Reversible Pulmonary Hypertension Research Articles

Repurposing FK506 to Increase BMPR2 Signaling and Improve Pulmonary Arterial Hypertension: A Fast Track From Cells to People

To improve long-term survival in pulmonary arterial hypertension (PAH), new treatment approaches that target occlusive vasculopathy instead of vasoconstriction of pulmonary arteries are necessary. Identifying genes or pathways that unify different pathologies and etiologies in PAH is a crucial first step for drug development. The bone morphogenetic protein receptor 2 (BMPR2) pathway, originally described as the cause of familial PAH, has gained significant interest over the past few years as a potential master switch in PAH, and therefore presents a promising treatment target in PAH. FK506 (tacrolimus) was found in a high-throughput screen of US Food and Drug Administration (FDA)-approved drugs to significantly increase BMPR2 signaling. Low-dose FK506 was able to restore normal BMPR2 signaling and function in patient pulmonary artery (PA) endothelial cells, inhibit proliferation and induce apoptosis in PA smooth muscle cells, and prevent and reverse pulmonary hypertension (PH) in 3 experimental rodent models of PH. As an FDA-approved drug, it was possible to relatively quickly (in approximately 2 years) translate the basic science discoveries from the bench to the clinic. A Phase 2 proof-of-concept safety and tolerability trial is underway (ClinicalTrials.gov Identifier: NCT01647945) to evaluate the use of low-dose FK506 in PAH and to identify patients who might respond best to FK506 depending on their impairment in BMPR2 signaling.

Letter to the Editor A 53-year-old woman with thrombocytosis and pulmonary embolism

Letter to the Editor A 53-year-old woman with thrombocytosis and pulmonary embolism

Unexpected causes of pulmonary hypertension in a previously healthy Thai rural man with right-sided heart failure.

PatientMale, 52Final Diagnosis: Pulmonary hypertensionSymptoms: Diarrhea • dyspnea • jaundiceMedication: —Clinical Procedure: —Specialty: Endocrinology and MetabolicObjective:Unusual clinical courseBackground:Hyperthyroidism is one of the important causes of high-output failure and reversible pulmonary artery hypertension. Severe pulmonary artery hypertension is rarely found in associated with hyperthyroidism due to the small number of cases reported. We present an interesting case with multiple unexpected findings of the possible causes of severe pulmonary artery hypertension: hyperthyroidism, pulmonary embolism, and ostium secundum atrial septal defect.Case Report: We present the case of a previously healthy rural Thai man who progressively developed dyspnea on exertion, chronic diarrhea, and jaundice for the previous 3 months. Physical examination revealed right-sided predominate chronic heart failure with signs of pulmonary hypertension. The investigation demonstrated autoimmune hyperthyroidism, cholestatic jaundice, moderate tricuspid regurgitation, ostium secundum atrial septal defect, and severe pulmonary artery hypertension. After treatment with an anti-thyroid drug and closure of the ostium secundum atrial septal defect, his symptoms of jaundice and pulmonary artery pressure were completely resolved.Conclusions:Severe pulmonary artery hypertension may not solely be a result of hyperthyroidism. Further investigation for other causes is recommended.

Abstract B78: A Phase Ib study of demcizumab (DEM, anti-DLL4) with gemcitabine (GEM) in patients with first line locally advanced or metastatic pancreatic cancer.

