High Pulmonary Vascular Resistance Research Articles

Liposomal Delivery of a Phosphodiesterase 5 Inhibitor Enhances Prostacyclin-Mediated Adenosine Triphosphate Release from Human Red Blood Cells

Pulmonary arterial hypertension (PAH) is characterized by high pulmonary vascular resistance (PVR) and right heart failure. Red blood cells (RBCs) of PAH patients fail to release the vasodilator, adenosine triphosphate (ATP), when deformed as would occur when traversing the lung. Such a defect could contribute to increased PVR. However, RBCs of PAH patients do release ATP in response to prostacyclin (PGI2) analogs and this is augmented by phosphodiesterase 5 (PDE5) inhibitors. Current PAH treatment includes PGI2 analogs and PDE5 inhibitors alone or in combination. Unfortunately, these drugs can have untoward side effects. Encapsulation of drugs within liposomes (small lipid-membraned vesicles) that can be targeted to RBCs has been shown to increase effectiveness and tolerability of some medications.The objective of this study was to determine if encapsulation of the PDE5 inhibitor zaprinast (ZAP) within liposomes is an effective means to deliver this class of drugs to human RBCs and if this approach would augment ATP release stimulated by the PGI2 analog UT-15c. Human RBCs were isolated and incubated with either blank liposomes (n=10), liposomes containing ZAP (n=9) or liposomes containing the PDE3 inhibitor, cilosatzol (CILO, n=10). RBCs (20% hematocrit) were then treated with UT-15c (1 µM). ATP release was measured before and 5, 10, and 15 min after the addition of UT-15c. In the presence of empty liposomes, the dose of UT-15c used did not stimulate ATP release. However, UT-15c did stimulate ATP release from RBCs pretreated with ZAP encapsulated by liposomes (P<0.01). The average time for maximal release was 9 ± 1 min. In contrast, when exposed to liposomes containing CILO, there was no ATP release following UT-15c administration.These studies demonstrate that the selective delivery of a PDE5 inhibitor to human RBCs potentiates UT-15c induced ATP release. Moreover the findings are consistent with the hypothesis that directed delivery of this class of drugs to PAH RBCs could be a new and important method to augment PGI2 analog-induced ATP release from these cells. Such an approach could significantly limit side effects of both drugs without compromise of their therapeutic effectiveness in PAH. DisclosuresNo relevant conflicts of interest to declare.

Prevalence of Coronary Artery to Pulmonary Artery Collaterals in Patients with Chronic Thromboembolic Pulmonary Hypertension: Retrospective Analysis from a Single Center.

Our aim was to determine the prevalence of coronary artery - pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension (CTEPH) by retrospectively evaluating coronary angiograms of eligible consecutive patients who had undergone pulmonary endarterectomy (PEA). We also aimed to evaluate predictors and potential clinical associates of these collaterals. Coronary angiograms of 83 consecutive CTEPH patients who had undergone coronary angiography before PEA operation between January 1, 2012 and June 1, 2015 were retrospectively evaluated for presence of coronary artery - pulmonary artery collaterals. Medical records of all patients were also retrospectively reviewed for demographic information, cardiovascular risk factors, preoperative right heart catheterization reports, operation reports, and follow-up data. Data of CTEPH patients with coronary artery - pulmonary artery collaterals were compared with data of CTEPH patients without such collaterals. There were 15 patients (18.1%) with definite and 4 patients (4.8%) with probable coronary artery - pulmonary artery collaterals among the study population. CTEPH patients with collaterals had higher preoperative pulmonary artery pressures, higher pulmonary vascular resistance (PVR) and lower cardiac index values compared with CTEPH patients without collaterals. However, CTEPH patients with collaterals displayed higher amount of reduction in PVR after PEA compared with patients without collaterals. There were no significant differences between groups regarding incidence of reperfusion injury or mortality. Prevalence of coronary artery - pulmonary artery collaterals seems to be increased in our CTEPH patients compared with the general population. The presence of coronary artery - pulmonary artery collaterals is often combined with proximal disease with the possibility of increased reduction of PVR after PEA operation.

