Effect of riociguat on right ventricular function in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: In the Phase III PATENT-1 (NCT00810693) and CHEST-1 (NCT00855465) studies, riociguat demonstrated efficacy vs placebo in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Clinical effects were maintained at 2 years in the long-term extension studies PATENT-2 (NCT00863681) and CHEST-2 (NCT00910429). METHODS: This post hoc analysis of hemodynamic data from PATENT-1 and CHEST-1 assessed whether riociguat improved right ventricular (RV) function parameters including stroke volume index (SVI), stroke volume, RV work index, and cardiac efficiency. REVEAL Risk Score (RRS) was calculated for patients stratified by SVI and right atrial pressure (RAP) at baseline and follow-up. The association between RV function parameters and SVI and RAP stratification with long-term outcomes was assessed. RESULTS: In PATENT-1 (n = 341) and CHEST-1 (n = 238), riociguat improved RV function parameters vs placebo (p < 0.05). At follow-up, there were significant differences in RRS between patients with favorable and unfavorable SVI and RAP, irrespective of treatment arm (p < 0.0001). Multiple RV function parameters at baseline and follow-up were associated with survival and clinical worsening-free survival (CWFS) in PATENT-2 (n = 396; p < 0.05) and CHEST-2 (n = 237). In PATENT-2, favorable SVI and RAP at follow-up only was associated with survival and CWFS (p < 0.05), while in CHEST-2, favorable SVI and RAP at baseline and follow-up were associated with survival and CWFS (p < 0.05). CONCLUSION: This post hoc analysis of PATENT and CHEST suggests that riociguat improves RV function in patients with PAH and CTEPH.

Stiff left atrial syndrome after low-dose radiotherapy for right breast cancer: The need for invasive hemodynamics at exercise.

Stiff left atrial (LA) syndrome is a distinct phenotype of heart failure with preserved ejection fraction, characterized by predominant high LA pressure. We describe the case of a middle-aged woman who developed exertional breathlessness during low-dose radiotherapy for right breast cancer and who was eventually found to be affected by stiff LA syndrome. Invasive hemodynamics allowed the recognition of pathognomonic tall V waves in the wedge position during exercise, in spite of inconclusive noninvasive investigations.

Hemodynamic, Hormonal, and Renal Actions of Phosphodiesterase-9 Inhibition in Experimental Heart Failure.

BACKGROUND: Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of heart failure (HF). OBJECTIVES: This study investigated for the first time the integrated hemodynamic, endocrine, and renal effects of phosphodiesterase-9 inhibition (PDE9-I). METHODS: A total of 8 normal sheep and 8 sheep with pacing-induced HF received incremental intravenous boluses of PDE9-I (30, 100, and 300 mg PF-04749982 at 1-h intervals). RESULTS: PDE9-I dose-dependently increased plasma cyclic guanosine monophosphate (cGMP) in normal sheep (p < 0.05) while concurrently reducing circulating atrial natriuretic peptide levels (p < 0.01). Similar trends were evident in HF, resulting in significant elevations in the cGMP/NP ratio in both states (p < 0.001 and p < 0.05, respectively). PDE9-I also produced progressive falls in arterial pressure (HF: p < 0.001), atrial pressure (Normal: p < 0.001; HF: p < 0.001), and peripheral resistance (HF: p < 0.001), and transiently increased cardiac output at the top dose (Normal: p < 0.05; HF: p < 0.001). Inhibition of PDE9 had a negligible effect on circulating hormones at the lower doses, but post-high dose, acutely increased renin activity (Normal: p < 0.001; HF: p < 0.05), vasopressin (Normal: p < 0.001; HF: p < 0.01), and cyclic adenosine monophosphate (HF: p < 0.001). Plasma aldosterone increased briefly after high-dose PDE9-I in normal sheep, and fell following the top dose in HF. PDE9-I dose-dependently increased urinary cGMP in both states (both p < 0.001). In HF, this was associated with increases in urine volume (p < 0.01), sodium excretion (p < 0.01), and creatinine clearance (p < 0.001). CONCLUSIONS: PDE9-I improves NP efficacy in conjunction with beneficial hemodynamic and renal effects in experimental HF. These results support a role for PDE9 in HF pathophysiology and suggest its inhibition may constitute a novel therapeutic approach to this disease.

