Higher Right Ventricular Pressure Research Articles

Abstract 10163: Ca 2+ Within the Mitochondria Can Affect the Occurrence of Triggered Arrhythmias in Rats with Right Ventricular Hypertrophy

Background: Ca 2+ within the sarcoplasmic reticulum affects the propagation of intracellular Ca 2+ (Ca i ) waves, and the velocity of Ca i waves play important roles in the occurrence of triggered arrhythmias. It is still unknown, however, whether Ca 2+ within the mitochondria (Ca m ) affects the velocity of Ca i wave and the occurrence of arrhythmias in right ventricular (RV) hypertrophy. Objective: To know the roles of Ca m in the velocity of Ca i waves and the occurrence of triggered arrhythmias in rats with RV hypertrophy. Methods: Rats were subcutaneously injected with 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). Four weeks after the injection, trabeculae were dissected from the RVs. The force was measured using a silicon strain gauge, Ca m using rhod-2, Ca i using microinjected fura-2 and a CCD camera, and production of reactive oxygen species (ROS) from the slope DCF fluorescence during electrical stimulation. Ca 2+ waves and arrhythmias were induced by electrical stimulation (24°C). Results: MCT-rats showed a higher RV pressure, a larger weight ratio of RV free wall to left ventricle (RV/LV), and faster and larger Ca i waves than Ctr-rats (p<0.01). Among MCT-rats, Ru360 (10 μM), a mitochondrial calcium uniporter (MCU) inhibitor, decreased the occurrence of arrhythmias in trabeculae from rats with a higher RV pressure and a larger RV/LV (n=19). Ru360 decreased rhod-2 signal within trabeculae depending on the RV/LV (r=-0.85, p<0.01, n=10) without changes in Ca i transients, suggesting that inhibition of MCU decreases Ca m in MCT-rats with more severe RV hypertrophy. In addition, Ru360 decreased the velocity of Ca i waves depending on systolic RV pressure (r=-0.60, n=6) and the RV/LV (r=-0.64, n= 7), suggesting that inhibition of MCU decreased the velocity of Ca i waves in MCT-rats with higher RV pressure and more severe RV hypertrophy. Ru360 decreased the slope of DCF fluorescence (p<0.01, n=13). Conclusions: In the hearts with severe RV hypertrophy, inhibition of MCU can cause larger reduction of Ca m , decrease ROS production, and decrease the velocity of Ca i waves and arrhythmias. Thus, in the hearts with severe RV hypertrophy, more Ca 2+ may enter the mitochondria through the MCU, and higher Ca m may be involved in the occurrence of arrhythmias.

Abstract 10810: CMR Feature Tracking Can Estimate Right Ventricular Functional Reserve in Rats with Pulmonary Arterial Hypertension

Introduction: Patient survival with pulmonary arterial hypertension (PAH) is determined from right ventricular (RV) function. CMR feature tracking (CMR-FT) is used to assess RV function. It is not determined, however, whether CMR-FT can assess RV functional reserve in patients with PAH. Hypothesis: We assessed the hypothesis that CMR-FT can estimate RV functional reserve in rats with PAH. Methods: Rats were received injections with monocrotaline (MCT-rats, n=19) or solvent (Ctr-rats, n=5). After four weeks, retrospective ECG-gated cine MR (16 phases/beat) was imaged using a 7-T MRI scanner, and RVEF, RV global longitudinal strain (RVGLS) and RV global circumferential strain (RVGCS) were measured before and after addition of 0.5~3 nmol endothelin-1 (ET-1). After the measurements, trabeculae were dissected from the RVs and electrically stimulated with 2-s intervals ([Ca 2+ ] o 2.0 mM, 24°C). Force and maximum dF/dt (dF/dt max ) were obtained using a silicon strain gauge in the absence and presence of 0.1 μM ET-1. Results: MCT-rats showed higher RV pressure (RVP), lower RVEF, lower RVGLS, lower developed force and lower dF/dt max . RVGLS showed a liner correlation with dF/dt max (r=0.53, p<0.05) and had already been reduced in 5 MCT-rats with preserved RVEF (>50%), suggesting that RVGLS reflects RV contractile properties and is reduced earlier than RVEF. Addition of ET-1 increased RVP in MCT-rats (49.0±19.3 to 59.7±16.8 mmHg, n=6) and Ctr-rats (17.3±7.5 to 20.4±7.8 mmHg, n=2) and increased developed force and dF/dt max in MCT-rats (12.2±5.7 to 17.4±3.1 mN/mm 2 , 0.08±0.03 to 0.14±0.06 mN/mm 2 /sec, n=6). When MCT-rats with preserved-RVEF (>50%) were divided into 2 groups depending on RVGCS, addition of ET-1 further reduced RVGCS in reduced-RVGCS (>-20%) group but not in increased-RVGCS (<-30%) group, suggesting that RVGCS can reflect RV functional reserve. In addition, ET-1 killed MCT-rats with reduced-RVGCS and reduced-RVEF just after its addition. In contrast, ET-1 did not change RVGCS and RVEF in Ctr-rats. Conclusions: CMR-FT can estimate RV functional reserve earlier and more accurately with RVGLS and RVGCS in rats with PAH. Therefore, RV strain with CMR may become an important parameter to assess RV functional reserve in patients with PAH.

