Pulmonary Arterial Resistance Research Articles

Right ventricular pulmonary vascular coupling in secondary tricuspid regurgitation: a pressure volume loop study

Abstract Introduction The severity of secondary tricuspid regurgitation (sTR) predicts outcome of patients with left heart failure with reduced ejection fraction (HFrEF). In these patients sTR predominantly occurs as a result of secondary pulmonary hypertension (PH). However, more than 46% of patients with severe PH have only mild or none sTR. In this study we tested the hypothesis that intrinsic right ventricular (RV) contractility adaptation to the pulmonary arterial (PA) vascular load (RV-PA-coupling) is associated with the presence and severity of sTR. Methods In 110 patients with HFrEF (a post-hoc analysis of the Magdeburger CRT Responder Trial, DRKS00011133) we quantified the RV intrinsic contractility response (end-systolic elastance, Ees) to pulmonary vascular afterload (arterial elastance, Ea) and its coupling ratio (RV-PA coupling ratio: Ees/Ea) by the RV pressure-volume loop catheter technique at baseline, and combined it with echocardiography-derived parameter of sTR presence and severity and RV function. Results Echocardiography at baseline demonstrated no or trace TR (TR0) in 67 patients (61%), mild TR (TR1) in 23 (21%), moderate TR (TR2) in 11 (10%), and severe TR (TR3) in 9 (8%). The transition from TR0 to TR1 was characterized by a pronounced drop of the RV-PA coupling ratio (TR0: Ees/Ea= 0.88, 0.67–1.1 vs. TR1: Ees/Ea= 0.48, 0.3–0.83, p<0.001), caused by a non-adaptive, non-rising Ees (0.24 mmHg/ml, 0.34–0.44 vs. 0.3 mmHg/ml, 0.21–0.46, p=0.8, respectively, p<0.001). We observed a further but only marginal drop of Ees/Ea from TR1 to TR3 (p=0.008) caused by an additional small non-significant decrease of Ees and increase of Ea. Interestingly, other afterload parameter, such as PA-pressure, wedge pressure (PCWP), PA compliance, and PA resistance (PVR), and parameters of RV function, such as tricuspid annular plane systolic excursion (TAPSE) and fractional area shortening (FAC) followed the same course of a pronounced drop from TR0 to TR1, succeeded by an only marginal change from TR1 to TR3. In contrast, the progressive RV-PA un-coupling from TR0 to TR3 was accompanied by a more or less continuously increase of RV size and volume load (end-diastolic (ED) area in 4 chamber view, ED-RV outflow tract diameter, size of tricuspid annulus). In the binary logistic regression analysis, the decrease of RV-PA coupling ratio Ees/Ea (OR 0.14, CI 0.001–0.165) and PA compliance (OR 0.44, CI 0.25–0.79) were independently associated with the transition from TR0 to TR1–3. Conclusion The presence and severity of secondary TR in patients with HFREF is independently associated with a progressive RV-PA uncoupling. Most importantly, already the transition from none TR to mild TR is characterized by a significant and pronounced increase of pulmonary vascular afterload, a non-adaptive RV contractility response, and resulting RV-PA un-coupling. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boston Scientific

Pulmonary vascular resistance and pulmonary artery compliance in a large cohort of patients with sinus venosus septal defect

Abstract Background Left-to-right shunt in patients with sinus venosus septal defect (SVSD) may affect resistive (pulmonary vascular resistance – PVR) and elastic (pulmonary artery compliance-PAC) properties of the pulmonary arteries. This study aimed at evaluating (1) changes in hemodynamics over time and (2) the relationship between PVR and PAC in a large cohort of patients with SVSD. Methods Data of 136 patients with SVSD (median age at diagnosis 14 (IQR 5–48) years, 47% male) were included. Catheterization data was available in 87 patients. Pressures were measured and cardiac output evaluated using the Fick principle. PVR (mean pulmonary artery pressure (mPAP)-wedge pressure/cardiac output) and PAC (stroke volume/pulse pressure) were calculated and indexed for body surface area. Results Ninety percent had abnormal pulmonary venous connection. Median shunt ratio was 2.5 (IQR 2.0–2.9). Repair was performed in 128 (94%) at a median age of 13 (IQR 5–43) years. During a median follow-up time of 31 (IQR 17–55) years, 12 (9%) patients died, 13 (10%) developed heart failure, 19 (14%) atrial arrhythmia, 6 (4%) sick sinus syndrome and 7 (5%) required pacemaker implantation. PVR indexed and PAC indexed was 3.5 (IQR 2.4–7.5) WU·m2 and 1.8 (IQR 1.3–2.5) mL/mmHg·m2. There was an inverse, hyperbolic relationship between PVR and PAC with an RC time of 6.6 (IQR 4.4–8.9) sec. When comparing patients with age at catheterization <10 years, 10–50 years and >50 years, shunt ratio (2.5±0.6 vs 2.5±0.8 vs 2.5±0.6; p=0.836) and PVR indexed (2.9 (2.3–3.4) vs 3.1 (2.0–9.0) vs 6.6 (3.6–8.8) WU·m2; p=0.132) were not statistically different, whereas mPAP (19 (16–22) vs 21 (16–24) vs 28 (22–34) mmHg; p=0.002); wedge (6 (4–8) vs 13 (8–16)vs 14 (10–19) mmHg; p<0.0001) and PAC indexed (2.2 (1.5–2.9) vs 2.0 (1.4–2.8) vs 1.3 (0.9–1.7) mL/mmHg·m2; p=0.002) differed significantly. Conclusion SVSD is associated with late morbidity and mortality. In SVSD, PVR and PAC are inversely related. Over time, the changes in elastic resistance (PAC or pulsatile load) are more profound than changes in resistive (PVR – steady load). Figure 1 Funding Acknowledgement Type of funding source: None