Effects of high-dose alacepril on left atrial pressure and central aortic pressure in awake dogs with mitral valve regurgitation.

The purpose of this study was to clarify how alacepril in amounts greater than those recommended on the product labeling approved by drug regulatory agencies affects left atrial pressure (LAP) and central aortic pressure in dogs with experimentally induced mitral valve regurgitation (MR). Six healthy Beagle dogs were surgically induced for MR and received alacepril at either 1.5mg/kg/12-h (3.0mg/kg/day) or 3.0mg/kg/12-h (6.0mg/kg/day) per one administration for seven days. After a four-week washout period, another dosage was administrated as a crossover study. Dogs were randomised to receive 3.0mg/kg/day or 6.0mg/kg/day first. LAP and central systolic (SAP), mean (MAP), and diastolic (DAP) aortic pressure were measured for 24-h before and during the administration of alacepril. The earliest decreases in SAP, MAP, and DAP with 6.0mg/kg/day were observed on days 4, 4, and 5, respectively. With 3.0mg/kg/day, the earliest decrease in DAP was observed on day 7. The maximum LAP was decreased on days 5 and 7 with 6.0mg/kg/day. The mean LAP was decreased on day 7 with 6.0mg/kg/day. In conclusion, the administration of alacepril at 6.0mg/kg/day reduced the LAP and central aortic pressure within several days.

Modification of levosimendan-induced suppression of atrial natriuretic peptide secretion in hypertrophied rat atria.

This study aimed to determine the effects of levosimendan, a calcium sensitizer, on atrial contractility and atrial natriuretic peptide (ANP) secretion and its modification in hypertrophied atria. Isolated perfused beating rat atria were used from control and isoproterenol-treated rats. Levosimendan and its metabolite OR-1896 caused a positive inotropic effect and suppressed ANP secretion in rat atria. Similar to levosimendan, the selective phosphodiesterase 3 (PDE3) or PDE4 inhibitor also suppressed ANP secretion. Suppression of ANP secretion by 1 µM levosimendan was abolished by PDE3 inhibitor, but reversed by PDE4 inhibitor. Levosimendan-induced suppression of ANP secretion was potentiated by KATP channel blocker, but blocked by KATP channel opener. Levosimendan alone did not significantly change cyclic adenosine monophosphate (cAMP) efflux in the perfusate; however, levosimendan combined with PDE4 inhibitor markedly increased this efflux. The stimulation of ANP secretion induced by levosimendan combined with PDE4 inhibitor was blocked by the protein kinase A (PKA) inhibitor. In isoproterenol-treated atria, levosimendan augmented the positive inotropic effect and ANP secretion in response to an increased extracellular calcium concentration ([Ca+]o). These results suggests that levosimendan suppresses ANP secretion by both inhibiting PDE3 and opening KATP channels and that levosimendan combined with PDE4 inhibitor stimulates ANP secretion by activating the cAMP-PKA pathway. Modification of the effects of levosimendan on [Ca+]o-induced positive inotropic effects and ANP secretion in isoproterenol-treated rat atria might be related to a disturbance in calcium metabolism.

Possible role of rivaroxaban in attenuating pressure-overload-induced atrial fibrosis and fibrillation.