Abstract Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. DEM also showed synergistic activity when combined with GEM in human pancreatic tumor-derived xenograft models. Material and Methods: Patients with first line stage III or IV pancreatic cancer received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks) and GEM 1000 mg/m2 7 of the 1st 8 wks and then 3 of every 4 wks until disease progression. The primary objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic, and biomarkers of Notch signaling and CSCs. Results: Twenty four patients were enrolled; 8 pts received 2.5 mg/kg every 2 wks, 8 received 2.5 mg/kg every 4 wks and 8 received 5 mg/kg every 4 wks of DEM. The median age was 65.5 yrs. Three (12.5%) and 21 (87.5%) patients had stage III and IV disease, respectively. Seven, 16 and 1 patients were ECOG performance status 0, 1, and 2, respectively. Related adverse events (all grades) in ≥10% of patients included: fatigue (29%), hypertension (29%), vomiting (29%), nausea (25%), thrombocytopenia (21%), decreased appetite (21%), increased B-type natriuretic peptide (BNP) (13%), anemia (13%), peripheral edema (13%), pulmonary hypertension (13%), dizziness (13%) and rash (13%). The hypertension was successfully managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One patient who received 5 mg/kg developed reversible pulmonary hypertension and heart failure on study day 143. As a result, the duration of DEM will be limited to 70 days in subsequent cohorts and paclitaxel protein-bound particles will also be added to the regimen. Four of 16 (25%) evaluable patients had a RECIST partial response and 7 had stable disease. The median progression free survival for the 5 mg/kg cohort was 5.9 months. The pharmacokinetic and immunogenicity samples are being analyzed and these data will be presented. Conclusion: DEM plus GEM was generally well tolerated with fatigue, hypertension and vomiting being the most common drug related adverse events. The duration of demcizumab therapy is being limited to 70 days in subsequent cohorts due to cardiopulmonary toxicity which was observed following more prolonged administration. Encouraging early clinical activity has been observed. Subsequent cohorts will include paclitaxel protein-bound particles. Enrollment is ongoing and updated results will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B78. Citation Format: Antonio Cubillo, Michael Jameson, Enrique Grande, Francis Parnis, Peter Grimison, Prasad Cooray, Mark Jeffery, Robert Stagg, Jakob Dupont, Niall Tebbutt. A Phase Ib study of demcizumab (DEM, anti-DLL4) with gemcitabine (GEM) in patients with first line locally advanced or metastatic pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B78.

Abstract A71: A Phase Ib study of demcizumab (DEM, anti-DLL4) plus pemetrexed and carboplatin in patients with first line stage IIIb/IV non-squamous non-small cell lung cancer.

Abstract Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material and Methods: Patients received DEM (2.5, 5, or 7.5 mg/kg), pemetrexed 500 mg/m2, and carboplatin (AUC = 6) every 3 weeks followed by maintenance DEM (first 4 cohorts) or pemetrexed (7.5 mg/kg cohort) every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were administered as pemetrexed pre-medication. The primary study objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic and biomarkers of Notch signaling. Results: Thirty patients have been enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg and 4 received 7.5 mg/kg of DEM once every 3 weeks. The median age was 63 years and 90% had stage IV disease. Related adverse events (all grades) in ≥10% of pts included: nausea (53%), fatigue (50%), hypertension (37%), vomiting (33%), neutropenia (27%), increased B-type natriuretic peptide (BNP) (23%), anemia (20%), peripheral edema (20%), increased ALT (20%), increased AST (17%), dyspnea, (17%), diarrhea (17%), decreased appetite (17%), pulmonary hypertension (13%), dysgeusia (13%), thrombocytopenia (13%), constipation (10%), and rash (10%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two patients receiving 5 mg/kg developed reversible pulmonary hypertension and heart failure on days 167 and 183, respectively. As a result, the duration of DEM was limited to 63 days in the 7.5 mg/kg dose cohort. The pharmacokinetics and immunogenicity specimens are being analyzed and these data will be presented. Nine of the 23 (39%) evaluable patients had a RECIST partial response and 11 had stable disease. The median progression free survival for the 5 mg/kg cohort was 5.3 months. Conclusion: DEM, pemetrexed and carboplatin was generally well tolerated with nausea, fatigue and hypertension being the most common drug related toxicities. The duration of demcizumab therapy is being limited to 63 days in subsequent cohorts due to cardiopulmonary toxicity which was observed following more prolonged administration. Encouraging early clinical activity has been observed. Enrollment is ongoing and updated results will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A71. Citation Format: Mark McKeage, Dusan Kotasek, Ben Markman, Michael Millward, Manuel Hildalgo, Michael Jameson, Dean Harris, Robert Stagg, Jakob Dupont, Brett Hughes. A Phase Ib study of demcizumab (DEM, anti-DLL4) plus pemetrexed and carboplatin in patients with first line stage IIIb/IV non-squamous non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A71.

