High Pulmonary Vascular Resistance Research Articles

P1505 Echocardiographic assessment of different pulmonary hypertension groups

Abstract Introduction Noninvasive echocardiography evaluation of the right ventricle (RV) has been shown to have prognostic value in patients with pulmonary hypertension (PH). Different etiology groups might have different echocardiographic phenotypes. In this study, we aimed to study echocardiographic characterization of the different PH groups and its ability to predict pulmonary vascular disease severity. Methods We collected echocardiographic and right heart catheterization (RHC) data from 97 (75% female, age 65 ± 15 years) consecutive patients referred to an expert tertiary care referral PH centre from 12/2016 to 11/2018. Echocardiographic analysis was performed using Echo-Pac software from GE Healthcare®. Group 3 and 5 were not included in the group comparison analysis due to few patients included. Results Group 2 PH was the most frequent etiology of PH (35), followed by group 1 (26), group 4 (18), group 5 (3) and group 3 (2). The echocardiographic evaluation of this population as a whole showed borderline parameters of RV dysfunction (tricuspid annular plane systolic excursion (TAPSE) 18 ± 4 mm, fractional area change (FAC) 33 ± 10% and S’ tricuspid wave 10 ± 3 cm/sec). Mean RV global strain was -15 ± 5 and RV free wall strain was -17 ± 7. PH group 1 had a significantly lower FAC (26 ± 4%, p = 0.0025), higher eccentricity index (IE) (1.5 ± 0.1, p = 0.01), and more frequently RV outflow tract (RVOT) notching than other groups (62%, p = 0.012). Group 4 presented an intermedium echocardiographic phenotype between group 1 and 2, and showed more abnormal strain values than the other groups. Group 2 had fewer patients in sinus rhythm (atrial fibrillation in 34% of patients, p = 0.02), presented a thicker interventricular septum (11.3 ± 1.8, p = 0.014), a higher FAC (35 ± 3%, p = 0.0025), higher E mitral wave velocity (72 ± 6 cm/s, p < 0.001) and E/E’ ratio (12.7 ± 10.2, p = 0.006), and larger left (45 ± 3 cm3/m3, p < 0.01) and right atria (25 ± 2 cm2, p = 0.03). PH groups 1 and 4 had higher Pulmonary Vascular Resistance (PVR) and Pulmonary Mean Arterial Pressure (PMAP) values than group 2, which significantly correlated with echocardiographic RV function parameters as TAPSE, FAC, RV global strain and IE. In PH group 2, eccentricity index was the only predictor of PVR (β=4.1, p = 0.018). In this population, a left atria volume < 32.7 cm3/m2 (OR 4.25, CI 1.71 - 10.55) and a E/e’ ratio < 12 (OR 4.72, CI 2.05 - 10.87) predicted PECP < 15 mmHg. RV global strain > -17.1 predicted PVR > 3 wood (OR 3.46, CI 1.50 - 8.02) and PMAP > 20 mmHg (OR 4.92, CI 1.67 - 14.51). TAPSE < 18 mm predicted PVR > 3 wood (OR 7.41, CI 2.99 - 18.36, AUC 0.72). Conclusion Different PH groups present mild echocardiographic differences between them. PH group 1 presented with more echocardiographic signs of RV disfunction, and PH group 2 had higher FAC, E/E’ and larger right and left atria. RV function parameters predicted PVR in PH groups 1 and 4, and EI was the only predictor of PVR in PH group 2. Abstract P1505 Figure.

Hybrid approach for treating patient with chronic thromboembolic pulmonary hypertension and extrinsic compression of left main coronary artery

Background ― Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare life-threatening form of pulmonary artery hypertension. CTEPH is potentially curable by performing surgical operation – pulmonary thrombendarteriectomy. Unfortunately, about 36% of patients with CTEPH are considered as inoperable because of different conditions including left main coronary artery compression syndrome (LMCS), caused by compression with delated pulmonary artery. Appropriate management of patients with CTEPH and LMCS remains unknown. Case report ― We report for the first time a case of a successful hybrid treatment of patient with CTEPH and LMCS. Due to high pulmonary vascular resistance (PVR) and LMCS (90% stenosis) the risk for pulmonary thrombendarteriectomy for patient was considered as high. The multidisciplinary team decided to start treatment with new method of treatment for patients with CTEPH – balloon pulmonary angioplasty. In 5 months 4 sessions of balloon pulmonary angioplasty were successfully performed. In a follow-up mean pulmonary artery pressure decreased from 57 to 37 mm Hg, PVR decreased from 20 to 7 WU. Coronary angiography showed no compression of left main coronary artery. The diameter of pulmonary artery decreased from 4.2 to 3.6 cm. Patient was reconsidered as operable and transferred to a surgical unit for pulmonary thrombendarteriectomy. Conclusion ― Effective balloon pulmonary angioplasty can lead to regression of left main compression syndrome in CTEPH patients. Balloon pulmonary angioplasty can be a “bridge-treatment” to pulmonary thrombendarteriectomy in patients with high operation risk.