Ca2+ loading within mitochondria affects arrhythmogenesis in rat right ventricular hypertrophy

Abstract Introduction Delayed afterdepolarizations (DADs) causes triggered arrhythmias, and intracellular Ca2+ (Cai) waves play important roles in the formation of DADs. It remains unclear, however, whether Ca2+ loading within mitochondria affects arrhythmogenesis in right ventricular (RV) hypertrophy. Purpose We focused on the properties of Cai wave propagation, investigating whether changes in Ca2+ loading within mitochondria affects arrhythmogenesis in a rat model of RV hypertrophy. Methods Rats were given a subcutaneous injection of 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). Four weeks after the injection, trabeculae were dissected from RVs. Force was measured using a silicon strain gauge, membrane potential using a microelectrode, Cai using microinjected fura-2 and a CCD camera, and ROS production using 2',7'-dichlorofluorescein (DCF) fluorescence. Cai waves and arrhythmias were induced by electrical stimulation (24°C). To change Ca2+ loading within mitochondria, Ru360 (10 μM), a mitochondrial calcium uptake inhibitor, was added. Results MCT-rats showed lower survival rate (p=0.075), higher RV systolic pressure (48.8±4.6 vs 21.3±6.5 mmHg), and heavier weight ratio of RV free wall to left ventricle (LV) (0.44±0.03 vs 0.25±0.04). MCT-rats showed a wider action potential (APD90, 320±20 vs 205±11 ms), a higher diastolic Cai (177±20 vs 110±8 nM), and faster and larger Cai waves (p<0.01). The velocity and amplitude of Cai waves were correlated with the diastolic Cai in Ctr- and MCT-rats. The velocity of Cai waves in MCT-rats was higher than that in Ctr-rats at the given amplitude of Ca2+ waves (p<0.01). The velocity and amplitude of Cai waves was linearly correlated with the amplitude of DADs in Ctr- and MCT-rats. Ru360 decreased the inducibility of arrhythmias in some trabeculae (MCT-A-rats, n=7), while it did not change it or it inversely increased it in the others (MCT-B-rats, n=11). RV systolic pressure in MCT-A-rats was higher than that in MCT-B-rats (62.2±6.0 vs 41.0±5.2 mmHg), and the weight ratio of RV to LV in MCT-A-rats was higher than that in MCT-B-rats (0.51±0.04 vs 0.41±0.03). The changes in Cai wave propagation velocity after the addition of Ru360 was inversely correlated with the weight ratio of RV to LV (r=−0.64) and the RV pressure (r=−0.60, n=7), suggesting that under the condition of severe RV hypertrophy due to higher RV pressure, reduction of Ca2+ within mitochondria results in a decrease in the velocity of the Cai waves, thereby improving of arrhythmias. In the presence of Ru360, DCF oxidation rate was decreased during 0.5 or 2.5 Hz electrical stimulation (n=5, p<0.05). Conclusions In RV hypertrophy, acceleration of Cai waves occurs due to an increase in diastolic Cai and an increase in Ca2+ sensitivity of the SR Ca2+ release channels, thereby causing arrhythmias. In more severe RV hypertrophy, Ca2+ within mitochondria may also be involved in arrhythmogenesis probably through an increase in ROS production. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science