BACKGROUND: Coagulation factor Xa (FXa) promotes thrombus formation and exacerbates inflammation via activation of protease-activated receptor (PAR)-2. We tested the hypothesis of whether administration of direct oral anticoagulant, rivaroxaban, would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in mice. METHODS: Ten-week-old male CL57/B6 mice were divided into a sham-operation (CNT) group and TAC-surgery group. These two groups were then subdivided into vehicle (VEH) and rivaroxaban (RVX) treatment (30µg/g/day) groups. We assessed PAR-2 expression in response to TAC-related stimulation using rat cultured cells. RESULTS: TAC-induced left atrial thrombus formation was not observed in the TAC-RVX group. Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of mRNA levels, cardiac PAR-2 upregulation was attenuated in the TAC-RVX group compared to TAC-VEH group. In histological evaluation, the TAC-VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration. Electrophysiological examination revealed that AF duration in the TAC group was shortened by RVX administration. TAC-induced protein overexpression of monocyte chemoattractant protein-1, and mRNA overexpression of tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 in the left atrium was suppressed by RVX treatment. In cardiac fibroblasts, persistent intermittent stretch upregulated PAR-2, which was suppressed by RVX pre-incubation. CONCLUSIONS: These observations demonstrate that coagulation FXa inhibitor probably has a cardioprotective effect against pressure-overload-induced atrial remodeling.

Effects of endothelin family on ANP secretion.

The endothelins (ET) peptide family consists of ET-1, ET-2, ET-3, and sarafotoxin (s6C, a snake venom) and their actions appears to be different among isoforms. The aim of this study was to compare the secretagogue effect of ET-1 on atrial natriuretic peptide (ANP) secretion with ET-3 and evaluate its physiological meaning. Isolated nonbeating atria from male Sprague-Dawley rats were used to evaluate stretch-activated ANP secretion in response to ET-1, ET-2, ET-3, and s6C. Changes in mean blood pressure (MAP) were measured during acute injection of ET-1 and ET-3 with and without natriuretic peptide receptor-A antagonist (A71915) in anesthetized rats. Changes in atrial volume induced by increased atrial pressure from o to 1, 2, 4, or 6cm H2O caused proportional increases in mechanically-stimulated extracellular fluid (ECF) translocation and stretch-activated ANP secretion. ET-1 (10nM) augmented basal and stretch-activated ANP secretion in terms of ECF translocation, which was blocked by the pretreatment with ETA receptor antagonist (BQ123, 1µM) but not by ETB receptor antagonist (BQ788, 1µM). ETA receptor antagonist itself suppressed stretch-activated ANP secretion. As compared to ET-1- induced ANP secretion (3.2-fold by 10nM), the secretagogue effects of ANP secretion by ET-2 was similar (2.8-fold by 10nM) and ET-3 and s6C were less potent (1.7-fold and 1.5-fold by 100nM, respectively). Acute injection of ET-1 or ET-3 increased mean blood pressure (MAP), which was augmented in the presence of natriuretic peptide receptor-A antagonist. Therefore, we suggest that the order of secretagogue effect of ET family on ANP secretion was ET-1≥ET-2>>ET-3>s6C and ET-1-induced ANP secretion negatively regulates the pressor effect of ET-1.

Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension.

OBJECTIVE: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. PATIENTS AND METHODS: ADMA, SDMA, and arginine were measured (0-540 min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60 min. RESULTS: A reduction in ADMA was observed at 30 and 45 min with a median change of -11.1% (P=0.021) and -12.5% (P=0.002). SDMA decreased with a median -5.3% change (P=0.032) at 45 min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540 min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540 min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540 min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60 min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed. CONCLUSIONS: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

Blunted rate-dependent left atrial pressure response during isoproterenol infusion in atrial fibrillation patients with impaired left ventricular diastolic function: a comparison to pacing.

