Development of a 3-Dimensional Model to Study Right Heart Dysfunction in Pulmonary Arterial Hypertension: First Observations

Pulmonary arterial hypertension (PAH) patients eventually die of right heart failure (RHF). Currently, there is no suitable pre-clinical model to study PAH. Therefore, we aim to develop a right heart dysfunction (RHD) model using the 3-dimensional engineered heart tissue (EHT) approach and cardiomyocytes derived from patient-induced pluripotent stem cells (iPSCs) to unravel the mechanisms that determine the fate of a pressure-overloaded right ventricle. iPSCs from PAH and healthy control subjects were differentiated into cardiomyocytes (iPSC-CMs), incorporated into the EHT, and maintained for 28 days. In comparison with control iPSC-CMs, PAH-derived iPSC-CMs exhibited decreased beating frequency and increased contraction and relaxation times. iPSC-CM alignment within the EHT was observed. PAH-derived EHTs exhibited higher force, and contraction and relaxation times compared with control EHTs. Increased afterload was induced using 2× stiffer posts from day 0. Due to high variability, there were no functional differences between normal and stiffer EHTs, and no differences in the hypertrophic gene expression. In conclusion, under baseline spontaneous conditions, PAH-derived iPSC-CMs and EHTs show prolonged contraction compared with controls, as observed clinically in PAH patients. Further optimization of the hypertrophic model and profound characterization may provide a platform for disease modelling and drug screening.

Right Heart Dysfunction in Adults With Coarctation of Aorta: Prevalence and Prognostic Implications

Background: Chronic elevation of left heart filling pressure causes pulmonary vascular remodeling, pulmonary hypertension, and right heart dysfunction. Although diastolic dysfunction is relatively common in patients with coarctation of aorta, there are limited data about the prevalence and prognostic implications of pulmonary hypertension and right heart dysfunction in this population. The purpose of the study was to assess right heart function and hemodynamics in patients with coarctation of aorta and to determine the relationship between right heart indices and cardiovascular events defined as heart failure hospitalization, heart transplant, or cardiovascular death. Methods: Right heart structure, function, and hemodynamics were assessed with these indices: right atrial volume, right atrial pressure, right atrial reservoir strain, right ventricular global longitudinal strain, right ventricular end-diastolic area, right ventricular systolic pressure, and tricuspid regurgitation severity. Right heart hemodynamic score, range 0 to 5, was generated based on the correlation between the right heart indices and cardiovascular events, using half of the cohort (derivation cohort, n=411), and then tested on the validation cohort (n=410). The goodness of fit and discrimination power was compared using C statistics and risk score. Results: The median follow-up in the derivation cohort was 8.2 (4.0–11.1) years, and 59 (14%) patients had cardiovascular events during this period. Right heart hemodynamic score was independently associated with cardiovascular events (hazard ratio, 1.64 [95% CI, 1.38–2.17]) for every unit increase in right heart hemodynamic score after adjustment for clinical and echocardiographic indices (C statistic, 0.718 [95% CI, 0.682–0.746]). The right heart hemodynamic score was also independently associated with cardiovascular events in the validation cohort (C statistic, 0.711 [95% CI, 0.679–0.741]). The C statistic difference (0.007 [95% CI, 0.014–0.022]) and risk score (0.86 [95% CI, 0.54–1.17]) suggest a good model fit. Conclusions: The current study underscores the prognostic importance of right heart dysfunction in patients with coarctation of aorta and suggests that right heart indices should be used for risks stratification in this population.

The Anaesthetic Management of a Parturient with an Ebstein Anomaly and Prior Bidirectional Glenn Shunt

Parturients with Ebstein anomaly are an anaesthetic challenge due to the spectrum of disease. Patients palliated with bidirectional Glenn shunts are susceptible to right heart dysfunction due to the physiological changes during parturition. We present a 28-year-old primigravida with Ebstein anomaly surgically managed by a bidirectional Glenn shunt. Echocardiograms showed normal right ventricular function despite reported dyspnea as the pregnancy progressed. Following a comprehensive plan developed during multidisciplinary prenatal meetings, she safely delivered. In this case report, we discuss the preoperative evaluation, management of labour and delivery, and postpartum planning of parturients with palliated Ebstein anomaly.