Intraoperative Flow Study Predicted the Postoperative Pulmonary Artery Pressure in the Bidirectional Glenn Operation.

The aim of this study was to evaluate the predictability of postoperative pulmonary artery pressure (PAP) using intraoperative flow study in patients undergoing bidirectional Glenn operation. Patients who underwent Glenn operation under cardiopulmonary bypass (CPB) were included in the study. During the operation, after the completion of additional procedures under CPB, an intraoperative flow study was performed prior to Glenn anastomosis. After the completion of bidirectional Glenn, the patient was separated from the CPB and PAP was measured. The relationship between this pressure and flow study measurement was analyzed. Nine patients who underwent bidirectional Glenn operation with additional procedures under CPB between July 2018 and January 2019 were included in the study. The median PAP was 9 mm Hg (interquartile range [IQR]: 7-10 mm Hg) in the flow study and 10 mm Hg (IQR: 8-11 mm Hg) after CPB, and the median difference between these pressures was 1 mm Hg (IQR: 1-3 mm Hg). There was a strong correlation between these two measurements (r = 0.732; P = .025). The results of this study show that PAP after the Glenn procedure can be estimated using an intraoperative flow study. We believe that this method may be useful in intraoperative decision-making for Glenn operation in single ventricular patients who require extensive pulmonary artery (PA) reconstruction due to limited PA development, branch PA stenosis, or nonconfluent PAs. Also, this method can be used as a sort of intraoperative pulmonary resistance reversibility study in patients with high preoperative pulmonary vascular resistance due to surgically correctable pulmonary venous hypertension.

Clinical characteristics of patients with chronic thromboembolic pulmonary hypertension

Objective: To investigate the clinical characteristics of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: CTEPH cases consecutively admitted into China-Japan Friendship Hospital from September 2015 to June 2019 were enrolled with prospective data collection. The medical histories, clinical characteristics, laboratory tests, imaging manifestation and hemodynamic parameters were analyzed. Patients were divided into high pulmonary vascular resistance (PVR) group and low PVR group according to the PVR level>1 000 dyn·s·cm(-5) or not, and clinical characteristics were compared between these two groups. Results: In the 148 cases of CTEPH, right heart catheterization was performed in 103 cases with mPAP (45.1±11.0) mmHg and PVR of (992±430) dyn·s·cm(-5). At diagnosis, 88 (59.5%) cases were in WHO functional class Ⅲ and 27 (18.2%) in class Ⅳ. Most common presenting symptoms were dyspnea (147, 99.3%), chest tightness (68, 45.9%), hemoptysis (42, 28.3%), syncope (30, 20.3%), and most common signs were P2 accentuation (95, 64.9%), edema (65, 43.9%), cyanosis (47, 31.8%), systolic murmur (44, 29.7%) and jugular vein distention (35, 23.6%). In 103 cases with right heart catheterization, 52 were in the low PVR group and 51 in high PVR group. Compared to the low PVR group, high PVR group patients had higher WHO functional class and more jugular vein distention (both P<0.05). In all the 148 cases, previous venous thromboembolism (VTE) was confirmed in 105 (70.9%) patients, with a higher prevalence of previous VTE in low PVR group than that in high PVR group (P<0.001). 30 (20.3%) patients had varicose veins of the lower extremities, and 21 (14.2%) had other thrombophilic disorders including antiphospholipid syndrome, protein C and S deficiency and antithrombin Ⅲ deficiency. Conclusions: Dyspnea, P2 accentuation and edema are the most common clinical presentation of CTEPH. Previous history of VTE is common in CTEPH patients with thrombophilia in some cases.

Effect of Pulmonary Hypertension on Transplant Outcomes in Patients With Ventricular Assist Devices