Comparison of pulmonary vascular resistance and pulmonary artery compliance during exercise between IPAH and CTEPH with normal pulmonary artery pressure

Abstract Background Pulmonary vascular resistance (PVR) and pulmonary artery compliance (PAC) are inversely related. However, the little is known about dynamics during exercise by disease difference. The aim of this study was to reveal the relationships of PVR and PAC during exercise between idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients. Methods Sixty-two IPAH patients (45±9 y.o) and 359 CTEPH patients (63±13 y.o) with normal mean PAP and PAWP at rest underwent symptom-limited exercise test using supine cycle ergometer with right heart catheter. Results There were no differences between baseline mean PAP and PAWP in 2 groups, however, cardiac output, SaO2 and SvO2 were lower in CTEPH group. Lower PAC (2.9±1.1 vs. 3.7±1.7 ml/mmHg, p<0.001) and higher PVR (2.3±1.0 vs. 1.9±1.0 wood.unit, p=0.016) were observed in CTEPH group. These trends were also seen at peak exercise. PVR-PAC relationship in CTEPH group was leftward shift compared with IPAH group (Figure 1). Conclusion Resting and exercise PVR and PAC in CTEPH patients were worse than those in IPAH patients who had normal PAP and PAWP at rest. Figure 1 Funding Acknowledgement Type of funding source: None

Carcinoembryonic antigen levels are increased with pulmonary output in pulmonary hypertension due to congenital heart disease.

ObjectivePulmonary artery hypertension (PAH) is a severe complication of congenital heart disease (CHD). Monitoring of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) is essential during follow-up. This retrospective study aimed to examine carcinoembryonic antigen (CEA) as an additional marker for evaluation by investigating the correlation between CEA levels and hemodynamics in CHD-PAH.MethodsSeventy-six patients with CHD-PAH (mean PAP [mPAP] >25 mmHg and PVR >3 Wood units, group A), 71 patients with CHD and pulmonary hypertension (CHD-PH, mPAP >25 mmHg and PVR ≤3 Wood units, group B), and 102 patients with CHD without PH (mPAP ≤25 mmHg, group C) were enrolled. Serum CEA levels and the relationships between CEA levels and hemodynamic data were assessed.ResultsMean serum CEA levels were 1.99±1.61, 2.44±1.82, and 1.58±1.07 ng/mL, mPAP was 58.66±20.21, 30.2±4.83, and 17.31±4.51 mmHg, and PVR was 10.12±7.01, 2.19±0.56, and 2.2±1.1 Wood units in groups A, B, and C, respectively. Mean pulmonary output (PO) was 7.24±3.07, 15.79±5.49, 10.18±4.72 L/minute, respectively. CEA levels were positively correlated with PO and negatively correlated with PVR in all of the patients.ConclusionCEA levels are increased with PO and decreased with PVR in CHD-PH.