EXPRESS: Abnormal levels of Apolipoprotein A-I in Chronic Thromboembolic Pulmonary Hypertension

Recent studies have shown low high-density lipoprotein cholesterol (HDL-C) and dysregulated lipid metabolism in chronic thromboembolic pulmonary hypertension (CTEPH). Apolipoprotein A-I (ApoA-I) is the major protein component of HDL-C and mediates most of its functions. We hypothesize that ApoA-1 and its oxidative state might be more sensitive biomarkers in CTEPH. Plasma levels of HDL-C, ApoA-I, Paraoxonase-1 enzyme activity (PON1) and the oxidized dysfunctional ApoA-I (oxTrp72-ApoA-I) were measured in patients with CTEPH and compared to those in healthy controls. Association with markers of disease severity in CTEPH was assessed. We included a total of 61 patients with CTEPH (age:61.2±15 years; male 52.5%) and 28 control subjects (age:60.1±8 years; male 59.3%). When adjusting for age, sex, body mass index and statin use, ApoA-I was lower in CTEPH compared to controls (CTEPH:125.2±27 mg/dl; control:158.3±29.4 mg/dl; p<0.001), but HDL-C levels were not statistically different. There were no significant differences in PON and oxTrp72-ApoA-I/ApoA-I ratio. In exploratory analyses, ApoA-I was associated with mean right atrial pressure (rs = -0.32, p=0.013) and N-terminal pro B-type natriuretic peptide (rs= -0.31, p=0.038). There were no significant associations between HDL-C, PON1 or oxTrp72-ApoA-I/ApoA-I ratio and markers of disease severity. We conclude that ApoA-I is a more sensitive biomarker than HDL-C in CTEPH, and may be associated with right heart dysfunction.

Clinically inapparent right heart dysfunction is associated with reduced myofilament force development in coronary artery disease

Background Right ventricular dysfunction after CABG is associated with poor peri- and postoperative outcomes. We aimed to identify clinical and experimental predictors for preoperative inapparent right ventricular dysfunction and therefore hypothesized that reduced myofilament force development as well as altered levels of biomarkers might predict inapparent right ventricular dysfunction. Methods From 08/2016 to 02/2018, 218 patients scheduled for CABG were divided into two groups (TAPSE ≥ 20 mm, n = 178; TAPSE < 20 mm, n = 40). Baseline serum samples for biomarkers (Galectin, TGFß1, N Acyl-SDMA, Arginine, ADMA and Pentraxin-3), clinical laboratory and transthoracic echocardiographic parameters were evaluated. To examine the myocardial apparatus of the right ventricle intraoperative right auricular tissue was harvested for stepwise skinned fiber force measurements. Results Patients with TAPSE < 20 mm had a higher incidence of DM (55 vs. 34%, p = 0.018), preoperative AFib (43 vs. 16%, p < 0.001), reduced GFR (67 ± 18 vs. 77 ± 24 ml/min/1.73 m2, p = 0.013), larger LA area (22 ± 6 vs. 20 ± 5 cm2, p = 0.005) and reduced LVEF (50 vs. 55%, p = 0.008). Furthermore, higher serum ADMA (0.70 ± 0.13 vs. 0.65 ± 0.15 µmol/l, p = 0.046) and higher serum Pentraxin-3 levels (3371 ± 1068 vs. 2681 ± 1353 pg/dl, p = 0.004) were observed in these patients. Skinned fiber force measurements showed significant lower values at almost every step of calcium concentration (pCa 4.52 to pCa 5.5, p < 0.01 and pCa 5.75–6.0, p < 0.05). Multivariable analysis revealed DM (OR 2.53, CI 1.12–5.73, Euro Score II (OR 1.34, CI 1.02–1.78), preoperative AF (OR 4.86, CI 2.06–11.47), GFR (OR 7.72, CI 1.87–31.96), albumin (OR 1.56, CI 0.52–2.60), Pentraxin-3 (OR 19.68, CI 14.13–25.24), depressed LVEF (OR 8.61, CI 6.37–10.86), lower force values: (pCa 5.4; OR 2.34, CI 0.40–4.29 and pCa 5.2; OR 2.00, CI 0.39–3.60) as predictors for clinical inapparent right heart dysfunction. Conclusions These preliminary data showed that inapparent right heart dysfunction in CAD is already associated with reduced force development of the contractile apparatus.