Although extremely high pulmonary vascular resistance (PVR) is a relative contraindication for heart transplantation (HTx), recent data with continuous-flow left ventricular assist devices (LVADs) indicate HTx outcomes may be different when high PVR is managed with an LVAD. This study clarifies the contemporary association between PVR at HTx and posttransplant survival in LVAD vs non-LVAD cohorts. We reviewed the United Network for Organ Sharing registry for adults who received a transplant from 2008 to 2015. In those with continuous-flow LVADs and those with no VADs at HTx, (non-VAD), we grouped patients by low PVR (PVR <3), intermediate PVR (PVR 3 to <6), and high PVR (PVR ≥6) groups. Adjusted hazard ratios (aHRs) for death after HTx were calculated by Cox regression. The non-LVAD cohort included 6270 patients (4385 in low, 1643 in intermediate, and 242 in high PVR), and the LVAD cohort included 4111 patients (3227 in low, 798 in intermediate, and 86 in high PVR). The high PVR LVAD group had the worst survival, which was not significant, likely to low power (P= .300). The aHR for death in non-LVAD was 1.047 (95% confidence interval, 1.010-1.088) and in LVAD was 1.063 (95% confidence interval, 1.010-1.119). Cubic spline analysis demonstrated nonlinear associations between PVR and the aHR, especially in the LVAD cohort. There was no significant evidence to conclude the effect of pretransplant PVR on posttransplant survival is higher in LVAD vs non-LVAD patients, based on analysis of the United Network for Organ Sharing database. However, further investigations are indicated to clarify HTx candidacy in those with extremely high PVR even after LVAD.

Primary Sjogren's syndrome associated pulmonary arterial hypertension: 20 new cases

Objective: To describe baseline characteristics of patients with primary Sjogren's syndrome (pSS) with right heart catheterization (RHC)-confirmed pulmonary arterial hypertension (PAH). Methods: This retrospective study included consecutive patients hospitalized with pSS-PAH from Jan.2013 to June.2019 in Tianjin Medical University General Hospital. All patients fulfilled the 2002 revised criteria for pSS proposed by the American-European Consensus Group. PAH was defined according to RHC-based European Society of Cardiology/European Respiratory Society guidelines. Associated variables were described and analyzed. Predictive factors for achieving treatment goals were explored. Sub-groups(based on Anti-SSB antibody positive/negative) were analyzed. Results: Twenty patients with RHC-confirmed pSS-PAH were included (median age at onset, 54.5 years; median PAH duration, 12 months).PAH was the initial manifestation of pSS in 5 patients(26.3%), and shortness of breath was the most common symptom (17/20,85%). Mean pulmonary arterialpressure (mPAP) was 48(38, 55.75)mmHg, pulmonary vascularresistance (PVR) was 11.23 (6.17,14.69)IU, and mean cardiac index was 2.59(2.04,2.98)L·min(-1)·m(-2) in this group. In addition, right ventricular diameter≤40 mm[P=0.009, HR=5.92, 95%CI(1.55, 22.59)] was predictive factor for achieving the treatment goal. Furthermore, compared with Anti-SSB antibody negative patients, patients with Anti-SSB antibody positive had a higher PVR(IU) [14.1(11.23, 22.63)vs 6.4(6.15, 12.36),P=0.025], a higher mPAP(mmHg)[5(48.5,59)vs 39(32.5,50.75),P=0.013], and a lower cardiac index (L·min(-1)·m(-2)) [2.1(1.6,2.5)vs 2.9(2.56,3.41),P=0.002]. Conclusions: pSS-PAH patients are mainly middle-aged women with the most common symptom shortness of breath. And PAH can be the first manifestation of pSS. More attention should be paid to patients with Anti-La/SSB antibody positive and right ventricular diameter ≤40 mm because of higher mPAP, PVR, worse cardiac function and prognosis.

P3549Impact of mitral regurgitation on alveolo-capillar membrane diffusion: an hemodynamic and functional study

Abstract Background In HFrEF patients, high pulmonary vascular resistances (PVR) reflect a combined increase of pre- and post-capillary pressures, associated with worse outcome. Mitral regurgitation (MR) may play a role in this complex physiopathology. We sought to investigate MR impact on lung DLCO and pulmonary vascular hemodynamic in HFrEF patient. Methods 22 HFrEF patients (age 67±11; LV EF) underwent right heart catheterization, rest and exercise echocardiography, right ventricle 3D assessment and lung alveolo-capillary membrane DLCO. We identified 2 subgroups according to normal (&lt;3 WU, n=17) or abnormal (&gt;3 WU, n=5) PVR. Results Abnormal PVR patients showed increased pulmonary artery pressures and TPG, reduced CO and pulmonary artery compliance. Total DLCO was not significantly different between groups. The membrane component (Dm) and the alveolar volume (Va) were significantly reduced in abnormal PVR group, while the capillary volume (VC) showed a strong trend toward higher values. Abnormal PVR group had a very high percentage of moderate-to-severe MR. The TASPE/SPAP ratio and the circumferential component of RV systolic function were significantly reduced in abnormal PVR group. Normal PVR (n=17) Abnormal PVR (n=5) p NTproBNP, ng/L 3021±2527 7023±8785 0.55 MR moderate-to-severe, n (%) 3 (19%) 4 (80%) 0.025 TAPSE/SPAP, mm/mmHg 0.4761±0.1695 0.2956±0.0739 0.019 3D RV global EF, % 40.616±9.350 29.486±14.062 0.119 3D RV longitudinal EF, % 15.611±7.773 12.086±9.694 0.497 3D RV circumferential EF, % 31.0567±6.5744 21.1746±11.5823 0.019 Lung diffusion of CO (DLCO), ml/min/mmHg 19.021±4.643 15.233±1.761 0.197 Dm ml/min/mmHg 26.8±8.2 17.8±4.1 0.047 VC, ml 110±77 247±152 0.121 Graphics Conclusion The presence of severe MR, in this cohort of HFrEF patients, is associated with alveolar-capillary membrane remodeling (lower Dm), worse hemodynamic profile (higher PA pressures, lower PA compliance and higher PA resistance) and worse right ventricle to pulmonary circulation coupling (lower TAPSE/SPAP and lower 3D RV circumferential EF), confirming the use of therapeutic strategies aimed at correction of valvular disease.