S62798, a TAFIa inhibitor, accelerates endogenous thrombolysis in a murine model of pulmonary thromboembolism

Abstract Pulmonary embolism (PE) is the third leading cause of cardiovascular death in western countries. The enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. In patients, venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) antigen as well as the active form TAFIa. S62798 is a competitive, selective and potent human TAFIa inhibitor (IC50±SD=11.2±0.4nM). It is however less potent on mouse TAFIa (IC50±SD=270±39nM). Here, we tested the ability of S62798 to enhance endogenous fibrinolysis in a mouse model of pulmonary thromboembolism. Human Tissue Factor (TF) was injected in C57Bl6 male mice. Ten minutes later, mice (n=4 to 14 per group) were treated (IV) with S62798 (from 0.01 to 100mg/kg) or vehicle (0.9% NaCl). Ten or twenty minutes (min) later, mice were anesthetized and lungs were collected, homogenized and pulmonary fibrin was quantified by ELISA. Results are expressed as ratio of geometric mean of pulmonary fibrin (μg/mL): tested treatment/ vehicle [95% confidence interval (CI)]. Ten minutes after S62798 treatment, pulmonary fibrin deposition was dose-dependently decreased with a Minimal Effective Dose of 0.04mg/kg [90% prediction interval 0.037 - 0.051] and an ED50 of 0.03mg/kg [95% CI: 0.01; 0.06]. Mice were then treated with 0.1mg/kg S62798 or vehicle (10 min after TF induction) and fibrin deposition in lungs was quantified 10 and 20 minutes post S62798 treatment. The level of pulmonary fibrin deposition was significantly decreased (p<0.0001) compared to vehicle group (ratio 0.31 [0.21; 0.45] at 10 min; 0.35 [0.24; 0.51] at 20 min). Finally, the effect of S62798 (1mg/kg) in combination with heparin was evaluated (n=10/group). When administered 10 min before TF injection, heparin (2000IU/kg) significantly (p<0.0001) decreased pulmonary fibrin level (20 min post TF: ratio 0.03 [0.01; 0.05]). When treatment was done in a curative setting (10 min post TF), heparin alone had no effect (p=0.85) on fibrin deposition (ratio 0.96 [0.65; 1.43]) whereas a similar significant (p<0.0001) decreased pulmonary fibrin deposition was observed in response to S62798 alone or associated with heparin (ratio 0.27 [0.18; 0.40] (S62798 alone) and 0.29 [0.20; 0.43] (S62798+heparin)). In this model, curative S62798 treatment, alone or associated to heparin, accelerated clot degradation by potentiating endogenous fibrinolysis and thus decreased pulmonary fibrin deposition. Due to its capacity to enhance endogenous fibrinolysis, S62798, which has completed phase I studies, is expected to be a therapeutic option for intermediate high risk PE patients on top of anticoagulants. With early recanalization, S62798 should rapidly reduce pulmonary artery pressure and resistance, with concomitant improvement in right ventricular function, preserving cardiac function, and reducing acute PE-related morbidity and mortality in these patients. Funding Acknowledgement Type of funding source: None

ACUTE VASOREACTIVITY TESTING DURING RIGHT HEART CATHETERIZATION IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: RESULTS FROM THE PULMONARY VASCULAR DISEASE OMICS PROJECT

