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Echocardiographic validation of pulmonary hypertension due to heart failure with reduced ejection fraction in mice.

ABSTRACT: Pulmonary hypertension (PH) associated with left heart diseases is the most prevalent cause of PH. The scarcity of studies exploring the pathophysiology and therapies of group II PH resides in the lack of validated small animal models with non-invasive determination of the presence and severity of PH. Heart failure (HF) was induced in mice by coronary artery ligation. Mice developed PH as evidenced by an elevated right ventricular (RV) systolic pressure and RV hypertrophy. Detailed non-invasive echocardiographic analysis on the left and right ventricles showed impaired left ventricular (LV) systolic and diastolic function. In addition, RV hypertrophy was confirmed by echo and accompanied by impaired function as well as increased pulmonary resistance. Correlation analysis validated the use of the LV wall-motion score index (WMSI) at a threshold value of ?2.0 as a powerful and reliable indicator for the presence of PH and RV dysfunction. Echocardiography is an accurate non-invasive technique to diagnose PH in a HF mouse model. Moreover, an echocardiographic parameter of infarct size and LV function, the LV WMSI, reliably correlates with the presence of PH, RV hypertrophy and RV dysfunction and could be used to improve efficiency and design of pre-clinical studies.

SUBMITTER: Dayeh NR

PROVIDER: S-EPMC5778040 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Echocardiographic validation of pulmonary hypertension due to heart failure with reduced ejection fraction in mice.

Dayeh Nour R NR Tardif Jean-Claude JC Shi Yanfen Y Tanguay Mégane M Ledoux Jonathan J Dupuis Jocelyn J

Scientific reports 20180122 1

Pulmonary hypertension (PH) associated with left heart diseases is the most prevalent cause of PH. The scarcity of studies exploring the pathophysiology and therapies of group II PH resides in the lack of validated small animal models with non-invasive determination of the presence and severity of PH. Heart failure (HF) was induced in mice by coronary artery ligation. Mice developed PH as evidenced by an elevated right ventricular (RV) systolic pressure and RV hypertrophy. Detailed non-invasive ...[more]

PMID: 29358732

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Project description:AimsFailure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by the ratio of RV end-systolic to PA elastances (Ees/Ea). Using pressure-volume loop (PV-L) technique we aimed to identify an Ees/Ea cut-off predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to heart failure with reduced ejection fraction (HFREF).Methods and resultsThis post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography and a baseline PV-L and RV catheter measurement. A subgroup of patients (n = 50) without a pre-implanted cardiac device underwent magnetic resonance imaging at baseline. The analysis revealed that 0.68 is an optimal Ees/Ea cut-off (area under the curve: 0.697, P < 0.001) predictive for overall survival (median follow up = 4.7 years, Ees/Ea ≥ 0.68 vs. <0.68, log-rank 8.9, P = 0.003). In patients with PH (n = 76, 68%) multivariate Cox regression demonstrated the independent prognostic value of RV-Ees/Ea in PH patients (hazard ratio 0.2, P < 0.038). Patients without PH (n = 36, 32%) and those with PH but RV-Ees/Ea ≥ 0.68 showed comparable RV-Ees/Ea ratios (0.88 vs. 0.9, P = 0.39), RV size/function, and survival. In contrast, secondary PH with RV-PA coupling ratio Ees/Ea < 0.68 corresponded extremely close to cut-off values that define RV dilatation/remodelling (RV end-diastolic volume >160 mL, RV-mass/volume-ratio ≤0.37 g/mL) and dysfunction (right ventricular ejection fraction <38%, tricuspid annular plane systolic excursion <16 mm, fractional area change <42%, and stroke-volume/end-systolic volume ratio <0.59) and is associated with a dramatically increased short and medium-term all-cause mortality. Independent predictors of prognostically unfavourable RV-PA coupling (Ees/Ea < 0.68) in secondary PH were a pre-existent dilated RV [end-diastolic volume >171 mL, odds ratio (OR) 0.96, P = 0.021], high pulsatile load (PA compliance <2.3 mL/mmHg, OR 8.6, P = 0.003), and advanced systolic left heart failure (left ventricular ejection fraction <30%, OR 1.23, P = 0.028).ConclusionsThe RV-PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodelling, and left ventricular dysfunction. Prognostically favourable coupling (RV-Ees/Ea ≥ 0.68) in PH was associated with preserved RV size/function and mid-term survival, comparable with HFREF without PH.

Project description:BACKGROUND:We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. METHODS:Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ?40 mm?Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. RESULTS:The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls (P<0.0001 for all) but lower than PVOD (P?0.005 for all). PASP (mm?Hg) was lower in HF-PH (median, 59 [interquartile range, 50-70]) than in PVOD (median, 91 [interquartile range, 82-103]). PASP correlated with arterial percent medial thickness (r=0.41) and arterial %IT (r=0.35) but more strongly with venous %IT (r=0.49) and IV %IT (r=0.55) (P<0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. CONCLUSIONS:In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Project description:Background Both ventilatory abnormalities and pulmonary hypertension (PH) are frequently observed in patients with heart failure with reduced ejection fraction. We aim to investigate the association between ventilatory abnormalities and PH in heart failure with reduced ejection fraction, as well as their prognostic impacts. Methods and Results A total of 440 ambulatory patients (age, 66.2±15.8 years; 77% men) with left ventricular ejection fraction ≤40% who underwent comprehensive echocardiography and spirometry were enrolled. Total lung capacity, forced vital capacity, and forced expiratory volume in the first second were obtained. Pulmonary arterial systolic pressure was estimated. PH was defined as a pulmonary arterial systolic pressure of >50 mm Hg. The primary end point was all-cause mortality at 5 years. Patients with PH had significantly reduced total lung capacity, forced vital capacity, and forced expiratory volume in the first second. During a median follow-up of 25.9 months, there were 111 deaths. After accounting for age, sex, body mass index, renal function, smoking, left ventricular ejection fraction, and functional capacity, total lung capacity (hazard ratio [HR] per 1 SD, 0.66; 95% CI per 1 SD, 0.46-0.96), forced vital capacity (HR per 1 SD, 0.64; 95% CI per 1 SD, 0.48-0.84), and forced expiratory volume in the first second (HR per 1 SD, 0.72; 95% CI per 1 SD, 0.53-0.98) were all significantly correlated with mortality in patients without PH. Kaplan-Meier curve demonstrated impaired pulmonary function, defined as forced expiratory volume in the first second ≤58% of predicted or forced vital capacity ≤65% of predicted, was associated with higher mortality in patients without PH (HR, 2.85; 95% CI, 1.66-4.89), but not in patients with PH (HR, 1.05; 95% CI, 0.61-1.82). Conclusions Ventilatory abnormality was more prevalent in patients with heart failure with reduced ejection fraction with PH than those without. However, such ventilatory defects were related to long-term survival only in patients without PH, regardless of their functional status.

Project description:BackgroundLifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known.MethodsParticipant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks.ResultsWe included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction.ConclusionsLifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

Dataset Information

Echocardiographic validation of pulmonary hypertension due to heart failure with reduced ejection fraction in mice.

Publications

Echocardiographic validation of pulmonary hypertension due to heart failure with reduced ejection fraction in mice.

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