Outcomes in Patients on Digoxin Following LVAD Implantation

Introduction Digoxin use within the heart failure population remains controversial, as studies have suggested increased arrhythmia risk and lower survival. Despite decades of use in heart failure, little is known regarding digoxin utilization post-left ventricular assist device (LVAD). We aimed to evaluate if digoxin use impacts overall survival or incidence of right ventricular (RV) failure after LVAD implantation. Methods Analysis was performed on 320 patients who underwent LVAD implantation from 2004-2017 and survived to hospital discharge. Patients were divided into groups based on digoxin utilization at discharge following LVAD placement. RV failure was defined as a composite of central venous pressure > 16mmHg or need for inotropic medication post-discharge or admission for intravenous diuretic therapy. Survival was assessed via Kaplan-Meier method and compared via log-rank test. Between group differences were assessed using independent sample t-tests and Fisher's exact tests. Results The cohort (n=320) had an average age of 56.2 (±13) years and contained 70 (21.9%) female patients. A majority ((n=129 (60%)) were implanted as destination therapy with 112 (35%) patients prescribed digoxin at the time of discharge (See Figure 1). Patients on digoxin were more likely to have a non-ischemic cardiomyopathy (p=0.002), had higher pulmonary vascular resistance (PVR) (p=0.03), and had larger left ventricular (p Conclusions Despite concerns about its continued use in different heart failure populations, overall survival was similar in LVAD patients with and without digoxin use at the time of initial discharge. A trend of reduced RV failure was present with digoxin use. Further studies are needed to fully elucidate the optimal patient population that may benefit from digoxin use following LVAD implantation.

Intratracheal SERCA2a Gene Therapy Interrupts the Formation of Plexiform Lesions and Rescues from Heart Failure in Severe Pulmonary Arterial Hypertension

Introduction Drugs fail to improve long term outcomes in pulmonary hypertension (PAH), especially survival in end stages. Severe PAH presents with deadly high pulmonary vascular resistance [PVR] due to the progression of irreversible plexiform lesions [PLX], resulting in heart failure [HF]. SERCA2a [S2A], a calcium handling protein, has been shown effective in PAH via reprogramming endothelial and vascular smooth muscle cells via improving pulmonary flow and disrupting neointimal proliferation. Preliminary S2A studies have shown efficacy in reducing mean PA pressure [mPAP], however in less severe PAH models without HF or PLX. Here, we used a severe surgical PAH HF model and evaluated S2A gene therapy. Hypothesis S2A gene therapy will reduce PVR and rescue from HF via reducing the degree of PLX. Methods Twenty rats were divided between control or treatment groups, n=10 ea. All rats were induced with severe PAH via left pneumonectomy combined with Sugen (25mg/kg). Grade 4 maximum plexiform lesions develop with mPAP >35 mmHg @ 3 weeks. AAV1.S2A was administered via intratracheal aerosol at 2.5 × 1012 VGC after 3 weeks. MRI was performed at baseline, 3 and 6 weeks terminal with invasive mPAP. Harvest assays performed: QPCR of AAV1.S2A genome copies, S2A expression, and PLX pathology. Results S2A rats survived at 80% compared to control 50%. QPCR detection was very high in 5 S2A animals [1314±858 GC/cell], remaining 3 with average 2.5 fold in pulmonary smooth muscle anatomy 1B. Unlike control, which presented with higher frequency Grade 4 PLX 1C, the majority of S2A specimens had Grade 1-3 with less occurrence of PLX 1D. Conclusion S2A gene therapy is effective in reducing the progression of PLX. Gene therapy may serve as an adjunctive option for severe PAH patients.

Current status of pulmonary arterial hypertension in Korea.