Three-Dimensional Echocardiography-Derived Non-Invasive Right Ventricular Pressure-Volume Analysis

In patients with pulmonary hypertension, repeated evaluations of right ventricular (RV) function are still required for clinical decision making, but the invasive nature of current pressure-volume analysis makes conducting regular follow-ups in a clinical setting infeasible. We enrolled 12 patients with pulmonary arterial hypertension (PAH) and 10 with pulmonary venous hypertension (PVH) May 2016–October 2016. All patients underwent a clinically indicated right heart catheterization (RHC), from which the yielded right ventricular pressure recordings were conjugated with RV volume by 3-D echocardiography to generate a pressure-volume loop. A continuous-wave Doppler envelope of tricuspid regurgitation was transformed into a pressure gradient recording by the simplified Bernoulli equation, and then a systolic pressure gradient-volume (PG-V) diagram was generated from similar methods. The area enclosed by the pressure-volume loop was calculated to represent semi-invasive right ventricular stroke work (RVSWRHC). The area between the PG-V diagram and x-axis was calculated to estimate non-invasive RVSW (RVSWecho). Patients with PAH have higher RV pressure, lower pulmonary arterial wedge pressure and larger RV volume that was contributed by the dilation of RV mid-cavity minor dimension. We found no significant difference of traditional parameters between these two groups, but RVSW values were significantly higher in PAH patients. The RVSW values of these two methods were significantly correlated by the equation RVSWecho = 0.8447 RVSWRHC + 129.38 (R2 = 0.9151, p < 0.001). The linearity remained satisfactory in both groups. We conclude that a PG-V diagram is a reliable method to estimate RVSW and to depict pathophysiological status.

Three-Dimensional Echocardiography-Derived Non-Invasive Right Ventricular Pressure-Volume Analysis

In patients with pulmonary hypertension, repeated evaluations of right ventricular (RV) function are still required for clinical decision making, but the invasive nature of current pressure-volume analysis makes conducting regular follow-ups in a clinical setting infeasible. We enrolled 12 patients with pulmonary arterial hypertension (PAH) and 10 with pulmonary venous hypertension (PVH) May 2016–October 2016. All patients underwent a clinically indicated right heart catheterization (RHC), from which the yielded right ventricular pressure recordings were conjugated with RV volume by 3-D echocardiography to generate a pressure-volume loop. A continuous-wave Doppler envelope of tricuspid regurgitation was transformed into a pressure gradient recording by the simplified Bernoulli equation, and then a systolic pressure gradient-volume (PG-V) diagram was generated from similar methods. The area enclosed by the pressure-volume loop was calculated to represent semi-invasive right ventricular stroke work (RVSWRHC). The area between the PG-V diagram and x-axis was calculated to estimate non-invasive RVSW (RVSWecho). Patients with PAH have higher RV pressure, lower pulmonary arterial wedge pressure and larger RV volume that was contributed by the dilation of RV mid-cavity minor dimension. We found no significant difference of traditional parameters between these two groups, but RVSW values were significantly higher in PAH patients. The RVSW values of these two methods were significantly correlated by the equation RVSWecho = 0.8447 RVSWRHC + 129.38 (R2 = 0.9151, p < 0.001). The linearity remained satisfactory in both groups. We conclude that a PG-V diagram is a reliable method to estimate RVSW and to depict pathophysiological status.

Abstract 273: Sildenafil and Beraprost Therapy Improve Arrhythmogenicity Through Connexin 43 Expression and Electrophysiological Property in Monocrotaline-Induced Rat Pulmonary Hypertension: Optical Mapping Analysis

Severe pulmonary hypertension (PH) is associated with sudden cardiac death (SCD). Optical mapping analysis (OMP) with electrophysiological study (EPS) and connexin-43 measures were performed weekly in Sprague-Dawley rat with monocrotaline (MCTi, 60 mg/kg) induced PH. Right ventricular pressure (RVP) and pulmonary vascular remodeling (PVR) were measured. EPS for ventricular fibrillation (VF) induction and RT-PCR for mRNA expression of connexin-43 (Conx-Ex) were performed. Daily administration of sildenafil (5 mg/kg) and beraprost (100 μg/kg) was initiated at 2 or 3 weeks after MCTi. OMP revealed abnormal RV conduction and action potential dispersion with high VF induction rate. Decreased Conx-Ex with high RVP at 3,4 and 5 weeks after MCTi were observed. Sildenafil with beraprost improved PVR, RV arrhythmogenicity, Conx-Ex, cardiac function (Table) and survival rates. Conclusions: Sildenafil with beraprost therapy improves prognosis by preventing SCD and heart failure. These results give us further insights for understanding PH-induced SCD and therapeutic option for PH.