SESSION TITLE: Advances in the Diagnosis and Management of Pulmonary Hypertension SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing is seldom performed, so there is limited understanding of frequency and significance of acute response. Systematic vasodilator testing with oxygen and oxygen plus inhaled nitric oxide was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing opportunity to examine this issue. METHODS: Patients with CTEPH enrolled in PVDOMICS underwent right heart catheterization including vasodilator challenge with 100% oxygen (02) and 100% oxygen plus 40 PPM of inhaled nitric oxide (02 + NO). Mean pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output by thermodilution with calculation of pulmonary vascular resistance (PVR) was obtained at baseline and with each intervention. We examined acute vasoreactivity defined as > 20% drop in PVR, > 20% drop in both mPAP and PVR, and as a drop in mPAP > 10 mmHg to a value < 40 mmHg with normal cardiac output. RESULTS: Of the 61 patients who underwent vasoreactivity testing, 32 (52%) were on PH therapy (15 riociguat, 8 PDE5i, 9 other) and 29 (48%) were on no targeted PH therapy. Fourteen (23%) had prior pulmonary thromboendarterectomy, 1 (2%) had prior balloon pulmonary angioplasty. In the overall cohort, mean PVR was 5.49 WU at baseline, 4.81 with 02, and 4.01 with O2 + NO (mean ± SD change from baseline: -1.43 ± 1.32, 26%), p < .0001). In the subset who were on no PH therapy, mean PVR was 6.26 at baseline, 5.75 with 02, and 4.55 with 02 + NO (change from baseline of -1.62 ± 1.36, 26%), p < .0001). Overall, 25 (43%) had > 20% drop in PVR with 02. With 02 + NO, 36 (62%) had > 20% drop in PVR (decline of 1.43 ± 1.32 WU), including 9 (64%) of those with prior thromboendarterectomy and 19 who were on PH therapy. Six (10%) had a drop in mPAP by > 10 mmHg to < 40 mmHg with normal cardiac output. Thirteen (21%) had > 20% drop in both mPAP and PVR, 6 of whom were on no PH therapy and 4 out of 8 (50%) of those who were on PDE5i. Only 2/15 (13%) of those on riociguat had > 20% drop in both mPAP and PVR. CONCLUSIONS: An element of acute vasoreactivity is common in CTEPH including in those with prior pulmonary thromboendarterectomy. The 26% decline in PVR with acute testing for those who were on no PH therapy is similar to what was achieved chronically on average with riociguat in the pivotal randomized study [(29%, 226 dyn.sec.cm -5 = 2.83 WU,) from baseline of 791]. Whether acute vasoreactivity testing is predictive of clinical response to riociguat or other pulmonary vasodilators is worthy of additional investigation. CLINICAL IMPLICATIONS: Vasoconstriction is a significant contributor to the elevation in pulmonary artery pressure and resistance in the majority of patients with CTEPH. DISCLOSURES: No relevant relationships by Erika Berman Rosenzweig, source=Web Response Advisory Committee Member relationship with Liquidia Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Altavant Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Actelion Please note: $5001 - $20000 Added 07/16/2020 by Robert Frantz, source=Web Response, value=Consulting fee No relevant relationships by Paul Hassoun, source=Web Response Advisory Committee Member relationship with bayer Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Complexa Please note: $1-$1000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with United Therapeutics Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with actelion Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Scientific Medical Advisor relationship with PHPreMedicine Please note: $1-$1000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Ownership interest no disclosure on file for Evelyn Horn; No relevant relationships by Armand Larive, source=Web Response My spouse/partner as a Consultant relationship with Cellectis Please note: >$100000 Added 05/28/2020 by Jane Leopold, source=Web Response, value=Consulting fee no disclosure on file for Franz RIschard; Consultant relationship with Sequana Medical AG Please note: $5001 - $20000 Added 05/28/2020 by Wai Hong Tang, source=Web Response, value=Consulting fee Editor/Author relationship with Springer Nature Please note: $1-$1000 Added 05/29/2020 by Wai Hong Tang, source=Web Response, value=Honoraria My spouse/partner as a Consultant relationship with Cardiac Community Core Lab, LLC Please note: $1001 - $5000 Added 05/28/2020 by Wai Hong Tang, source=Web Response, value=Honoraria

UNUSUAL CAUSE OF ANGINA: PULMONARY ARTERY TO CORONARY ARTERY FISTULA

SESSION TITLE: Fellows Cardiovascular Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Coronary artery anomalies include abnormalities of number, origin or course, termination, or structure of the coronary arteries. We present a rare case of an aberrant communication between right pulmonary arteries and left coronary artery presenting as an acute coronary syndrome. CASE PRESENTATION: A 52-year-old male with a past medical history of hyperlipidemia and hypertension presented to the emergency department with one day of chest pain and palpitations after being referred from his primary doctor’s office for EKG changes; showing deep T wave inversions in lead V1 - V4 with p-wave enlargement. He denied any other cardiac symptoms except for dyspnea on exertion. He stated that he had a similar episode a few weeks before but had not received medical care at that time. He was admitted for management of acute coronary syndrome and to monitor for arrhythmias. Cardiac enzymes were obtained and were found to be normal. Imaging included transthoracic echocardiography, which showed normal left ventricular ejection fraction, right ventricular dilation and systolic dysfunction, elevated pulmonary artery systolic pressure of 80-100 mmHg, and moderate tricuspid regurgitation. Computed tomographic pulmonary angiography (CTPA) was performed and showed rapid tapering of right lower lobe descending pulmonary artery indicative of chronic pulmonary embolism and mosaic attenuation in the pulmonary parenchyma. The patient underwent left and right-sided cardiac catheterization with nitric oxide testing which showed an anomalous branch from the proximal left coronary artery to multiple sites in the right pulmonary arteries. Administration of nitric oxide showed a minimal reduction in the peripheral vascular resistance, and the calculated ratio of pulmonary blood flow vs cardiac output of 1.27 was suggestive of high pulmonary artery resistance and pressure which was decreasing the left to right shunt. Cardiac CTA was performed to further characterize the anatomic anomaly which showed fistulization from the right pulmonary artery to the circumflex artery with extensive collaterals in the subcarinal region. DISCUSSION: We believe that pulmonary hypertension was secondary to this fistula and the resulting chronic pressure/volume pulmonary overload resulting in right heart dysfunction along with CTEPH. This patient was discharged after initial stabilization and was referred for surgical evaluation for pulmonary artery thrombectomy. He was treated with clot retrieval and Riociguat at an advanced pulmonary arterial hypertension center CONCLUSIONS: The vascular connection between the coronary artery and branches of pulmonary artery can cause angina due to admixture of deoxygenated blood in the coronary circulation. Conventional angiography or multidetector computed tomography examinations of the coronaries can detect such anomalies which can present as a complex clinical presentation of acute coronary syndrome. Reference #1: Lee CM, Leung TK, Wang HJ, Lee WH, Shen LK, Chen YY. Identification of a coronary-to-bronchial-artery communication with MDCT shows the diagnostic potential of this new technology: case report and review. J Thorac Imaging. 2007;22(3):274-276. doi:10.1097/RTI.0b013e31802f134d Reference #2: Battal B, Saglam M, Ors F, Akgun V, Dakak M. Aberrant right bronchial artery originating from right coronary artery - MDCT angiography findings. Br J Radiol. 2010;83(989):e101-e104. doi:10.1259/bjr/49596063 DISCLOSURES: No relevant relationships by Lillian Chow, source=Web Response No relevant relationships by Chetana Pendkar, source=Web Response