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the distal pulmonary arteries resulting in high pulmonary vascular resistance and, eventually, right ventricular heart failure. Although current advances in PAH therapy have improved outcomes, poor survival remains a reality worldwide, including Korea. One of the most important issues in PAH is the late diagnosis, since screening or diagnostic efforts are often overlooked due to the rarity of disease. Data from Korean registries and observational cohorts show that delayed detection leads to increased morbidity. Additionally, low percentages of Korean patients are committed to intensive PAH-targeted therapy. Current Korean health insurance policies’ lack of coverage for new PAH-targeted drugs and upfront combination therapy may also hamper the improvement of treatment outcomes. Understanding individual variability in response to therapeutics through deep phenotyping is a novel strategy that should be considered when treating PAH. Overall, early detection of PAH by proactive screening together with early, intensive, individualized PAH therapy using deep phenotyping is crucial for improving prognoses for PAH patients in Korea.

Continuous Hemodialysis Does Not Improve Graft Function During Ex Vivo Lung Perfusion Over 24 Hours

BackgroundExtended periods of ex vivo lung perfusion (EVLP) lead to several inadvertent consequences including accumulation of lactate and increasing electrolyte concentrations in the perfusate. We sought to determine whether continuous hemodialysis (CHD) of the perfusate would be a suitable modality for improving ionic homeostasis in extended EVLP without compromising functional outcomes. MethodsTwelve porcine lungs were perfused using EVLP for 24 hours. All lungs were ventilated with negative pressure ventilation. Lungs in the treatment group (n = 6) underwent continuous hemodialysis of the perfusate. Functional parameters, edema formation, and histopathologic analysis were used to assess graft function. Electrolyte and lactate profiles were also followed to assess the efficiency of hemodialysis. ResultsLungs in both treatment and control groups demonstrated stable and acceptable oxygenation to 24 hours. Lungs demonstrated a decrease in compliance over time. There was no difference in oxygenation and compliance between groups. CHD-EVLP lungs had higher pulmonary vascular resistance and pulmonary artery pressures. Despite increased perfusion pressures, weight gain at both 11 and 23 hours was not different between groups. Perfusate sodium and lactate concentrations were significantly lower in the CHD-EVLP group. ConclusionThe addition of continuous hemodialysis to EVLP did not improve graft function up to 24 hours despite improved maintenance of perfusate composition.

Fetal umbilical, cerebral and pulmonary blood flow patterns in relation to lung function and asthma in childhood. The Generation R Study.

BackgroundFetal growth restriction is associated with higher risks of childhood respiratory morbidity. Fetal blood flow adaptations might contribute to these associations. We examined the associations of fetal umbilical, cerebral, and pulmonary blood flow with wheezing patterns, lung function, and asthma in childhood.MethodsIn a population‐based prospective cohort study among 903 children, we measured fetal umbilical, cerebral, and pulmonary blood flow by pulsed‐wave Doppler at a median gestational age of 30.3 (95% range 28.8‐32.3) weeks. We obtained information about wheezing patterns until the age of 6 years by questionnaires. Lung function was measured by spirometry and information about current asthma was obtained by questionnaire at the age of 10 years.ResultsResults showed a non‐significant relationship between a higher umbilical artery pulsatility index (PI) and umbilical artery PI/cerebral artery PI ratio, indicating fetal blood flow redistribution at the expense of the trunk, with higher risks of early wheezing (OR [95% CI]: 2.07 (0.70‐6.10) and 2.74 (0.60, 12.62) per unit increase, respectively). A higher pulmonary artery time velocity integral, indicating higher pulmonary vascular resistance, was associated with a higher risk of late/persistent wheezing (Z‐score 1.14 [1.01‐1.29]). A higher middle cerebral artery PI was associated with a higher FEV1/FVC (Z‐score [95% CI]: 0.21 [0.01‐0.42]). Results did not materially change after additional adjustment for birth and growth characteristics.ConclusionThird‐trimester fetal blood flow patterns might be related to childhood respiratory health. These findings should be considered as hypothesis generating and need further replication.

Reduced Right Ventricular Output Reserve in Patients With Systemic Sclerosis and Mildly Elevated Pulmonary Artery Pressure.