Combined Therapy of Sildenafil and Beraprost Improves Arrhythmogenicity Through Connexin 43 Expression and Action Potential Dispersion in Monocrotaline-Induced Rat Pulmonary Hypertension

Severe pulmonary hypertension (PH) is associated with sudden cardiac death (SCD). Optical mapping analysis (OMP) with electrophysiological study (EPS) and connexin-43 measures were performed weekly in Sprague-Dawley rat with monocrotaline (MCTi, 60 mg/kg)-induced PH. Right ventricular pressure (RVP) and pulmonary vascular remodeling (PVR) were measured. EPS for ventricular fibrillation (VF) induction, action potential dispersion (APD) measures and RT-PCR for mRNA expression of connexin-43 (Conx-Ex) were performed. Daily administration of sildenafil (5 mg/kg) and beraprost (100 µg/kg) was initiated at 2 or 3 weeks after MCTi. OMP revealed abnormal RV conduction with high VF induction rate. Decreased Conx-Ex and APD with high RVP at 3, 4 and 5 weeks after MCTi were observed. Sildenafil with beraprost improved PVR, RV arrhythmogenicity, Conx-Ex, cardiac function and survival rates. Conclusions: Sildenafil with beraprost therapy improves prognosis by preventing SCD and heart failure. These results give us further insights for understanding PH-induced SCD and therapeutic option for PH.

Right Ventricular Function in Patients with Beta Thalassemia: Relation to Serum Ferritin Level

Cardiac dysfunction is a major cause of death in patients with beta thalassemia. Right ventricular (RV) contribution to cardiac morbidity and mortality in these patients has been suggested. We aimed to assess RV function in beta thalassemia (beta-Th) patients and to detect the relation of serum ferritin level to RV dysfunction. Thirty young patients with beta-Th and 15 age-matched normal subjects (NL) were included. We measured RV end diastolic and end systolic diameters (RVEDD and RVESD), RV % fractional shortening (RVFS), RV pressure (RVP), lateral and septal tricuspid annular systolic and diastolic tissue Doppler velocities (Sa, Ea, Aa & Ea/Aa), and RV myocardial systolic and diastolic velocities at the basal RV segment (RVSm, RVEm, RVAm & RVEm/Am). Serum ferritin level was measured in beta-Th patients who were divided accordingly into two groups; G1 with serum ferritin > or =2,000 microg/L and G2 with serum ferritin < 2,000 microg/L. Compared to NL subjects, beta-Th patients had significantly higher RVEDD, RVESD & RVP, lower RVFS, higher Aa, and lower Ea/Aa at lateral and septal tricuspid annular sites, higher RVAm and lower RVEm/Am. Patients with higher serum ferritin level (G1) had higher RVP, higher RVEDD and RVESD, lower Sa at the lateral annular site and lower RVSm than patients in G2. High serum ferritin level was significantly associated with pulmonary hypertension. We concluded that patients with beta-Th have RV diastolic dysfunction, pulmonary hypertension is common, and the presence of RV systolic dysfunction in these patients is related to the higher level of serum ferritin.

Relation of Right Ventricular Peak Systolic Pressure to Major Adverse Events in Patients Undergoing Cardiac Resynchronization Therapy