Long-term results of additional pulmonary blood flow with bidirectional cavopulmonary shunt

ObjectiveWe evaluated additional pulmonary blood flow at the time of bidirectional cavopulmonary shunt and its effects on the Fontan procedure and long-term outcome of Fontan circulation and liver function.MethodsWe included 22 patients (16 boys, 6 girls) having undergone bidirectional cavopulmonary shunt with additional pulmonary blood flow between April 2002 and January 2016. Mean age and body weight were 20 ± 13 months and 7.5 ± 6.5 kg, respectively. We retrospectively evaluated the patients’ clinical data, including cardiac catheterization data, liver function, and liver fibrosis markers.ResultsAll patients were alive with a New York Heart Association status of I at the long-term follow-up. Changes between pre-bidirectional cavopulmonary shunt and 101 months after the Fontan procedure included the following: the cardiothoracic ratio of chest X-ray decreased from 52.2 ± 3.9% to 41.8 ± 5.9% (p < 0.001); systemic ventricle end-diastolic pressure decreased from 11.4 ± 3.2 mmHg to 6.9 ± 3.6 mmHg (p < 0.001); and the pulmonary artery index decreased from 485.1 ± 272.3 to 269.5 ± 100.5 (p = 0.02). Type IV collagen, hyaluronic acid, and procollagen levels increased over the normal range 116 months after the Fontan procedure.ConclusionsThe additional pulmonary blood flow at the time of bidirectional cavopulmonary shunt may contribute to pulmonary arterial growth at the Fontan procedure with low pulmonary arterial resistance and without ventricle volume overload. The Fontan circulation was well-maintained at the long-term follow-up, while liver fibrosis markers were above their normal values.

Role of smooth muscle Rac1 in the vascular remodeling associated with pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by an increase in pulmonary artery (PA) resistance leading to right ventricle (RV) failure. Endothelial dysfunction and alteration of NO/cGMP signaling play a major role in PAH. We previously described the major role of smooth muscle cell (SMC) Rac1 in NO-induced dilation of systemic arteries. Here, our aim was to analyze the role of SMC Rac1 in pulmonary circulation and in PAH. Rac1 activity was assessed by immunofluorescence in lung biopsies. PAH has been induced by exposure of wild-type (WT) and SMC Rac1-deficient mice (SM-Rac1-KO mice) to chronic hypoxia (10% O2, 4 weeks). In vitro, the proliferation of PASMC in hypoxic condition was measured by EdU staining and contractility of PA rings was analyzed by myography. Oxidative stress was assessed using the DHE probe and by electron paramagnetic resonance (EPR). A 3-fold increase of Rac-GTP in PA was observed in PAH patients compared to control ( n = 4-6). To determine whether Rac1 activation plays a causal role in PAH, WT and SM-Rac1-KO mice were exposed to hypoxia. As expected, exposure to chronic hypoxia induced an increase in systolic pressure in RV and RV hypertrophy which were reduced by 32.5% and 60% respectively, in SM-Rac1-KO mice compared to WT ( n = 5–7). PA remodeling was also significantly reduced in hypoxic SM-Rac1-KO compared to WT mice, while PA contractility was not affected by SMC Rac1 deletion. In vitro, exposure of primary PASMC to hypoxia stimulated proliferation and ROS production that were decreased by 50% and 66%, respectively, by the Rac1 inhibitor, EHT1864. Our results show that SMC Rac1 activity is increased in PA of PAH patients and plays a causal role in hypoxia-induced PAH in mice by stimulating ROS-dependent PA remodeling. These data suggest that pharmacological Rac1 inhibition might have a beneficial effect in the treatment of PAH.