Clinically Inapparent Right Heart Dysfunction is Associated with Reduced Myofilament Force Development in Coronary Artery Disease

Background: Right ventricular dysfunction after CABG is associated with poor peri- and postoperative outcomes. We hypothesized that inapparent RV dysfunction in these patients is already associated with pathological changes at the level of myofilaments in concert with altered biomarkers of myocardial remodeling and endothelial dysfunction.Methods: From 08/2016 to 02/2018, 218 patients scheduled for CABG were divided into two groups (TAPSE ≥20mm, n=178;TAPSE<20mm,n=40). Baseline serum samples for biomarkers (Galectin,TGFß1,N Acyl-SDMA, Arginine, ADMA and Pentraxin-3), clinical laboratory and transthoracic echocardiographic parameters were evaluated. To examine the myocardial apparatus of the right ventricle intraoperative right auricular tissue was harvested for stepwise skinned fiber force measurements.Results: Patients with TAPSE <20mm had a higher incidence of DM (55vs34%,p=0.018), preoperative AFib (43vs16%,p=0.000), reduced GFR (67±18vs77±24 ml/min/1.73m2,p=0.013), larger LA area (22±6vs20±5cm2,p=0.005) and reduced LVEF (50vs55 %,p=0.008). Furthermore, higher serum ADMA (0.70±0.13vs0.65±0.15µmol/l, p=0.046) and higher serum Pentraxin-3 levels (3371±1068vs2681±1353pg/dl,p=0.004) were observed in these Patients. Skinned fibre force measurements showed significant lower values at almost every step of calcium concentration (pCa 4.52 to pCa 5.5,p<0.01 and pCa 5.75 to 6.0,p< 0.05). Multivariable analysis revealed DM (OR 2.53 CI1.12-5.73, Euro Score II (OR1.34 CI 1.02-1.78), preoperative AF (OR4.86 CI2.06-11.47), GFR (OR7.72 CI 1.87-31.96), albumin (OR1.56 CI 0.52-2.60), Pentraxin-3 (OR19.68 CI14.13-25.24), depressed LVEF (OR8.61 CI 6.37-10.86), lower force values: (pCa 5.4; OR2.34 CI 0.40-4.29 and pCa 5.2; OR2.00 CI 0.39-3.60) as predictors for clinical inapparent right heart dysfunction. Conclusions: These preliminary data showed that inapparent right heart dysfunction in CAD is already associated with reduced force development of the contractile apparatus.

The prognostic impact of right ventricular dysfunction in patients with septic cardiomyopathy

Background Sepsis is a systemic condition of profoundly impaired health in which an infection leads to a dysregulated host response, and consecutively causes organ dysfunction, shock, and even death. Septic cardiomyopathy (SCM) is one of the multiple organ dysfunctions. SCM is typically defined as left ventricular (LV) dysfunction, presented by decreased LV ejection fraction (LVEF). However, it remains unclear about the detailed mechanism of cardiac dysfunction. In addition, the prognostic impact of right heart dysfunction in SCM patients has not been fully investigated. Purpose The purpose of this study was to investigate the prognostic impact of right heart dysfunction in patients with SCM. Methods We used the MIMIC-III (Medical Information Mart for Intensive Care III) critical care database, which is a large, freely-available database comprising deidentified health-related data associated with over forty thousand patients who stayed in critical care units of the Beth Israel Deaconess Medical Center between 2001 and 2012. We retrospectively analyzed data of patients with septic shock on admission to intensive care unit (ICU). Septic shock was defined as the presence of any suspected infections, the need for vasopressors, and the lactate level exceeding 2 mmol/L, based on the Sepsis-3 criteria. Patients were performed portable transthoracic echocardiography (TTE) during hospitalization. LVEF and right ventricular (RV) function were determined predominately by visual estimation in the parasternal long-axis view. SCM was defined as having a minimum LVEF of 50% or less during hospitalization. Patients with hyperdynamic motion of LVEF &gt;70% were excluded. Results In total, there were 2254 patients with septic shock. Of these, 604 patients who underwent TTE were enrolled, and 314 patients were diagnosed with SCM. At baseline, age, gender, Sequential Organ Failure Assessment (SOFA) score, maximum lactate levels, and maximum norepinephrine dosage were 70 [59–79] years, 194 males, 13 [11–15], 4.0 [2.7–6.2] mmol/L, and 0.20 [0.10–0.31] mcg/kg/min, respectively. All patients were treated with vasopressors. In Kaplan-Meier survival analysis, patients with SCM had increased 28-day mortality compared with those without SCM (log-rank, p=0.09). In addition, we divided SCM patients into two groups; SCM with and without RV dysfunction. SCM patients with RV dysfunction had significant increased 28-day mortality compared with those without RV dysfunction (log-rank, p=0.01) (Figure). In Cox proportional hazard regression analysis adjusted for age, male sex, SOFA score, and maximum lactate levels, RV dysfunction was an independent determinant of 28-day mortality (hazard ratio, 1.59; 95% confidence interval, 1.03–2.46; p=0.03). Conclusions The presence of RV dysfunction increased 28-day mortality in patients with SCM. It might be useful for predicting the prognosis of SCM to evaluate not only left heart function but also right heart function. Kaplan-Meier survival curves Funding Acknowledgement Type of funding source: None