Pulmonary and Systemic Vascular Resistances After Cardiopulmonary Bypass: Role of Hemolysis

Prolonged cardiopulmonary bypass (CPB) is associated with hemolysis, resulting in increased plasma oxyhemoglobin and vascular nitric oxide depletion. The authors hypothesized that hemolysis associated with CPB would reduce nitric oxide bioavailability, resulting in high pulmonary and systemic vascular resistances that after CPB would normalize gradually over time, due to clearance of plasma oxyhemoglobin. The authors also investigated whether prolonged CPB (≥140 min) produced increased levels of hemolysis and greater pulmonary and systemic vasoconstriction. Prospective cohort study. Single-center university hospital. The study comprised 50 patients undergoing elective cardiac surgery requiring CPB. Plasma hemoglobin and plasma nitric oxide consumption were measured before surgery and after CPB. Pulmonary and systemic hemodynamics were measured after CPB. The effects of short (<140 min) and prolonged (≥140 min) CPB on these parameters were considered. Pulmonary and systemic vascular resistances and plasma hemoglobin and nitric oxide consumption were highest at 15 minutes after CPB and then decreased over time. Pulmonary and systemic vascular resistances and plasma hemoglobin and plasma nitric oxide consumption were higher in patients requiring prolonged CPB. The reduction in plasma nitric oxide consumption from 15 minutes to 4 hours after CPB was correlated independently with the reductions in pulmonary and systemic vascular resistances. Prolonged CPB was associated with increased plasma hemoglobin and plasma nitric oxide consumption and pulmonary and systemic vascular resistances. The reduction in plasma nitric oxide consumption at 4 hours after CPB was an independent predictor of the concomitant reductions in pulmonary and systemic vascular resistances.

Moderate-to-severe obstructive sleep apnea is associated with subclinical myocardial injury and impaired hemodynamics in pulmonary hypertension patients

BackgroundThe clinical significance of obstructive sleep apnea (OSA) in pulmonary hypertension (PH) patients remains unclear. We investigated the hemodynamics and serum troponin T concentrations associated with OSA in PH patients. MethodsCross-sectional study was performed on data from 97 clinically stable PH patients. Using overnight sleep study, we evaluated apnea–hypopnea index (AHI) and divided patients into two groups: none-to-mild OSA (AHI < 15/h, N = 81) and moderate-to-severe OSA (AHI ≥ 15/h, N = 16). Clinical, hemodynamic, and laboratory data were compared with OSA severity. ResultsModerate-to-severe OSA patients had higher pulmonary vascular resistance (PVR; 6.5 [5.7–12.9] vs 4.4 [2.9–6.4] Wood units, p = 0.001) and mean pulmonary artery pressure (mPAP; 37 [30–49] vs 30 [22–37] mmHg, p = 0.045), and a lower cardiac index (2.2 [1.6–2.6] vs 2.8 [2.3–3.5] L/min/m2, p = 0.001) than those without. There was no association between plasma B-type natriuretic peptide (BNP) or serum C-reactive protein levels and OSA. However, high-sensitivity troponin T (hs-TnT) level was significantly higher in moderate-to-severe OSA patients (13 [8–18] vs 6 [4–10] ng/L, p < 0.001). The hs-TnT level positively correlated with the plasma BNP level, mPAP, PVR, AHI, obstructive apnea index, and 6-min walking distance. After adjustment for age, estimated glomerular filtration rate, hypertension, smoking, and plasma BNP level, moderate-to-severe OSA was an independent factor for determining the plasma level of log hs-TnT level (β = 0.419, 95% confidence interval 0.119–0.718, p = 0.007). ConclusionsModerate-to-severe OSA is associated with impaired hemodynamics and subclinical myocardial damage in PH patients. Thus, OSA-related myocardial injury may play a role in hemodynamic destabilization with its associated poor prognosis.