The degree to which increased right-sided heart pressures influence outcome in cardiac resynchronization therapy (CRT) is unclear. High right ventricular (RV) pressures may contribute to septal malpositioning, thus hindering effective resynchronization. We hypothesized that patients with high RV systolic pressures before CRT implantation would have poorer outcome. We evaluated echocardiograms, electrocardiograms, and clinical records from 75 consecutive patients with CRT. RV systolic pressure was calculated from the peak tricuspid regurgitant, time-velocity profile. The primary end point was a composite of mortality, cardiac transplantation, or need for a left ventricular assist device. Events were evaluated by Kaplan-Meier curves and Cox proportional hazard ratios. Patients grouped by RV systolic pressure divided at the median of 35 mm Hg were similar except for more renal insufficiency and RV dysfunction when RV systolic pressure was >35 mm Hg. Univariate analysis identified RV systolic pressure >35 mm Hg (hazard ratio [HR] 3.32), diabetes (HR 2.45), renal insufficiency (HR 3.52), atrial fibrillation (HR 3.07), use of nonamiodarone antiarrhythmic medications (HR 2.86), atrial pacing (HR 2.57), and prolonged PR interval (HR 1.009) as associated with poorer outcome. Normal sinus rhythm at implantation (HR 0.34), baseline left bundle branch block (HR 0.44), and beta-blocker use (HR 0.47) were associated with improved outcome. In a multivariable model, high RV systolic pressure (HR 3.71, 95% confidence interval 1.31 to 10.4), renal insufficiency (HR 3.18, 95% confidence interval 1.29 to 7.86), and atrial fibrillation (HR 4.22, 95% confidence interval 1.54 to 11.6) remained significant. In conclusion, despite resynchronization, patients with high RV pressures have significantly decreased survival after adjusting for significant contributing influences.

Endothelin-1 Receptor Antagonist BQ123 Prevents Pulmonary Artery Hypertension Induced by Low Ambient Temperature in Broilers

Evidence has indicated that endothelin-1 is related to the pathogenesis of hypertension. To characterize the role of endothelin-1 (ET-1) in the development of pulmonary hypertension syndrome in broilers, the blockade effect of ETA receptor (ET(A)) antagonist, BQ123, on blood pressure in experimental models of pulmonary hypertension was examined. Birds were locally anesthetized and instrumented with venous catheters for pulmonary arterial pressure (PAP) and right ventricular pressure (RVP), followed by packed cell volume (PCV) and Ascites heart index (AHI) measured, after exposed to low ambient temperature for 7 or 14 d. In treated groups, BQ123 (0.4 or 2.0 microg each time, 2 times a day), administered in abdominal cavities for 7 or 14 d during birds kept in low ambient temperature, prevented both PAP and RVP increasing, especially the high dose BQ123 lowered PAP and RVP to normotensive levels as that in control under normal temperature, whereas significant increases (p<0.05) were found in the two parameters of broilers in both untreated and saline treated group under low ambient temperature compared with those of birds in control. Furthermore, there was also a reduction in low ambient temperature-induced right ventricular hypertrophy in the groups administered BQ123. The preventive effect of BQ123 suggests that ET-1 is associated with the development of broilers' pulmonary hypertension, which leads to the development of ascites, and BQ123 can prevent the occurrence of pulmonary hypertension.

Ventricular septal flattening at end systole falsely predicts right ventricular hypertension in patients with ostium primum atrial septal defects

Purpose: To assess the reliability of ventricular septal position in predicting elevated right ventricular pressure (RVP) in patients with ostium primum atrial septal defects (ASD 1). Methods: Echocardiograms of 4 groups were retrospectively analyzed: Patients with ASD 1 and low RVP, patients with ASD 1 and high RVP, and 2 age-matched control groups: one with isolated ostium secundum atrial septal defects (ASD 2), and 1 with normal cardiac findings. End-systolic left ventricular sectional diameters along the midmitral diameter (D1) and a diameter orthogonal to it (D2) were measured off-line by a blinded observer. The ratio D2/D1, the eccentricity index (EI), was calculated; a higher index represents greater septal flattening. Results: The mean EI in the ASD 1 with low RVP group was significantly higher than both the group with ASD 2 and the healthy control group. The mean EI of the ASD 1 group with high RVP was significantly higher than the mean EI of the ASD 1 group with low RVP, although there was a poor correlation between EI and RVP in this group, r = 0.54. Conclusion: The ventricular septum is flatter in the ASD 1 patients with low RVP than in an age-matched control group with ASD 2 and compared with an age-matched control group of healthy subjects, giving a false impression of elevated RVP in the ASD 1 group. Although the mean EI is significantly higher in the ASD 1 group with high RVP than in the group with low RVP, there is a poor correlation between EI and RVP, which limits the reliability of this index. (J Am Soc Echocardiogr 2002;15:247-52.)