Reversible Pulmonary Hypertension and Isolated Right Heart Failure Associated With Multiple Myeloma

Reversible Pulmonary Hypertension and Isolated Right Heart Failure Associated With Multiple Myeloma

Severe right heart failure in a tunisian patient with thyrotoxicosis: a case report

Hyperthyroidism has many characteristic manifestations of various organ systems. Cardiovascular effects are frequent in these patients. A less known complication of hyperthyroidism is reversible right-sided heart failure and pulmonary hypertension. In the patient presented, the symptoms of atrial fibrillation and right-sided heart failure were the first manifestations of hyperthyroidism. Doppler echocardiography confirmed pulmonary hypertension. Other secondary reasons for pulmonary hypertension were excluded. Graves' disease was the only reasonable choice. The treatment of hyperthyroidism resulted in conversion in sinus rhythm, withdrawal of symptoms and signs of right-sided heart failure, and normalization of pulmonary artery pressure.

Circulation Editors’ Picks

<i>Circulation</i> Editors’ Picks

Reversal of Pulmonary Hypertension after Diaphragm Pacing in an Adult Patient with Congenital Central Hypoventilation Syndrome

Patients with the congenital central hypoventilation syndrome (CCHS) suffer from life-threatening hypoventilation when asleep, making them dependent on mechanical ventilation (MV) at night or during naps. State-of-art respiratory management consists of intermittent positive-pressure ventilation via a tracheotomy or mask. In some patients hypoventilation is permanent, in which case ventilatory support must be extended to the waking hours. Diaphragm pacing can prove useful in such situations. This report describes the case of a 26-year-old woman with CCHS in whom failure to achieve adequate MV led to life-threatening pulmonary hypertension (PH), with a systolic pulmonary artery pressure (PAP) of 80 mmHg and right ventricular hypertrophy, despite optimization of all possible measures and despite extensive therapeutic education efforts. Diaphragm pacing using laparoscopically implanted intradiaphragmatic phrenic nerve stimulation electrodes corrected alveolar hypoventilation and lastingly reversed PH (systolic PAP below 40 mmHg after 2 months, sustained after 2 years). Diaphragm pacing induced shoulder pain, however, involving the chronic use of analgesics. The pacing had to be stopped for tolerance reasons after two years, leading to PH worsening and the need for diurnal MV. Diaphragm pacing appears likely effective to restore alveolar ventilation and reverse PH in adult CCHS patients.

Comparison of Drugs for Pulmonary Hypertension Reversibility Testing: A Meta‐Analysis

Multiple drugs are used for reversibility testing of pulmonary hypertension (PH) in advanced heart failure (HF), especially in the process of heart transplant evaluation. Effects of these drugs were never systematically compared. The aim of this meta-analysis was to compare hemodynamic effects of different drugs. We identified 20 prospective studies reporting hemodynamic variables before and after acute pharmacologic testing for PH reversibility in patients with advanced HF. The data from individual studies were grouped by an outcome measure and analyzed. A mixed model meta-analysis was performed using SAS to give weighted mean effect of pre- and post-test change and inverse variance. The mean effects were weighted by the published sample size. Prostacyclin, inhaled or intravenous, and prostaglandin E1 (PGE1) had the most potent effect on pulmonary vascular resistance (PVR). Sodium nitroprusside and nitroglycerin decreased pulmonary capillary wedge pressure (PCWP), and mean pulmonary arterial pressure (MPAP) better than other drugs. Sildenafil provided overall good hemodynamic outcomes but was not the strongest drug with regard to any particular outcome. PCWP, MPAP, and systolic pulmonary arterial pressure respond better to nitroglycerin and sodium nitroprusside than to other drugs in the setting of reversibility testing. Prostacyclin and PGE1 are superior to other drugs in their acute effects on PVR.