Pulmonary hypertension or cardiology aerobatics

Pulmonary hypertension (PH) is a group of diseases with a hemodynamic pattern of progressive increase in pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP), which leads to right ventricular dysfunction and the development of right ventricular heart failure.

The Differential Impact of the Left Atrial Pressure Components on Pulmonary Arterial Compliance–Resistance Relationship in Heart Failure

An increase in the pulmonary capillary wedge pressure (PAWP) has been shown to impact on the inherent relationship between the pulmonary arterial compliance (PAC) and pulmonary vascular resistance (PVR), thus augmenting the pulsatile relative to the resistive load of the right ventricle. However, the PAWP comprises the integration of both the steady and the pulsatile pressure components. We sought to address the differential impact of the these distinct PAWP components on the PAC-PVR relationship in a cohort of patients with heart failure. The study population consisted of 192 patients with hemodynamic findings diagnostic for heart failure. Off-line analysis was performed using the MATLAB software. The steady and pulsatile PAWP components were calculated as mid-A pressure and mean pressure during the V-wave oscillation, respectively. The PAC and PVR were hyperbolically and inversely associated and the subgroup of patients with PAWP above the median (>18 mm Hg) displayed a significant left and downward shift of the curve fit (P < .001). The shift in the PAC-PVR fit between patients with higher versus low steady PAWP was not significant (P = .43). In contrast, there was a significant downward and leftward shift of the PVR-PAC curve fit for the subgroup with a higher pulsatile PAWP (P < .001). Furthermore, only the pulsatile PAWP was significantly associated with the time-constant of the pulmonary circulation, assessed as the PAC × PVR product (P < .001). In patients with heart failure, the pulsatile rather than the steady PAWP component stands for the previously documented shift of the PAC-PVR relationship occurring at an elevated PAWP.

Purinergic Dysfunction in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which result in an increase in afterload imposed onto the right ventricle, leading to right heart failure. Current therapies are incapable of reversing the disease progression. Thus, the identification of novel and potential therapeutic targets is urgently needed. An alteration of nucleotide‐ and nucleoside‐activated purinergic signaling has been proposed as a potential contributor in the pathogenesis of PAH. Adenosine‐mediated purinergic 1 receptor activation, particularly A2AR activation, reduces pulmonary vascular resistance and attenuates pulmonary vascular remodeling and right ventricle hypertrophy, thereby exerting a protective effect. Conversely, A2BR activation induces pulmonary vascular remodeling, and is therefore deleterious. ATP‐mediated P2X7R activation and ADP‐mediated activation of P2Y1R and P2Y12R play a role in pulmonary vascular tone, vascular remodeling, and inflammation in PAH. Recent studies have revealed a role of ectonucleotidase nucleoside triphosphate diphosphohydrolase, that degrades ATP/ADP, in regulation of pulmonary vascular remodeling. Interestingly, existing evidence that adenosine activates erythrocyte A2BR signaling, counteracting hypoxia‐induced pulmonary injury, and that ATP release is impaired in erythrocyte in PAH implies erythrocyte dysfunction as an important trigger to affect purinergic signaling for pathogenesis of PAH. The present review focuses on current knowledge on alteration of nucleot(s)ide‐mediated purinergic signaling as a potential disease mechanism underlying the development of PAH.

Predictive Value of Pulmonary Arterial Compliance in Systemic Lupus Erythematosus Patients With Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a serious complication of systemic lupus erythematosus. It is characterized by increased right ventricular afterload which mainly comprises pulmonary arterial compliance (PAC) and pulmonary vascular resistance. The role of PAC in predicting the outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been investigated yet. Between February 2012 to December 2016, 120 consecutive patients diagnosed with systemic lupus erythematosus-associated pulmonary arterial hypertension based on right heart catheterization were enrolled, prospectively. Baseline clinical characteristics and hemodynamic assessment were analyzed. Baseline right ventricular afterload was stratified according to the PAC and pulmonary vascular resistance. The end point was a composite of all-cause mortality and clinical worsening. Among them, end points occurred in 49 (41%) patients after 15 months (interquartile range, 8.5-24.0). Patients with a PAC <1.39 mL/mm Hg had a 3.09-fold higher risk (95% CI, 1.54-6.20, P=0.001) of the end point events than the patients with a PAC ≥1.39 mL/mm Hg. Multivariable Cox regression analysis showed that stratified right ventricular afterload was the only independent predictor for the end point (hazard ratio, 2.009 [95% CI, 1.390-2.904], P<0.001). A 3-group prediction risk was created. The patients with the highest right ventricular afterload (PAC <1.39 mL/mm Hg and pulmonary vascular resistance ≥10.3Wood Unit) had the highest risk (χ2, 6.10; P<0.014) of experiencing the end point. Our results suggest that PAC is a good predictor of mortality and clinical worsening in systemic lupus erythematosus-associated pulmonary arterial hypertension. PAC, in addition to pulmonary vascular resistance, may be an attractive tool for screening high-risk populations in these patients.