This prospective study was undertaken to evaluate right ventricular function and pulmonary arterial compliance (PAC; ratio of stroke volume to pulse pressure) at rest and during exercise in patients with systemic sclerosis (SSc) with normal mean pulmonary artery pressure (PAP), patients with SSc with mildly elevated mean PAP, and patients with SSc with manifest pulmonary hypertension (PH). Patients with SSc (n = 112) underwent clinical assessment and right-sided heart catheterization at rest and during exercise and were divided into 3 groups according to their resting mean PAP values: normal mean PAP (≤20 mm Hg), mildly elevated mean PAP (21-24 mm Hg), and PH (mean PAP ≥25 mm Hg). Results were compared between groups by analysis of variance followed by post hoc Student's t-test. Compared to patients with normal mean PAP, patients with mildly elevated mean PAP had a lower 6-minute walking distance (P = 0.008), lower cardiac index (P = 0.027) and higher pulmonary vascular resistance (P = 0.0002) during exercise, and lower PAC at rest (P = 0.016) and different stages of exercise (P = 0.033 for 25W and P = 0.024 for 75W). The results of this study suggest that impaired 6-minute walking distance in SSc patients with mildly elevated mean PAP might be caused by reduced PAC during exercise and reduced right ventricular output reserve, presumably due to impaired coupling between the right ventricle and the pulmonary vasculature. These findings provide further evidence of the clinical relevance of mildly elevated mean PAP in patients with SSc.

High Transpulmonary Artery Gradient Obtained at the Time of Left Ventricular Assist Device Implantation Negatively Affects Survival After Cardiac Transplantation

Preoperatively elevated pulmonary vascular resistance (PVR) is a contraindication to heart transplantation (HT). Transpulmonary pressure gradient (TPG) is one of the main variables used in PVR determination (ie, PVR = TPG/cardiac output). Unlike PVR, which is subject to the shortcoming of cardiac output estimation, TPG is directly measured. We aimed to evaluate the relationship of TPG obtained before left ventricular assist device (LVAD) implantation on post-HT survival. A total of 490 patients were implanted with Heartmate II LVADs in the multicenter Heartmate II Bridge-to-Transplantation clinical trial, and 416/490 had pre-LVAD TPG data available. Outcomes during LVAD support and after HT stratified by both PVR and TPG were studied. The median pre-LVAD TPG was 10 mm Hg. Baseline demographic and clinical characteristics were similar for patients with and without TPG >10 mm Hg. Outcomes during LVAD support (ie, recovery to LVAD explantation, HT, or ongoing device support) for patients below and above the median TPG were similar. However, post-HT 1-year survival rate was significantly higher for patients with TPG ≤10 mm Hg compared with those with TPG >10 mm Hg (91% vs 80%; P = .016). Analysis based on the median PVR of 2.68 Wood units did not stratify post-HTx 1-year survival rates between the groups (89% vs 83%; P = .25). Elevated TPG, rather than high PVR, before LVAD implantation was associated with increased mortality following HT. Pre-LVAD TPG may be useful to identify a cohort that requires close follow-up with serial hemodynamic monitoring before HT.

Prone Positioning During Ex Vivo Lung Perfusion Influences Regional Edema Accumulation

BackgroundEx vivo lung perfusion (EVLP) is developed to increase the quantity and quality of suitable grafts for lung transplantation. Standardly, lungs are mounted supine with the risk of fluid accumulation in the dorsal regions. Therefore, we investigated the impact of experimental prone position on graft function during EVLP. Materials and methodsPorcine lungs were mounted on a normothermic EVLP for 6 h in supine [S], (n = 7) or prone position [P], (n = 7). Physiology during EVLP was recorded. After EVLP, biopsies were assessed for wet-to-dry weight (W/D) ratios and pathology, broncho-alveolar lavage was measured, and the left lung was computed tomography (CT) scanned. ResultsPhysiological parameters were similar between both groups, despite a higher pulmonary vascular resistance in [P] (P = 0.0002). In [S], W/D ratios and CT density of dorsal areas were higher compared to ventral (P = 0.0017 and P = 0.053, respectively). In [P], W/D and CT density between ventral and dorsal regions were similar, meaning that pulmonary edema was distributed more homogeneously throughout the lung. Histology and cytokine levels in perfusate and broncho-alveolar lavage did not differ between both groups. ConclusionsProne positioning during EVLP is feasible and leads to more homogenous distribution of interstitial fluid. Supine position resulted in more concentrated edema accumulation in lower dependent regions.

High Heart Rate and Pulmonary Vascular Resistance Predict Poor Prognosis after Referral for Lung Transplantation in Patients with Pulmonary Arterial Hypertension