AIMS: A heart rate (HR)-dependent haemodynamic linkage between peak left atrial (LA) pressure during sinus rhythm (LAPpeak) and estimated left ventricular (LV) filling pressure (E/Em) has not yet been explored. We hypothesized that rate-dependent LAPpeak response differs depending on E/Em in patients with atrial fibrillation (AF). METHODS AND RESULTS: A total of 331 patients (68.0% male, 59.8 ± 10.8 years old) undergoing radiofrequency catheter ablation (RFCA) for AF were included, and their LAPpeak in sinus rhythm was recorded at the beginning of the procedure and at the HRs of 90, 100, 110, and 120 b.p.m. during right atrial pacing and isoproterenol (ISO-stress) infusion. We compared LAPpeak changes between patients with E/Em ≥ 15 (n = 58) and those with <15 (n = 273). (i) The patterns of pacing rate-dependent LAPpeak increase were similar in both the E/Em < 15 (P < 0.001) and E/Em ≥ 15 groups (P = 0.002). (ii) The ISO-stress reduced LAPpeak in patients with E/Em < 15 (P = 0.015), but not in those with E/Em ≥ 15 (P = 0.582). (iii) Paradoxical ISO-stress LAP elevation in patients with E/Em ≥ 15 was independently associated with 1-year follow-up E/Em reduction (B = -4.07, 95% CI -5.41 to -2.72, P < 0.001). Coexistence of E/Em ≥ 15 and ISO-stress LAP elevation increased specificity in predicting 1-year follow-up E/Em reduction after AF ablation than E/Em alone. CONCLUSION: Isoproterenol LAPpeak reduction was blunted in patients with impaired LV diastolic function estimated by E/Em ≥ 15. The improvement of LV diastolic dysfunction 1 year after AF ablation was independently associated with both paradoxical ISO-stress LAP elevation and E/Em ≥ 15 at the time of procedure. CLINICALTRIALSGOV: NCT02138695.

Leftward bulging of atrial septum is provoked by nitroglycerin and by sustained valsalva strain.

BACKGROUND: The motion of the interatrial septum primum (septum) is dependent on the interatrial pressure relation, normally with slightly higher pressure in the left atrium and the septum bulging toward the right atrium. The aim of this study was to explore the physiologic mechanisms that reverse interatrial pressures and provoke leftward bulging of septum (LBA). The hypothesis was that both left ventricular unloading with nitroglycerin and sustained Valsalva strain would independently provoke LBA and that their combination would further intensify the effect. METHODS: Prospectively collected transesophageal echocardiography recordings from 13 patients with obstructive sleep apnea were retrospectively analyzed for the presence or absence of LBA during resting respiration and during Valsalva strain. In each condition, LBA beats were counted at time points before and after nitroglycerin spray had been administered, which enabled a comparison of the independent effects and the combined effect of the nitroglycerin and the Valsalva maneuver. An LBA beat was defined as a heartbeat displaying any LBA during the cardiac cycle. RESULTS: Nitroglycerin increased the proportion of LBA beats significantly during resting respiration, from 21 ± 27% to 54 ± 43% (P = .008). During Valsalva strain, the proportion increased with nitroglycerin spray from 48 ± 21% to 80 ± 17% (P = .001). After nitroglycerin administration, LBA occurred in at least three beats during strain in all Valsalva periods. CONCLUSIONS: Unloading of the left ventricle by nitroglycerin administration and by sustained Valsalva strain independently provoked LBA. The combination of these two interventions further intensified the effect.

Prognosis and response to first-line single and combination therapy in pulmonary arterial hypertension.

