David Boulate

Non-invasive indices of right ventricular function are markers of ventricular–arterial coupling rather than ventricular contractility: insights from a porcine model of chronic pressure overload

AIMS To investigate the physiological correlates of indices of RV function in a model of chronic pressure overload. METHODS AND RESULTS Chronic pulmonary hypertension (PH) was induced in piglets by ligation of the left pulmonary artery (PA) followed by weekly embolization of right lower lobe arteries for 5 weeks (the PH group, n = 11). These animals were compared with sham-operated animals (controls, n = 6). At 6 weeks, a subgroup of five PH pigs underwent surgical reperfusion of the left lung and four others were followed until 12 weeks without treatment. Right ventricular function was assessed using echocardiography and conductance catheter measurements. At 6 weeks, mean PA pressure was higher in PH group compared with controls (35 ± 9 vs. 14 ± 2 mmHg, P < 0.01). Although RV elastance (Ees) increased at 6 weeks in the PH group (0.55 ± 0.09 vs. 0.38 ± 0.05 mmHg/mL, P < 0.001), ventricular-arterial coupling measured by the ratio of Ees on PA elastance (Ea) was decreased (0.68 ± 0.17 vs. 1.18 ± 0.18, P < 0.001). There was a strong direct relationship between Ees/Ea and indices of RV function, while relationship between Ees and indices of RV function was moderate. Changes in indices of RV function with time and after left lung reperfusion were associated with changes in Ees/Ea. CONCLUSION Usual indices of RV function are associated with ventricular-arterial coupling rather than with ventricular contractility in a model of chronic pressure overload.

Pulmonary microvascular lesions regress in reperfused chronic thromboembolic pulmonary hypertension

BACKGROUND Pulmonary microvascular disease (PMD) develops in both occluded and non-occluded territories in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and may cause persistent pulmonary hypertension after pulmonary endarterectomy. Endothelin-1 (ET-1) and interleukin-6 (IL-6) are potential PMD severity biomarkers, but it remains unknown whether they are related to occluded or non-occluded territories. We assessed PMD and ET-1/IL-6 gene expression profiles in occluded and non-occluded territories with and without chronic lung reperfusion in an animal CTEPH model. METHODS Chronic PH was induced in 10 piglets by left pulmonary artery (PA) ligation followed by weekly embolization of right lower lobe arteries with enbucrilate tissue adhesive for 5 weeks. At Week 6, 5 of 10 animals underwent left PA reperfusion. At Week 12, animals with and without reperfusion were compared with sham animals (n = 5). Hemodynamics, lung morphometry and ET-1/IL-6 gene expression profiles were assessed in the left lung (LL, occluded territories) and right upper lobe (RUL, non-occluded territories). RESULTS At Week 12, mean PA pressure remained elevated without reperfusion (29.0 ± 2.8 vs 27.0 ± 1.1 mm Hg, p = 0.502), but decreased after reperfusion (30.0 ± 1.5 vs 20.5 ± 1.7 mm Hg, p = 0.013). Distal media thickness in the LL and RUL PAs and systemic vasculature to the LL were significantly lower in the reperfused and sham groups compared with the non-reperfused group. PMD progression was related to ET-1 and IL-6 gene expression in the RUL and to the ET-A/ET-B gene expression ratio in the LL. CONCLUSIONS PMD regressed in occluded and non-occluded territories after lung reperfusion. Changes in ET-1 and IL-6 gene expression were associated with PMD in non-occluded territories.

Right ventricular reserve in a piglet model of chronic pulmonary hypertension

Right ventricular (RV) response to exercise or pharmacological stress is not well documented in pulmonary hypertension (PH). We investigated the relationship between RV reserve and ventricular–arterial coupling. Surgical ligation of the left pulmonary artery was performed in 13 Large White piglets (PH group), thereafter weekly embolisations of the right lower lobe were performed for 5 weeks. A control group of six piglets underwent sham procedures. Right heart catheterisation and echocardiography were performed at week 6. Pressure–volume loops were recorded before and after dobutamine infusion. Induction of experimental PH resulted in a higher mean±sd pulmonary artery pressure (34±9 versus 14±2 mmHg; p<0.01) and in a lower ventricular–arterial coupling efficiency (0.66±0.18 versus 1.24±0.17; p<0.01) compared with controls at 6 weeks. Dobutamine-induced relative changes in RV stroke volume index (SVI) and end-systolic elastance were lower in the PH group (mean±sd 47±5% versus 20±5%, p<0.01, and 81±37% versus 32±14%, p<0.01, respectively). Change in SVI was strongly associated with resting ventricular–arterial coupling (R2=0.74; p<0.01). RV reserve was associated with ventricular–arterial coupling in a porcine model of chronic pressure overload. Dobutamine testing in right ventricular pressure overload: a potentially useful method to assess contractile reserve http://ow.ly/E9NMK

Right ventricular plasticity in a porcine model of chronic pressure overload.