Purpose Recent progress in the treatment of pulmonary arterial hypertension (PAH) such as high-dose epoprostenol and upfront combination therapy brought a marked improvement in prognosis of PAH. However, severely ill cases with PAH still need lung transplantation. Considering the first-come-first-served system and resulting long waiting period Japan, the timing of referral for lung transplantation is critical. Methods Consecutive 31 patients with PAH (including pulmonary veno-occlusive disease) referred to our hospital to be considered eligibility for lung transplantation were enrolled in this study. We retrospectively analyzed patients’ characteristics at referral for lung transplantation and their clinical outcomes. Results Seventeen of 31 patients (55%) were female and average age at referral was 30.6±11.8 year-old. Twenty-six patients were idiopathic/heritable PAH, 4 were connective tissue disease associated PAH and 1 was pulmonary veno-occlusive disease. They were referred to our hospital 2127±1691 days after diagnosis. All but one patients were introduced parenteral prostanoid. Mean received dose of parenteral prostanoid was 98±56 ng/kg/min at referral. Although their mean pulmonary artery pressure was severely elevated (51.1±11.6 mmHg), cardiac index and six-minute walk distance were relatively maintained (3.63±0.98 L/min/m2 and 394±174m, respectively). Two patients were not registered as candidates for lung transplantation for medical or social reason. Three patients underwent successful lung transplantation, while eight patients died on the waiting list. Three-year survival after referral was 67% in total. Multivariate analysis revealed that heart rate (HR) and pulmonary vascular resistance (PVR) were independent predictors of all-cause mortality after referral (p=0.016 and p=0.016, respectively). Conclusion High HR and PVR are independent predictors of mortality in patients with PAH receiving parenteral prostanoid and awaiting lung transplantation. Although high-dose parenteral prostanoid improved hemodynamics in patients with PAH, the high output status and relatively maintained exercise capacity might have delayed referral for lung transplantation.

Cardiac Transplantation Primary Graft Dysfunction Incidence and Predictors

Purpose Primary graft dysfunction (PGD) is the leading cause of mortality within 30 days following heart transplantation (HT). We sought to identify the incidence and outcomes of PGD in our HT population. Methods We reviewed peri-operative clinical data of consecutive patients who underwent HT at our center (10/2012 - 12/2016). Using the 2014 ISHLT PGD definition and classification, PGD patients were identified and further classified into mild (MILD-PGD), moderate (MOD-PGD), and severe (SEV-PGD) left ventricular PGD. For each PGD patient, further data obtained included comorbidities, pre-transplant hemodynamics, donor information (comorbidities, hemodynamics cause of death), ischemic time, intra-operative bleeding and transfusion requirements, and peri-operative renal and hepatic function. RADIAL scores were calculated for all studied PGD patients. Results Of our 181 HT patients, 29 patients developed PGD (16%), of which 21% were MILD-PGD, 27% were MOD-PGD, and 52% were SEV-PGD. Before HT, 17/29 of patients were on amiodarone. Further, 7/15 of the SEV-PGD patients had mechanical circulatory support (MCS; 6 LVAD/ 1 TAH), and 4/8 of MOD-PGD patients had MCS (3 LVAD/ 1 TAH). The pre-operative right atrial pressures were higher in SEV-PGD patients when compared to MILD-PGD (p=0.003) and when compared to MOD-PGD (p=0.004). More SEV-PGD patients had a higher donor inotrope requirement (87%) than the MOD-PGD patients (38%; p=0.026) or the MILD-PGD patients (33%; p=0.031). They also had a higher intra-operative blood loss than the MILD-PGD group (p=0.0197). With respect to MOD-PGD, SEV-PGD had a higher pulmonary vascular resistance (p=0.0481). There was no difference in RADIAL scores between groups. Survival to hospital discharge was 79%. Three of the 29 PGD patients died within 30 days; and within one year, 7/29 patients died. Of the 7 deceased patients, 6 had SEV-PGD and 1 had MOD-PGD. In addition, SEV-PGD had earlier post-operative hemodynamic decline compared with MILD-PGD (p Conclusion Among HT patients with PGD, pre-operative right atrial pressure, pulmonary vascular resistance, donor inotrope requirement, and intra-operative blood loss are predictive of the development of SEV-PGD. No differences in RADIAL scores were found.

Post-Implant Phosphodiesterase-5 Inhibitor Use is Associated with Increased Rates of Late Right Heart Failure after LVAD: An INTERMACS Analysis

Purpose Late right heart failure (LRHF) is a major cause of morbidity after LVAD. Phosphodiesterase-5 inhibitors (PDE5i) are often used for post-LVAD right heart dysfunction, but their impact on LRHF is unknown. Methods We identified adult patients from the INTERMACS registry undergoing continuous-flow LVAD (CFLVAD) after 2012 and stratified them by use of PDE5i at 1 month. Early RHF (ERHF) was defined as the need for RVAD within 1 month or inotropes for > 2 weeks. Among patients surviving > 1 month after discharge from the index LVAD implant, LRHF was defined as any of the following: death from RHF, need for RVAD or inotropes, re-hospitalization for RHF or volume overload , or fulfilling INTERMACS criteria of documentation and manifestation of RHF. Freedom from LRHF was compared with the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 9627 CFLVAD patients surviving >1 month after discharge, 2463 (26%) were treated with PDE5i at 1 month. Patients on PDE5i were more likely to require >2 weeks of inotropic support (27% vs 14%), be INTERMACS Profile 1 or 2 (52% vs 46%), and have higher pulmonary vascular resistance (2.8 vs 2.2 WU), p Conclusion Irrespective of ERHF, post-implant PDE5i use is associated with an increased risk of LRHF after LVAD. Further studies are required to determine if selective pulmonary vasodilator therapy has a role in preventing LRHF after LVAD.