Effects of β‐adrenoceptor activation on haemodynamics during hypoxic stress in rats

What is the central question of this study? The acute hypoxic compensatory reaction is based on haemodynamic changes, and β-adrenoceptors are involved in haemodynamic regulation. What is the role of β-adrenoceptors in haemodynamics during hypoxic exposure? What is the main finding and its importance? Activation of β2 -adrenoceptors attenuates the increase in pulmonary artery pressure during hypoxic exposure. This compensatory reaction activated by β2 -adrenoceptors during hypoxic stress is very important to maintain the activities of normal life. The acute hypoxic compensatory reaction is accompanied by haemodynamic changes. We monitored the haemodynamic changes in rats undergoing acute hypoxic stress and applied antagonists of β-adrenoceptor (β-ARs) subtypes to reveal the regulatory role of β-ARs on haemodynamics. Sprague-Dawley rats were randomly divided into control, atenolol (β1 -AR antagonist), ICI118,551 (β2 -AR antagonist) and propranolol (non-selective β-AR antagonist) groups. Rats were continuously recorded for changes in haemodynamic indexes for 10min after administration. Then, a hypoxic ventilation experiment [15% O2 , 2200 m a.sl., 582 mmHg (0.765 Pa), 87.3 mmHg; Xining, China] was conducted, and the indexes were monitored for 5min after induction of hypoxia. Plasma catecholamine concentrations were also measured. We found that, during normoxia, the mean arterial pressure, heart rate, ascending aortic blood flow and pulmonary artery pressure were reduced in the propranolol and atenolol groups. Catecholamine concentrations were increased significantly in the atenolol group compared with the control group. During hypoxia, mean arterial pressure and total peripheral resistance were decreased in the control, propranolol and ICI118,551 groups. Pulmonary arterial pressure and pulmonary vascular resistance were increased in the propranolol and ICI118,551 groups. During hypoxia, catecholamine concentrations were increased significantly in the control group, but decreased in β-AR antagonist groups. In conclusion, the β2 -AR is involved in regulation of pulmonary haemodynamics in the acute hypoxic compensatory reaction, and the activation of β2 -ARs attenuates the increase in pulmonary arterial pressure during hypoxic stress. This compensatory reaction activated by β2 -ARs during hypoxic stress is very important to maintain activities of normal life.

Concealed role of red blood cells in pathogenesis of pulmonary arterial hypertension: Decreased red blood cell nitric oxide generation and effect of Rho-Kinase inhibitor fasudil.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized with alterations in pulmonary vasculature yielding increased pulmonary arterial resistance. Emerging evidences suggest important regulatory roles of red blood cells (RBCs) on nitric oxide (NO) bioavailability, mainly by modulating their endothelial nitric oxide synthase (eNOS) enzyme activity. The aim of this pilot study was to evaluate the alterations in RBC eNOS activity and intracellular NO generation in PAH patients and the modulatory effects of Rho-Kinase (ROCK) inhibitors. RBCs were isolated from patients with PAH and age-matched healthy subjects and were analyzed for their eNOS activity and NO generation capacity under the conditions of the presence or absence of ROCK inhibitor, fasudil. Phosphotidylserine (PS) exposure was also defined. eNOS activity and intracellular NO generation were lower in RBC from PAH patients. ROCK inhibitor increased basal eNOS activity and improved NO generation capacity of RBC of PAH patients to healthy control levels. PS exposure levels were also higher in RBC of PAH patients. This study provides first evidences for decreased RBC eNOS activity due to its ROCK mediated negative regulation in PAH patients. Considering increased ROCK activity contribution to progression of PAH, ROCK inhibition influences NO bioavailability through RBC eNOS, in addition to endothelial eNOS.

Adaptive and innate immune mechanisms in cardiac fibrosis complicating pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a syndrome diagnosed by increased mean pulmonary artery (PA) pressure and resistance and normal pulmonary capillary wedge pressure. PAH is characterized pathologically by distal pulmonary artery remodeling, increased pulmonary vascular resistance, and plexiform lesions (PLs). Right ventricular fibrosis and hypertrophy, leading to right ventricular failure, are the main determinants of mortality in PAH. Recent work suggests that right ventricular fibrosis results from resident cardiac fibroblast activation and conversion to myofibroblasts, leading to replacement of contractile cardiomyocytes with nondistensible tissue incapable of conductivity or contractility. However, the origins, triggers, and consequences of myofibroblast expansion and its pathophysiological relationship with PAH are unclear. Recent advances indicate that signals generated by adaptive and innate immune cells may play a role in right ventricular fibrosis and remodeling. This review summarizes recent insights into the mechanisms by which adaptive and innate immune signals participate in the transition of cardiac fibroblasts to activated myofibroblasts and highlights the existing gaps of knowledge as relates to the development of right ventricular fibrosis.