Severity of Pulmonary Hypertension and Obesity are Not Associated with Worse Functional Outcomes after Pulmonary Thromboendarterectomy

Predictors of functional outcomes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary thromboendarterectomy (PTE) are important to identify preoperatively. We hypothesized that baseline severity of pulmonary hypertension and obesity would not be associated with 6-month functional outcomes after PTE. Clinical and hemodynamic data were collected on consecutive patients undergoing PTE from 2008 to 2014. Patients were stratified according to baseline pulmonary vascular resistance (PVR) and body mass index (BMI). Six-minute walk distance (6MWD), New York Heart Association functional class (FC), and echocardiography were assessed in each group at baseline and 6 months after PTE. Regression analyses were performed to evaluate for associations between functional outcomes and baseline PVR and BMI. Forty-two patients underwent PTE and had 6-month follow up data. In comparisons of patients with high and low baseline PVR, the baseline characteristics, distribution of disease, 6MWD, and FC were similar. Postoperative hemodynamics for both groups were similar. At 6 months, both groups achieved improvements in FC, and there were no between-group differences in the change in 6MWD or FC. In comparisons of obese and nonobese patients, perioperative and FC improvement were similar; however, obese patients achieved a greater improvement in 6MWD than nonobese patients (P = 0.04). In conclusion, our data suggest that baseline severity of CTEPH and obesity were not associated with worse functional outcome. Further studies are needed to confirm these results, as these findings could have implications for patient selection for PTE.

(790) - Heterotopic Heart Transplantation in Argentina

The presence of irreversible pulmonary hypertension and/ or anthropometric significant differences between donor and recipient (> 20%) are one of the main constraints in the selection of suitable donors to enable the completion of a successful orthotopic heart transplant. The use of pre-transplant ventricular assistance or the selection of heavier donors, and the heterotopic heart transplantation (HHTx) had been considered in different transplant programs to try to overcome this drawback and also as a bridge to recovery. We present here our experience in HHTx. In an attempt to address this issue we evaluate our experience in 11 HHTx performed at our institution between 2001 and 2013, in 10 patients [8 Males (73 %), 3 Females (27 %); Age 42.5 ± 15 years (18/65)]; one patient (Pts) received a second HHTx at 15 month post first HTxC. Pre transplant diagnosis were: idiopathic dilated cardiomyopathy 7 Pts (63.6%), necrotic dilated cardiomyopathy 1 Pts (9.1%), Chagas cardiomyopathy 1 Pts (9.1%), hypothyroid cardiomyopathy 1 Pts (9.1%) and graft vascular disease 1 Pts (9.1%). Three of the recipients were in national emergency waiting list at the time of transplantation, 2 in urgency and 6 in elective lists. The donor / recipient selection criteria was done taking in account significant high pulmonary vascular resistances and / or anthropometric mismatch, and/or sex mismatch. In all Pts the donor pulmonary artery was anastomosed to the recipient right atrium without the use of any prosthetic material to spare the donor right ventricle and assisting recipient’s left ventricle using the recipient right ventricle to support the pulmonary circulation. Proper synchronization between the two hearts was performed using pacemakers. Ischemic times varied between 76 and 245 minutes (mean 184.1 ± 57.8). Standard immunosuppression scheme was used. The actuarial survival including hospital mortality was 67% at one year and 56% at 5 years. The average follow-up of patients was 4.46 years, and longer survival reached is 13.6 years. All patients who survive more than 3 month returned to normal life. Several attempts to perform HHTx in our country failed using the conventional surgical technic. In our experience, applying the technic described by Yacoub and Khaghani, we consider that is feasible for a selected group of patients with acceptable medium term results.

Pulmonary Hypertension After Heart Transplantation in Patients Bridged with the Total Artificial Heart.

Pulmonary hypertension (PH) among heart transplant recipients is associated with an increased risk of mortality. Pulmonary hemodynamics improves after left ventricular assist device (LVAD) implantation; however, the impact of PH before total artificial heart (TAH) implantation on posttransplant hemodynamics and survival is unknown. This is a single center retrospective study aimed to evaluate the impact of TAH implantation on posttransplant hemodynamics and mortality in two groups stratified according to severity of PH: high (≥3 Woods units [WU]) and low (<3 WU) baseline pulmonary vascular resistance (PVR). Hemodynamic data were obtained from right heart catheterization performed at baseline (before TAH) and posttransplant at 1 and 12 months. Patients in the high PVR group (n = 12) experienced improvement in PVR (baseline = 4.31 ± 0.7; 1-month = 1.69 ± 0.7, p < 0.001; 12-month = 48 ± 0.9, p < 0.001) and transpulmonary gradient (baseline = 15.8 ± 3.3; 1-month = 11.57 ± 5.0, p = 0.07; 12-month = 8.50 ± 4.0, p = 0.008) after transplantation, reaching similar values as the low PVR group at 12 months. The filling pressures improved in the high PVR group after heart transplantation (HT), but remained elevated. There was no significant difference in survival between the two groups at 12 months follow-up. Patients with high PVR who are bridged to transplant with TAH had improvement in PVR at 12 months after transplant, and the degree of PVR did not impact posttransplant survival.