BACKGROUND Ventricular-arterial coupling is a measure of the relationship between ventricular contractility and afterload. We sought to determine the relationship between ventricular-arterial coupling and right ventricular (RV) remodeling in a novel porcine model of progressive pulmonary hypertension (PH). METHODS Chronic PH was induced in pigs by ligation of the left pulmonary artery (PA) followed by 5 weekly injections of cyanoacrylate to progressively obstruct the right lower lobe arteries (PH group, n = 10). At 6 weeks, 5 PH animals underwent reperfusion of the left lung through conduit anastomosis to decrease RV afterload, whereas 5 other animals received no treatment. Five sham-operated piglets were used as controls. RV function was assessed using echocardiography and conductance catheterization. RV gene expression of beta-myosin heavy chain (β-MHC) and B-type natriuretic peptide (BNP) were quantified by polymerase chain reaction. RESULTS At 6 weeks, compared with controls, the PH group had higher mean PA pressure (32 ± 6 vs 14 ± 2 mm Hg, p < 0.01). The increase in RV elastance was insufficient to compensate for the increase in pulmonary arterial elastance in the PH group and altered ventricular-arterial coupling occurred (0.65 ± 0.16 vs 1.28 ± 0.14, p < 0.01). The degree of ventricular-arterial uncoupling was related to RV enlargement and systolic dysfunction. Ventricular-arterial uncoupling and increased RV mass index were associated with up-regulation of β-MHC and BNP expression. CONCLUSIONS Ventricular-arterial coupling is closely associated with ventricular remodeling and systolic function as well as contractile and BNP gene expression. Dynamic changes in myosin expression may determine RV work efficiency in PH.

Biventricular VAD versus LVAD for right heart failure

Right ventricular failure (RVF) in the era of left ventricular assist device (LVAD) therapy remains a significant problem. Approximately 6% to 10% of patients with an LVAD will require the implantation of a right ventricular assist device (RVAD) (1) with an additional 15% to 20% requiring prolonged inotropic support for RVF (2,3). Several mechanisms may contribute to RVF post LVAD implantation, most importantly the unloading of the left ventricle and resultant loss of septal contribution to right ventricular (RV) function. In addition, perioperative factors such as myocardial ischemia can further compromise a vulnerable right ventricle. As these factors may lead to rescue implantation of an RVAD, which is associated with increased mortality (4), research should focus on identifying patients that would benefit from preemptive implantation of an RVAD. Here we highlight recent advances in the field, focusing on risk stratification scores, the use of pulmonary vasodilators, the use of biventricular assist devices (BIVAD) versus a total artificial heart (TAH), and the use of a temporary RVAD (tRVAD). We also briefly present recent data on right heart recovery post LVAD using tRVAD support.

Load Adaptability in Patients With Pulmonary Arterial Hypertension

Right ventricular (RV) adaptation to pressure overload is a major prognostic factor in patients with pulmonary arterial hypertension (PAH). The objectives were first to define the relation between RV adaptation and load using allometric modeling, then to compare the prognostic value of different indices of load adaptability in PAH. Both a derivation (n = 85) and a validation cohort (n = 200) were included. Load adaptability was assessed using 3 approaches: (1) surrogates of ventriculo-arterial coupling (e.g., RV area change/end-systolic area), (2) simple ratio of function and load (e.g., tricuspid annular plane systolic excursion/right ventricular systolic pressure), and (3) indices assessing the proportionality of adaptation using allometric pressure-function or size modeling. Proportional hazard modeling was used to compare the hazard ratio for the outcome of death or lung transplantation. The mean age of the derivation cohort was 44 ± 11 years, with 80% female and 74% in New York Heart Association class III or IV. Mean pulmonary vascular resistance index (PVRI) was 24 ± 11 with a wide distribution (1.6 to 57.5 WU/m2). Allometric relations were observed between PVRI and RV fractional area change (R2 = 0.53, p < 0.001) and RV end-systolic area indexed to body surface area right ventricular end-systolic area index (RVESAI) (R2 = 0.29, p < 0.001), allowing the derivation of simple ratiometric load-specific indices of RV adaptation. In right heart parameters, RVESAI was the strongest predictor of outcomes (hazard ratio per SD = 1.93, 95% confidence interval 1.37 to 2.75, p < 0.001). Although RVESAI/PVRI0.35 provided small incremental discrimination on multivariate modeling, none of the load-adaptability indices provided stronger discrimination of outcome than simple RV adaptation metrics in either the derivation or the validation cohort. In conclusion, allometric modeling enables quantification of the proportionality of RV load adaptation but offers small incremental prognostic value to RV end-systolic dimension in PAH.