Continuous Hemodialysis during Ex Vivo Lung Perfusion Allows for Improved Maintenance of Perfusate Composition, without Compromising Functional Performance

Purpose Extended periods of ex vivo lung perfusion (EVLP) lead to several inadvertent consequences including accumulation of lactate and increasing electrolyte concentrations in the perfusate. Cellular perfusate based systems, such as the OCS Lung and Vivoline LS1, require a membrane-exchange system for electrolyte correction if they are to maintain a desired perfusate hemoglobin concentration. We sought to determine whether continuous hemodialysis (CHD) of the perfusate would be a suitable modality for improving ionic homeostasis in extended EVLP without compromising functional outcomes. Methods Twelve porcine lungs were perfused using EVLP for 24 hours. Lungs in the treatment group (n=6) underwent continuous hemodialysis of the perfusate. Functional parameters, edema formation, inflammatory cytokines and histopathologic analysis were used to assess graft function. Electrolyte and lactate profiles were also followed to assess the efficiency of hemodialysis. Results Lungs in both treatment and control groups demonstrated stable and acceptable oxygenation for 24 hours. Lungs demonstrated stable compliance over the first 18 hours, followed by a slow decline over the last 6 hours of perfusion. There was no difference in oxygenation and compliance between groups. CHD-EVLP lungs had higher pulmonary vascular resistance and pulmonary artery pressures. Despite increased perfusion pressures, weight gain at both 12 and 24 hours was not different between groups. Perfusate sodium and lactate concentrations were significantly lower in the CHD-EVLP group. TNF-α, IL-6, and IL-8 perfusate concentrations were similar between groups. Histopathologic assessment of lung injury did not differ between groups. Conclusion The addition of continuous hemodialysis to EVLP allows for stable functional performance up to 24 hours and improved physiologic perfusate composition despite increased perfusion pressures.

Relation of Macrophage Migration Inhibitory Factor to Pulmonary Hemodynamics and Vascular Structure and Carbamyl-Phosphate Synthetase I Genetic Variations in Pediatric Patients with Congenital Cardiac Shunts.

Macrophage migration inhibitory factor (MIF) plays an important pathophysiological role in pulmonary hypertension (PHT). Previously, we demonstrated that serum MIF is increased in pediatric PHT associated with congenital heart disease (CHD). In the present study, we determined possible associations between MIF levels, hemodynamic and histological parameters, and mitochondrial carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism in a similar population. The asparagine 1405 variant (related to A alleles in the C-to-A transversion) has been shown to be advantageous in pediatric PHT compared to the threonine 1405 variant (C alleles). Forty-one patients were enrolled (aged 2-36 months) and subsequently divided into 2 groups after diagnostic evaluation: the high-pulmonary blood flow (high PBF) group (pulmonary-to-systemic blood flow ratio 2.58 (2.21-3.01), geometric mean with 95% CI) and the high-pulmonary vascular resistance (high PVR) group (pulmonary vascular resistance 6.12 (4.78-7.89) Wood units × m2). Serum MIF was measured using a chemiluminescence assay. The CPSI polymorphism was analyzed by polymerase chain reaction followed by high-resolution melting analysis. Medial hypertrophy of pulmonary arteries was assessed by the histological examination of biopsy specimens. Serum MIF was elevated in patients compared to controls (p = 0.045), particularly in the high-PVR group (n = 16) (p = 0.022) and in subjects with the AC CPSI T1405N genotype (n = 16) compared to those with the CC genotype (n = 25) (p = 0.017). Patients with high-PVR/AC-genotype profile (n = 9) had the highest MIF levels (p = 0.030 compared with the high-PBF/CC-genotype subgroup, n = 18). In high-PVR/AC-genotype patients, the medial wall thickness of intra-acinar pulmonary arteries was directly related to MIF levels (p = 0.033). There were no patients with the relatively rare AA genotype in the study population. Thus, in the advantageous scenario of the asparagine 1405 variant (AC heterozygosity in this study), heightened pulmonary vascular resistance in CHD-PHT is associated with medial hypertrophy of pulmonary arteries where MIF chemokine very likely plays a biological role.