16±0.32m/s in group 1), related to severe DD (phenogroup 2) or MR (phenogroup 3). In both phenogroups, the left atrium was significantly enlarged and the right ventricle was remodeled, compared with phenogroup 1. Despite more severe remodeling and more compromised hemodynamic in phenogroups 2 and 3, the echocardiographic response to sacubitril/valsartan was comparable in all groups with similar improvement of EF and reduction of cardiac chambers dimensions (response of treatment, defined by improvement of FE +15% and/or decreased of indexed left ventricule diastolic volume −15% = group 2: 22 (76%); group 3: 18 (60%); group 1: 9 (50%); p=0.17; OR group 2 vs 1: OR=3.14; IC95% [0.9–11.03]; p=0.074; OR group 3 vs 1: OR=1.5; IC95% [0.46–4.87]; p=0.5)). The clinical response was even better in phenogroups 2 and 3 (Group 2: 19 (66%); group 3: 21 (78%) vs group 1: 9 (50%); p=0.05). Heat map Conclusion HF-REF patients with severe diastolic dysfunction, significant mitral regurgitation and elevated pulmonary hypertension by echocardiographic had similar reverse remodeling but better clinical improvement than patients with isolated left ventricular systolic dysfunction.

scholarly journals Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension

2009 ◽  
Vol 296 (6) ◽  
pp. H2007-H2014 ◽  
Author(s):  
Inês Falcão-Pires ◽  
Nádia Gonçalves ◽  
Tiago Henriques-Coelho ◽  
Daniel Moreira-Gonçalves ◽  
Roberto Roncon-Albuquerque ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pressure Rise ◽  
Chronic Administration ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Peak Rate ◽  
Male Wistar Rats ◽  
Neurohumoral Activation

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle ( day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 μg·kg−1·day−1 ip) or a similar volume of saline, resulting in four groups: sham ( n = 11), sham-AP ( n = 11), MCT ( n = 16), and MCT-AP ( n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 ± 38%), diameter of cardiomyocyte (40 ± 10%), myocardial fibrosis (95 ± 20%), peak systolic pressure (99 ± 22%), peak rate of ventricular pressure rise (dP/d tmax; 74 ± 24%), peak rate of ventricular pressure decline (dP/d tmin; 73 ± 19%), and time constant τ (55 ± 16%). In these animals, RV expression of apelin (−73 ± 10%) and its receptor APJ (−61 ± 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 ± 713%), angiotensinogen (191 ± 147%), endothelin-1 (RV, 497 ± 156%; and LV, 799 ± 309%), plasmatic levels of apelin (104 ± 48%), and angiotensin 1-7 (161 ± 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

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