Serum Cytokines in Young Pediatric Patients with Congenital Cardiac Shunts and Altered Pulmonary Hemodynamics.

Background and Objective. Inflammation is central in the pathogenesis of pulmonary hypertension. We investigated how serum cytokines correlate with clinical features, hemodynamics, and lung histology in young patients with pulmonary hypertension associated with congenital cardiac shunts. Design. Prospective, observational study. Methods and Results. Patients (n = 44) were aged 2.6 to 37.6 months. Group I patients (n = 31) were characterized by pulmonary congestion and higher pulmonary blood flow compared to group II (p = 0.022), with no need for preoperative cardiac catheterization. Group II patients (n = 13) had no congestive features. At catheterization, they had elevated pulmonary vascular resistance (5.7 [4.4–7.4] Wood units·m2, geometric mean with 95% CI). Cytokines were measured by chemiluminescence. Macrophage migration inhibitory factor (MIF) was found to be inversely related to pulmonary blood flow (r = −0.33, p = 0.026) and was higher in group II (high pulmonary vascular resistance) compared to group I (high pulmonary blood flow) (p = 0.017). In contrast, RANTES chemokine (regulated on activation, normal T cell expressed and secreted) was characteristically elevated in Group I (p = 0.022). Interleukin 16 was also negatively related to pulmonary blood flow (r S = −0.33, p = 0.029) and was higher in patients with obstructive vasculopathy at intraoperative lung biopsy (p = 0.021). Conclusion. Cytokines seem to be important and differentially regulated in subpopulations of young patients with cardiac shunts.

Age-related upper limits of normal for maximum upright exercise pulmonary haemodynamics.

The exercise definition of pulmonary hypertension was eliminated from the pulmonary hypertension guidelines in part due to uncertainty of the upper limits of normal (ULNs) for exercise haemodynamics in subjects >50 years old.The present study, therefore, evaluated the pulmonary haemodynamic responses to maximum upright incremental cycling exercise in consecutive subjects who underwent an invasive cardiopulmonary exercise testing for unexplained exertional intolerance, deemed normal based on preserved exercise capacity and normal resting supine haemodynamics. Subjects aged >50 years old (n=41) were compared with subjects ≤50 years old (n=25). ULNs were calculated as mean + 2 sdPeak exercise mean pulmonary arterial pressure was not different for subjects >50 and ≤50 years old (23 ± 5 versus 22 ± 4 mmHg, p=0.22), with ULN of 33 and 30 mmHg, respectively. Peak cardiac output was lower in older subjects (median (interquartile range): 12.1 (9.4-14.2)versus16.2 (13.8-19.2) L·min(-1), p<0.001). Peak pulmonary vascular resistance was higher in older subjects compared with younger subjects (mean ± sd: 1.20 ± 0.45 versus 0.82 ± 0.26 Wood units, p<0.001), with ULN of 2.10 and 1.34 Wood units, respectively.We observed that subjects >50 and ≤ 50 years old have different pulmonary vascular responses to exercise. Older subjects have higher pulmonary vascular resistance at peak exercise, resulting in different exercise haemodynamics ULNs compared with the younger population.

Serum Bilirubin and 6-min Walk Distance as Prognostic Predictors for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Prospective Cohort Study.