The Clinical Efficacy of Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension.

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.

Nutraceuticals in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by the loss and obstructive remodeling of the pulmonary arterial wall, causing a rise in pulmonary arterial pressure and pulmonary vascular resistance, which is responsible for right heart failure, functional decline, and death. Although many drugs are available for the treatment of this condition, it continues to be life-threatening, and its long-term treatment is expensive. On the other hand, many natural compounds present in food have beneficial effects on several cardiovascular conditions. Several studies have explored many of the potential beneficial effects of natural plant products on PAH. However, the mechanisms by which natural products, such as nutraceuticals, exert protective and therapeutic effects on PAH are not fully understood. In this review, we analyze the current knowledge on nutraceuticals and their potential use in the protection and treatment of PAH, as well as whether nutraceuticals could enhance the effects of drugs used in PAH through similar mechanisms.

Safety and effectiveness of riociguat for chronic thromboembolic pulmonary hypertension in real‐world clinical practice: interim data from post‐marketing surveillance in Japan

This multicenter, prospective, non-interventional study (ClinicalTrials.gov: NCT02117791) evaluated the safety and effectiveness of riociguat for chronic thromboembolic pulmonary hypertension in Japanese clinical practice, registering all patients with chronic thromboembolic pulmonary hypertension treated with riociguat following its launch in Japan in April 2014. Safety was assessed by analyzing the adverse drug reactions. Effectiveness measurements included the assessment of change in World Health Organization functional class, six-minute walk test, and hemodynamics. Overall, 1031 patients were included in the safety analysis with 811 (78.7%) patients in World Health Organization functional class II/III. The mean treatment duration was 591.4 days (median 441.0 days). Adverse drug reactions were reported in 19.5% of patients, the most common being hypotension (5.9%), headache (3.0%), dizziness (1.9%), and gastroesophageal reflux disease (1.5%). Serious adverse drug reactions were reported in 2.1% of patients. Estimated survival was 97.0% at one year, 95.8% at two years, and 94.4% at three years. The effectiveness analysis (n = 1027) showed significant increases from baseline in six-minute walking distance, and significant reductions from baseline in mean pulmonary arterial pressure and pulmonary vascular resistance. These interim results of riociguat in Japanese patients with chronic thromboembolic pulmonary hypertension demonstrated a safety profile that was generally consistent with those of pivotal clinical studies. The study is ongoing, and will continue to provide insights into the safety and effectiveness of riociguat in real-world practice.

Absence of the MFG-E8 gene prevents hypoxia-induced pulmonary hypertension in mice.

Pulmonary hypertension (PH) is a chronic vascular disease characterized by elevated pulmonary arterial resistance and vascular remodeling, and chronic hypoxia plays an important role in PH. Milk fat globule‐EGF factor 8 (MFG‐E8) is a glycoprotein that regulates cell proliferation and apoptosis, but its role in hypoxia‐induced PH is unknown. The current study aimed to determine the function and fundamental mechanisms of MFG‐E8 in hypoxia‐induced PH. Herein, we exposed mice to hypoxia for 5 weeks, and MFG‐E8 was found to be elevated in mouse lung tissues, arteries, and plasma. Compared with wild‐type littermates, mice lacking MFG‐E8 showed a significant increase in the ratio of pulmonary artery acceleration time to ejection time (PAT/PET), while they showed decreases in right ventricular systolic pressure, the Fulton's Index, percent medial wall thickness (%WT), and vascular muscularization in pulmonary arteries. In addition, MFG‐E8 protein levels were also increased in the serum of patients with chronic PH. Similarly, we observed a higher expression of MFG‐E8 in human pulmonary artery smooth muscle cells (PASMCs) in the presence of hypoxic stimulation than MFG‐E8 in cells in normoxic conditions. Furthermore, MFG‐E8 silencing resulted in partial inhibition of proliferation, migration and cell cycle progression in human PASMCs, and the possible mechanisms might involve the interaction between MFG‐E8 and the p‐Akt/cyclin D1 pathway. Collectively, our study suggests that the absence of MFG‐E8 can attenuate the development of hypoxia‐induced PH and vascular remodeling. MFG‐E8 can be a potential therapeutic target or a biomarker for PH.