OBJECTIVES: To investigate survival, treatment escalation, effects of first-line single- and first-line combination therapy and prognostic markers in idiopathic- (IPAH), hereditary- (HPAH) and connective tissue disease-associated (CTD-PAH) pulmonary arterial hypertension (PAH). DESIGN: Retrospective analysis of medical journals from PAH patients at Skåne University Hospital 2000-2011. RESULTS: 1-, 2- and 3-year survival was 87%, 67%, and 54%, respectively, for the entire population, but worse (p = 0.003) in CTD-PAH than IPAH/HPAH. After 1, 2 and 3 years, 58%, 41% and 24% of patients starting on single therapy were alive on single therapy. 37.5% of patients on first-line single therapy received escalated treatment at first follow-up. First-line combination therapy more greatly decreased pulmonary vascular resistance index (PVRI, p = 0.017) than first-line single therapy. Only first-line combination therapy improved (p = 0.042) cardiac index (CI). Higher mean right atrial pressure (MRAP, p = 0.018), MRAP/CI (p = 0.021) and WHO functional class (p < 0.001) and lower 6-min walking distance (6MWD, p = 0.001) at baseline, and higher PVRI (p = 0.008) and lower 6MWD (p = 0.004) at follow-up were associated with worse outcome. CONCLUSIONS: We confirm improved survival with PAH-targeted therapies. Survival is still poor and early treatment escalation frequently needed. First-line combination therapy may more potently improve haemodynamics. MRAP/CI may represent a new prognostic marker in PAH.

Effects of a sustained-release form of isosorbide dinitrate on left atrial pressure in dogs with experimentally induced mitral valve regurgitation.

BACKGROUND: The effects of isosorbide dinitrate (ISDN) have not been sufficiently investigated in conscious dogs with mitral valve regurgitation (MR). OBJECTIVE: The objective was to investigate the effects of a sustained-release form of ISDN (sr-ISDN) on hemodynamics and the autonomic nervous system in dogs with MR. ANIMALS: Six healthy Beagles weighing 11.2 ± 2.2 kg (2 years of age; 2 males and 4 females) were used. METHODS: Experimental, crossover, and interventional study. Dogs with experimentally induced MR were administered placebo, 2, 5, and 10 mg/kg sr-ISDN PO on separate days with a 7-day washout period between randomized dosings. Left atrial pressure (LAP) had been recorded continuously from 30 minutes before administration of sr-ISDN to 12 hours after administration. RESULTS: LAP was significantly decreased after administration in the 5 and 10 mg/kg groups. Significant decrease was observed at 3 and 4 hours after administration in the 5 mg/kg group. In the 10 mg/kg group, significant decrease was observed at 2, 3, 4, 5, 6, 7, 10, and 11 hours after administration. The lowest value was observed at 4 hours after administration in the 5 and 10 mg/kg groups (20.9 ± 4.2 to 15.9 ± 3.9 mmHg, P < .01, and 21.3 ± 4.0 to 13.6 ± 4.2 mmHg, P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Sustained-release form of ISDN showed significant decrease of LAP in the 5 mg/kg and 10 mg/kg groups, and duration of effect was dose related.

Angiotensin AT2 receptor agonist stimulates high stretch induced- ANP secretion via PI3K/NO/sGC/PKG/pathway.

Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT2R are still controversial. The aim of the present study is to define the effect of AT2R agonist CGP42112A (CGP) on high stretch-induced ANP secretion and its mechanism using in vitro and in vivo experiments. CGP (0.01, 0.1 and 1µM) stimulated high stretch-induced ANP secretion and concentration from isolated perfused rat atria. However, atrial contractility and the translocation of extracellular fluid did not change. The augmented effect of CGP (0.1µM) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT2R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT1R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT2R mRNA and protein levels were up-regulated and the response of plasma ANP level to CGP infusion in renal hypertensive rats augmented. The pretreatment with AT2R antagonist for 10min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT1R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT2R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/sGC/PKG pathway and these effects are augmented in renal hypertensive rats.

Hemodynamic, hormonal, and renal effects of (pro)renin receptor blockade in experimental heart failure.

BACKGROUND: The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. METHODS AND RESULTS: Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (P=0.004), with similar trends observed for plasma angiotensin II and aldosterone (P=0.093 and P=0.088, respectively). Circulating natriuretic peptides, endothelin-1, and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (P=0.024), a natriuresis (P=0.046), and a tendency for creatinine excretion and clearance to improve. CONCLUSIONS: (P)RR antagonism in experimental HF resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in HF and identifies the receptor as a potential therapeutic target in this disease.