Background:Inoperable chronic thromboembolic pulmonary hypertension (CTEPH) is a severe clinical syndrome characterized by right cardiac failure and possibly subsequent liver dysfunction. However, whether serum markers of liver dysfunction can predict prognosis in inoperable CTEPH patients has not been determined. Our study aimed to evaluate the potential role of liver function markers (such as serum levels of transaminase, bilirubin, and gamma-glutamyl transpeptidase [GGT]) combined with 6-min walk test in the prediction of prognosis in patients with inoperable CTEPH.Methods:From June 2005 to May 2013, 77 consecutive patients with inoperable CTEPH without confounding co-morbidities were recruited for this prospective cohort study. Baseline clinical characteristics and 6-min walk distance (6MWD) results were collected. Serum biomarkers of liver function, including levels of aspartate aminotransferase, alanine aminotransferase, GGT, uric acid, and serum bilirubin, were also determined at enrollment. All-cause mortality was recorded during the follow-up period.Results:During the follow-up, 22 patients (29%) died. Cox regression analyses demonstrated that increased serum concentration of total bilirubin (hazard ratio [HR] = 7.755, P < 0.001), elevated N-terminal of the prohormone brain natriuretic peptide (HR = 1.001, P = 0.001), decreased 6MWD (HR = 0.990, P < 0.001), increased central venous pressure (HR = 1.074, P = 0.040), and higher pulmonary vascular resistance (HR = 1.001, P = 0.018) were associated with an increased risk of mortality. Serum concentrations of total bilirubin (HR = 4.755, P = 0.007) and 6MWD (HR = 0.994, P = 0.017) were independent prognostic predictors for CTEPH patients. Patients with hyperbilirubinemia (≥23.7 μmol/L) had markedly worse survival than those with normobilirubinemia.Conclusion:Elevated serum bilirubin and decreased 6MWD are potential predictors for poor prognosis in inoperable CTEPH.

Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.

High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.

The right heart in heart failure with preserved ejection fraction: insights from cardiac magnetic resonance imaging and invasive haemodynamics.

Recent data indicate that right ventricular systolic dysfunction (RVSD) by cardiac magnetic resonance imaging (CMR) is a strong predictor of outcome in heart failure. However, the prognostic significance of RVSD by CMR in heart failure with preserved ejection fraction (HFpEF) is unknown. We prospectively enrolled 171 HFpEF patients who underwent CMR in addition to invasive and non-invasive testing. RVSD, defined as right ventricular (RV) EF <45% by CMR, was present in 33 (19.3 %) patients. Patients were followed for 573 ± 387 days, during which 41 had a cardiac event. Patients with RVSD presented with more frequent history of AF (P = 0.038), significantly higher resting heart rate (P = 0.009), shorter 6-min walk distance (P = 0.036), and higher NT-pro BNP serum levels (P < 0.001), and were more symptomatic (P < 0.001). With respect to haemodynamic parameters, RVSD was associated with respect to haemodynamic parameters, RVSD was associated with higher diastolic pulmonary artery pressure (P = 0.045), with higher pulmonary vascular resistance (P = 0.048), higher transpulmonary gradient (P = 0.042), and higher diastolic pulmonary vascular pressure gradient (P = 0.007). In the multivariable Cox analysis, RVSD (P < 0.001) remained significantly associated with cardiac events, in addition to diabetes (P = 0.011), 6-min walk distance (P = 0.018), and systolic pulmonary artery pressure (P = 0.003). Although HFpEF is considered a disease of the left ventricle, respective imaging parameters are not related to outcome. In contrast, RVSD by CMR is independently associated with mortality and clinical status in these patients, and provides a useful tool for risk stratification.

ASSOCIATION BETWEEN THE DIASTOLIC PULMONARY GRADIENT, TRANSPULMONARY GRADIENT AND PULMONARY VASCULAR RESISTANCE AND MORTALITY IN PATIENTS WITH PULMONARY HYPERTENSION UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION

Pulmonary hypertension (PH) in aortic stenosis is complex, consisting of both pre and post-capillary components. While it has been associated with worse outcomes in patients after transcatheter aortic valve implantation (TAVI), the degree to which measures of pre-capillary pulmonary hypertension--such as the diastolic pulmonary gradient (DPG), transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR)--influence outcomes is unknown. We evaluated the association between these 3 parameters and mortality in patients with PH undergoing TAVI. This was a retrospective cohort study involving patients with PH undergoing TAVI. We identified all patients at our institution that underwent TAVI from 2005 to 2014, with a baseline right heart catheterization (RHC) demonstrating PH (mean pulmonary artery pressure > 25 mmHg). We excluded patients without complete hemodynamic data. Mortality was determined by phone interview. We evaluated the association between high DPG (DPG≥7mmHg), high TPG (TPG>12mmHg) and high PVR (PVR>3WU) and mortality in both a univariate and multivariate analysis. The multivariate analysis included age, gender, body mass index and pulmonary artery systolic pressure on echocardiogram. We identified 133 patients who met inclusion criteria. The mean age was 80.3±8.4 years, and 47% of the population was female. Of the total cohort, 111 had low DPG and 22 had high DPG. When comparing the baseline echocardiogram to RHC, the correlation in pulmonary pressure was not strong (r=0.6). Patients with high DPG had higher mean pulmonary artery pressures (41.5±9.0 vs. 37.1±8.1 mmHg, P=0.04) and lower wedge pressures (16.8±5.6 vs. 24.8±6.1 mmHg, P<0.001). The mean duration of follow up was 21.0±19.0 months. In our univariate analysis, high DPG, TPG and PVR were all associated with higher mortality post TAVI, with HR of 2.1 (95% CI 1.1-3.9, P=0.02), 3.4 (95% CI 1.8-6.4, P<0.001) and 2.5 (95% CI 1.4-4.5, P=0.003), respectively. In our multivariate analysis, both high TPG and PVR remained predictors of mortality, with HR of 3.4 (95% CI 1.7-6.9, P=0.001) and 2.1 (95% CI 1.1-4.1, P=0.04), respectively. Echocardiographic pulmonary artery systolic pressure was not predictive of mortality in either of these models. High DPG was not associated with mortality in our multivariate analysis, with a HR of 1.8 (95% CI 0.9-3.7, P=0.1). Parameters reflecting pre-capillary PH on RHC are associated with mortality in patients undergoing TAVI. The DPG did not appear more predictive of mortality compared to TPG and PVR. Further prospective studies are warranted to explore this association.

High pulmonary vascular resistance in addition to low right ventricular stroke work index effectively predicts biventricular assist device requirement.

Although the right ventricular stroke work index (RVSWI) is a good index for RV function, a low RVSWI is not necessarily an indicator for the need for a right ventricular assist device at the time of left VAD implantation. We here aimed to determine a more precise indicator for the need for a biventricular assist device (BiVAD). In total, 116 patients (mean age, 38 ± 14 years), who underwent hemodynamic assessments preoperatively including 12 BiVAD patients, and had been followed at our institute from 2003 to 2015, were included. Multivariate logistic regression analysis indicated that RVSWI and pulmonary vascular resistance (PVR) were independent predictors of BiVAD requirement (P < 0.05 for both). In addition, all patients were classified into 4 groups: (1) normal (RVSWI > 5 g/m, PVR < 3.7 WU), (2) pulmonary hypertension (RVSWI > 5, PVR > 3.7), (3) RV failure (RVSWI < 5, PVR < 3.7), and (4) both pulmonary hypertension and RV failure (RVSWI < 5, PVR > 3.7), and examined. Most of the patients in Group 4 (75 %), with acutely depressed hemodynamics and inflammatory responses in the myocardium, required BiVAD. Overall, patients with BiVAD had a worse survival rate as compared with those with LVAD alone. In conclusion, high PVR in addition to low RVSWI effectively predicts BiVAD requirement.

Maternal-pup interaction disturbances induce long-lasting changes in the newborn rat pulmonary vasculature.

The factors accounting for the pathological maintenance of a high pulmonary vascular (PV) resistance postnatally remain elusive, but neonatal stressors may play a role in this process. Cross-fostering in the immediate neonatal period is associated with adult-onset vascular and behavioral changes, likely triggered by early-in-life stressors. In hypothesizing that fostering newborn rats induces long-lasting PV changes, we evaluated them at 14 days of age during adulthood and compared the findings with animals raised by their biological mothers. Fostering resulted in reduced maternal-pup contact time when compared with control newborns. At 2 wk of age, fostered rats exhibited reduced pulmonary arterial endothelium-dependent relaxation secondary to downregulation of tissue endothelial nitric oxide synthase expression and tetrahydrobiopterin deficiency-induced uncoupling. These changes were associated with neonatal onset-increased ANG II receptor type 1 expression, PV remodeling, and right ventricular hypertrophy that persisted into adulthood. The pulmonary arteries of adult-fostered rats exhibited a higher contraction dose response to ANG II and thromboxane A2, the latter of which was abrogated by the oxidant scavenger Tempol. In conclusion, fostering-induced neonatal stress induces long-standing PV changes modulated via the renin-angiotensin system.