Reversal of pulmonary hypertension in children after adenoidectomy or adenotonsillectomy

IntroductionAdenotonsillar hypertrophy is a common condition in pediatric patients with upper respiratory airways complaints, and pulmonary arterial hypertension (PAH) may be one complication of that condition. ObjectivesTo study the occurrence of PAH (mean pulmonary artery pressure higher than or equal to 25mmHg) in a group of children with adenotonsillar hypertrophy and upper respiratory complaints (snoring or oral breathing), and to verify the pulmonary arterial pressure (PAP) changes after adenotonsillectomy. Study designCase–control prospective study. SettingsStudy conducted at São Lucas Hospital, approaching both public and private sector. Subject and methodsThirty-three pediatric patients with adenotonsillar hypertrophy and evidence of obstructive upper airways complaints were treated with adenotonsillectomy. All 33 patients underwent echocardiogram before and after the surgery with determination of the pulmonary arterial pressure (PAP), through either the tricuspid regurgitation or artery linear flow acceleration time estimation. Similar determinations were performed in 10 normal non operated controls. ResultsPulmonary hypertension was verified 12 (36%) of the 33 patients with adenotonsillar hypertrophy. Adenoidectomy or adenotonsillectomy was associated to a significant 27% decrease in mean PAP (27±2.8 to 20±5.1mmHg, p<0.001) and to a non significant 26% decrease in systolic PAP (35±6.2mmHg to 25±0.5mmHg, p=0.243). The PAP values in children with no pulmonary hypertension were not changed after the surgery. ConclusionsIn children with pulmonary hypertension associated to adenotonsillar hypertrophy, the adenotonsillectomy decreased PAP to normal values in all patients.

Pulmonary hypertension in POEMS syndrome.

POEMS syndrome is a rare clonal plasma cell disease. Patients with POEMS syndrome are at risk of developing pulmonary hypertension, but the data on its incidence and impact on outcome are limited. We reviewed records of 154 POEMS syndrome patients with complete duplex echocardiography data for estimation of pulmonary artery systolic pressure (sPAP) at the time of diagnosis. Forty-two (27%) of 154 patients with pulmonary hypertension (estimated sPAP ≥50 mmHg) were identified. Median age was 46 years (range 31-71 years). Patients with pulmonary hypertension were more likely to have peripheral edema (P=0.04), ascites (P=0.02), pleural effusion (P=0.005), and have longer time from onset to diagnosis (P=0.004) when compared with those without pulmonary hypertension. Restrictive abnormalities and decreased diffusion capacity of carbon monoxide were observed in 83% and 96% patients with pulmonary hypertension, compared with 50% and 72% in patients without pulmonary hypertension, respectively. Reversibility of pulmonary hypertension was observed after treatment of POEMS syndrome. After median follow of 32 months, survival of patients with pulmonary hypertension was worse than those without (median overall survival 54 months vs. median not reached, P=0.021). In conclusion, pulmonary hypertension is a common feature of POEMS syndrome, and is associated with signs of extravascular volume overload. Although active treatment of POEMS syndrome can reverse pulmonary hypertension, survival of these patients is worse than those without pulmonary hypertension.

Sildenafil vs. Nitroprussiato de Sódio durante Teste de Reatividade Pulmonar pré-transplante cardíaco

Pulmonary hypertension is associated with a worse prognosis after cardiac transplantation. The pulmonary hypertension reversibility test with sodium nitroprusside (SNP) is associated with a high rate of systemic arterial hypotension, ventricular dysfunction of the transplanted graft and high rates of disqualification from transplantation. This study was aimed at comparing the effects of sildenafil (SIL) and SNP on hemodynamic, neurohormonal and echocardiographic variables during the pulmonary reversibility test. The patients underwent simultaneously right cardiac catheterization, echocardiography, BNP measurement, and venous blood gas analysis before and after receiving either SNP (1 - 2 µg/kg/min) or SIL (100 mg, single dose). Both drugs reduced pulmonary hypertension, but SNP caused a significant systemic hypotension (mean blood pressure - MBP: 85.2 vs. 69.8 mm Hg; p < 0.001). Both drugs reduced cardiac dimensions and improved left cardiac function (SNP: 23.5 vs. 24.8%, p = 0.02; SIL: 23.8 vs. 26%, p < 0.001) and right cardiac function (SIL: 6.57 ± 2.08 vs. 8.11 ± 1.81 cm/s, p = 0.002; SNP: 6.64 ± 1.51 vs. 7.72 ± 1.44 cm/s, p = 0.003), measured through left ventricular ejection fraction and tissue Doppler, respectively. Sildenafil, contrary to SNP, improved venous oxygen saturation, measured on venous blood gas analysis. Sildenafil and SNP are vasodilators that significantly reduce pulmonary hypertension and cardiac geometry, in addition to improving biventricular function. Sodium nitroprusside, contrary to SIL, was associated with systemic arterial hypotension and worsening of venous oxygen saturation.