Early Development of Right Ventricular Ischemic Lesions in a Novel Large Animal Model of Acute Right Heart Failure in Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND Our aim was to develop a model of acute right heart failure (ARHF) in the setting of pulmonary hypertension and to characterize acute right ventricular lesions that develop early after hemodynamic restoration. METHODS AND RESULTS We used a described piglet model of chronic pulmonary hypertension (cPH) induced by pulmonary artery occlusions. We induced ARHF in animals with cPH (ARHF-cPH group, n = 9) by volume loading and iterative acute pulmonary embolism until hemodynamic compromise followed by dobutamine infusion for hemodynamic restoration before sacrifice for right ventricular tissue evaluation. The median duration of ARHF before sacrifice was 162 (135-189) minutes. Although ventriculoarterial coupling (measured with multibeat pressure-volume loops) and stroke volume decreased after iterative pulmonary embolism and improved with dobutamine, relative pulmonary to systemic pressure increased by 2-fold and remained similarly increased with dobutamine. Circulating high-sensitivity troponin I increased after hemodynamic restoration. We found an increase in right ventricular subendocardial and subepicardial focal ischemic lesions and in expression of autophagy-related protein LC3-II (Western blot) in the ARHF-cPH group compared with the cPH (n = 5) and control (n = 5) groups. CONCLUSIONS We developed and phenotyped a novel large animal model of ARHF on cPH in which right ventricular ischemic lesions were observed early after hemodynamic restoration.

Pulmonary Circulatory – Right Ventricular Uncoupling: New Insights Into Pulmonary Hypertension Pathophysiology

The pulmonary circulatory – right ventricular uncoupling is a key pathophysiological feature of pulmonary hypertension. Uncoupling develops when the ventricular contractility is not matched to its afterload due to a discordant response of the RV to increased afterload, or to an impaired right ventricular function. In this chapter we reported the methods which were developed to quantify the right ventricular –pulmonary artery (RV-PA) coupling in patients with PH and in experimental models of PH. The RV pressure-volume loop analysis are the gold standard to quantify RV-PA coupling metrics but more simple and less invasive methods were developed. We also reported how the RV-PA coupling metrics may be used to improve the phenotyping of patients and experimental models with PH. RV-PA coupling was also used to quantify the pharmacological effects of treatments in animal models with PH and to improve the understanding of the pathophysiological differences in different PH types. In recent studies, RV-PA coupling quantification with imaging methods showed interesting application to prognosis stratification of patients with PH.

IMPACT OF INITIATION OF BALLOON PULMONARY ANGIOPLASTY PROGRAM ON REFERRAL OF PATIENTS WITH CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION TO SURGERY

Balloon pulmonary angioplasty (BPA) is a rising technique for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to assess whether initiation of BPA has modified the referral of patients undergoing pulmonary endarterectomy (PEA). This prospective study

Impact of the initiation of balloon pulmonary angioplasty program on referral of patients with chronic thromboembolic pulmonary hypertension to surgery

BACKGROUND Balloon pulmonary angioplasty (BPA) is a technique proposed for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study we aimed to determine whether initiation of the BPA program has modified the characteristics and outcome of patients undergoing pulmonary endarterectomy (PEA), and compared the characteristics of patients undergoing one or the other procedure. METHODS This prospective registry study included all patients with CTEPH who underwent PEA in the French National Reference Center before (2012 to 2013) and after (2015 to 2016) BPA program initiation (February 2014). Pre-operative clinical and hemodynamics profiles, peri-operative (Jamieson classification, surgery duration, need of assistance) characteristics of both groups, and all-cause mortality were compared using the t-test or chi-square test. Characteristics of patients subjected to surgery or BPA since February 2014 were also compared. RESULTS The total number of patients referred to the CTEPH team increased in the BPA era (n = 291 vs n = 484). The pre-operative characteristics of patients from the pre-BPA era (n = 240) were similar to those from the BPA era (n = 246). Despite more Jamieson Type 3 cases (29%) in the second period, 30- and 90-day mortality remained stable (both p > 0.30). Patients subjected to BPA (n = 177) were older than those subjected to PEA (n = 364) (64 ± 14 vs 60 ± 14 years, respe`ctively), and had higher rates of splenectomy (10% vs 1%) or implantable port (9% vs 3%), lower total pulmonary resistance, better cardiac index, and better renal function (all p < 0.01). CONCLUSIONS This study shows the influence of the initiation of the BPA program on the profile of patients with CTEPH undergoing PEA.