Right Ventricular Outflow Tract Doppler Envelope Notching Predicts Pulmonary Vascular Resistance in Patients with Advanced Liver Disease

Portopulmonary hypertension (POPH) affects 6% of liver transplant (LT) candidates and is associated with poor outcomes. Screening for POPH with a transthoracic echocardiogram (TTE) is the standard of care, but diagnosis requires right heart catheterization (RHC) which carries risks in pts with advanced liver disease (ALD). Systolic deceleration or “notching” of the right ventricular outflow tract Doppler flow velocity envelope (FVERVOT) correlates with high pulmonary vascular resistance (PVR) in mixed pulmonary hypertension (PH) but has not been validated in pts with ALD. The ratio of peak tricuspid regurgitant velocity (TRV, m/s) and time-velocity integral of the RVOT (TVIRVOT) per the formula PVR=TRV/TVIRVOT x 10 has been shown to reliably estimate PVR. We investigated whether PVR can be predicted by the shape of FVERVOT or estimated by the TRV/TVIRVOT ratio in pts undergoing evaluation for LT. We included 100 pts who underwent RHC and TTE as part of LT evaluation from 01/10 to 03/15. Median time between the two tests was 5 days. We categorized the shape of FVERVOT as no (NN), late-systolic (LSN) or mid-systolic (MSN) notching. Unpaired t-tests were used to compare sample means for continuous variables and linear regression analysis to test the correlation between invasive and non-invasive PVR. The mean patient age was 57±8.5 years; 50% were male with diverse etiologies of ALD (35% HCV, 21% alcoholic, 10% cryptogenic, 6% NASH, 4% autoimmune, 24% other) and 79% were transplanted. The prevalence of POPH as defined by PVR≥3 on RHC was 12%. Elevated systolic pulmonary artery pressure (PAPs≥40mmHg) on TTE was present in 54% and mean PAP≥25mmHg on RHC in 24%. The shape of the FVERVOT Doppler exhibited NN in 81%, LSN in 10% and MSN in 9%. Pts with either LSN or MSN had higher mean PAP than those with NN (28±9 vs 35±11mmHg, p=0.007) and higher transpulmonary gradient (TPG), diastolic pulmonary gradient (DPG) and PVR; the difference between LSN and MSN was not significant. TAPSE was lower in pts with LSN or MSN compared to NN (Fig 1), and non invasively estimated PVR was higher (1.8±0.5 vs 1.4±0.5 WU, p=0.003). Poor correlation was observed between noninvasive and invasive PVR (R2=0.10, p=0.001). RVOT notching and non-invasive PVR were poor predictors of mortality. Elevated PAPs on TTE was a sensitive but not specific screening tool for PVR≥3 (Sn=82%, Sp=48%). RVOT Doppler flow velocity notching reliably predicts POPH in pts with ALD.

Numerical Simulation of a Biventricular Assist Device with Fixed Right Outflow Cannula Banding During Pulmonary Hypertension.

As a left ventricular assist device is designed to pump against the systemic vascular resistance (SVR), pulmonary congestion may occur when using such device for right ventricular support. The present study evaluates the efficacy of using a fixed right outflow banding in patients receiving biventricular assist device support under various circulatory conditions, including variations in the SVR, pulmonary vascular resistance (PVR), total blood volume (BV), as well as ventricular contractility. Effect of speed variation on the hemodynamics was also evaluated at varying degrees of PVR. Pulmonary congestion was observed at high SVR and BV. A reduction in right ventricular assist device (RVAD) speed was required to restore pulmonary pressures. Meanwhile, at a high PVR, the risk of ventricular suction was prevalent during systemic hypotension due to low SVR and BV. This could be compensated by increasing RVAD speed. Isolated right heart recovery may aggravate pulmonary congestion, as the failing left ventricle cannot accommodate the resultant increase in the right-sided flow. Compared to partial assistance, the sensitivity of the hemodynamics to changes in VAD speed increased during full assistance. In conclusion, our results demonstrated that the introduction of a banding graft with a 5 mm diameter guaranteed sufficient reserve of the pump speed spectrum for the regulation of acceptable hemodynamics over different clinical scenarios, except under critical conditions where drug administration or volume management is required.