Reversible pulmonary hypertension associated with lungworm infection in a young cat

Two ten-week-old kittens presented with dyspnea. Two weeks later dyspnea had worsened and both kittens had developed a heart murmur. One kitten died and necropsy showed severe granulomatous pneumonia and moderate bronchi(oli)tis and peribronchi(oli)tis caused by Aelurostrongylus abstrusus. The results from echocardiography, thoracic radiography and the other kitten's fecal examination were interpreted as severe parasitic pneumonia caused by A. abstrusus infection with pulmonary hypertension. Repeated administration of milbemycine-oxime and praziquantel resulted in cessation of larvae shedding and resolution of clinical, radiographic and echocardiographic signs of bronchopneumonia and pulmonary hypertension.

World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation

Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Reversible pulmonary hypertension in a kidney transplant with patent A-V fistula.

Pulmonary hypertension (PH) occurs in end-stage renal disease (ESRD) patients on long-term haemodialysis (HD) using an arterio-venous (A-V) access and can be attenuated by either kidney transplantation per se or surgical fistula ligation/revision. We report an exceptional case with severe PH after kidney transplantation due to ESRD and prior chronic intermittent HD via a patent A-V fistula. Gold-standard right heart catheterization findings have—for the first time—proven that following surgical shunt ligation of the A-V fistula, haemodynamics normalized completely in this patient.

Usefulness of A Mouse Model of Reversible Pulmonary Arterial Hypertension: Be Cautious, Choose Carefully

Usefulness of A Mouse Model of Reversible Pulmonary Arterial Hypertension: Be Cautious, Choose Carefully

Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries

The potassium channel TWIK-related acid sensitive potassium (TASK)-1 channel, together with other potassium channels, controls the low resting tone of pulmonary arteries. The Src family tyrosine kinase (SrcTK) may control potassium channel function in human pulmonary artery smooth muscle cells (hPASMCs) in response to changes in oxygen tension and the clinical use of a SrcTK inhibitor has resulted in partly reversible pulmonary hypertension. This study aimed to determine the role of SrcTK in hypoxia-induced inhibition of potassium channels in hPASMCs. We show that SrcTK is co-localised with the TASK-1 channel. Inhibition of SrcTK decreases potassium current density and results in considerable depolarisation, while activation of SrcTK increases potassium current in patch-clamp recordings. Moderate hypoxia and the SrcTK inhibitor decrease the tyrosine phosphorylation state of the TASK-1 channel. Hypoxia also decreases the level of phospho-SrcTK (tyr419) and reduces the co-localisation of the TASK-1 channel and phospho-SrcTK. Corresponding to this, hypoxia reduces TASK-1 currents before but not after SrcTK inhibition and, in the isolated perfused mouse lung, SrcTK inhibitors increase pulmonary arterial pressure. We propose that the SrcTK is a crucial factor controlling potassium channels, acting as a cofactor for setting a negative resting membrane potential in hPASMCs and a low resting pulmonary vascular tone.

431 Is Improvement in Pulmonary Vascular Hemodynamics in Patients Supported with Continuous-Flow Left Ventricular Assist Devices Sustained after Heart Transplantation?

Pulmonary hypertension (PHT) is common in patients with advanced heart failure (HF) and is also a risk factor for mortality after heart transplantation (HTx). Severe PHT is a contraindication for HTx. Continuous-flow left ventricular assist devices (CF-LVADs) are widely used as a bridge to HTx in these patients. Several studies have shown that reversal of PHT after LVAD placement allows for HTx in these patients. However, it is debatable whether CF-LVADs are as effective as pulsatile LVADs in unloading the heart.