Echocardiographic and Hemodynamic Predictors of Survival in Precapillary Pulmonary Hypertension: Seven-Year Follow-Up.

In this study, we looked at the prognostic value of echocardiographic and hemodynamic measures in a large cohort of patients with precapillary pulmonary hypertension before and after initiation of treatment. Data were collected prospectively in a cohort of consecutive patients with precapillary pulmonary hypertension referred between 2002 and 2011. A range of clinical and echocardiographic variables were collected and stored on a database to assess predictors of survival. Invasive hemodynamic data including pulmonary artery pressure, pulmonary vascular resistance, capillary wedge pressure, and cardiac index were also obtained at baseline in all patients. Outcome was defined as mortality because of cardiovascular-related death. The study cohort comprised 777 patients (514 women) with precapillary pulmonary hypertension. A total of 195 (25%) died. In multivariable analysis, moderate or severe tricuspid regurgitation (hazard ratio [HR], 26.537; 95% confidence interval, 11.536-61.044; P<0.001), right ventricular myocardial performance index (HR, 3.421; 95% confidence interval, 1.777-6.584; P<0.001), and the presence of pericardial effusion (HR, 1.38; 95% confidence interval, 1.023-1.862; P=0.035) were independent predictors of mortality. High pulmonary vascular resistance and right atrial pressure by invasive hemodynamic measurements were independent predictors of mortality (HR, 1.084; 95% confidence interval, 1.041-1.130, and 1.079, respectively; 95% confidence interval, 1.049-1.111; P<0.001 for both), whereas patients with a higher cardiac index had better survival overall (HR, 0.384; 95% confidence interval, 0.307-0.481; P<0.001). Right ventricular dysfunction, moderate-severe tricuspid regurgitation, low cardiac index, and raised right atrial pressure were associated with poor survival for both pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertensive disease patients. The severity of tricuspid regurgitation, myocardial performance index, presence of pericardial effusion, pulmonary vascular resistance, cardiac index, and right atrial pressure may be used to stratify risk of death.

Fontan Circulatory Assist Device1

Fontan Circulatory Assist Device1

Banding the Right Ventricular Assist Device Outflow Conduit: Is It Really Necessary With Current Devices?

Implantable left ventricular assist devices (LVADs) have been adapted clinically for right-sided mechanical circulatory support (RVAD). Previous studies on RVAD support have established the benefits of outflow cannula restriction and rotational speed reduction, and recent literature has focused on assessing either the degree of outflow cannula restriction required to simulate left-sided afterload, or the limitation of RVAD rotational speeds. Anecdotally, the utility of outflow cannula restriction has been questioned, with suggestion that banding may be unnecessary and may be replaced simply by varying the outflow conduit length. Furthermore, many patients have a high pulmonary vascular resistance (PVR) at the time of ventricular assist device (VAD) insertion that reduces with pulmonary vascular bed remodeling. It is therefore important to assess the potential changes in flow through an RVAD as PVR changes. In this in vitro study, we observed the use of dual HeartWare HVAD devices (HeartWare Inc., Framingham, MA, USA) in biventricular support (BiVAD) configuration. We assessed the pumps' ability to maintain hemodynamic stability with and without banding; and with varying outflow cannulae length (20, 40, and 60 cm). Increased length of the outflow conduit was found to produce significantly increased afterload to the device, but this was not found to be necessary to maintain the device within the manufacturer's recommended operational parameters under a simulated normal physiological setting of mild and severe right ventricular (RV) failure. We hypothesize that 40 cm of outflow conduit, laid down along the diaphragm and then up over the RV to reach the pulmonary trunk, will generate sufficient resistance to maintain normal pump function.