Phase 2B Study of Inhaled RVT-1601 for Chronic Cough in Idiopathic Pulmonary Fibrosis: A Multicenter, Randomized, Placebo-controlled Study (SCENIC Trial).

Rationale: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2A study, inhaled RVT-1601 (cromolyn sodium) reduced daytime cough and 24-hour average cough counts in patients with IPF. Objectives: To determine the efficacy, safety, and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF. Methods: In this multicenter, randomized, placebo-controlled phase 2B study, patients with IPF and chronic cough for ⩾8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough-specific quality of life. Safety was monitored throughout the study. Measurements and Main Results: The study was prematurely terminated owing to the impact of the coronavirus disease (COVID-19) pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-square mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and the placebo group. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated. Conclusions: Treatment with inhaled RVT-1601 (10, 40, and 80 mg three times a day) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF.

The effects of catheter ablation of outflow tract premature ventricular complexes on atrial electromechanical delay.

BACKGROUND: Consistent data from several studies have shown that catheter ablation of frequent premature ventricular complexes (PVCs) results in substantial improvement in left ventricular ejection fraction (LVEF), left ventricular diastolic function, and left atrial volume and mechanics. However, the effects of catheter ablation of PVCs on atrial electromechanical properties have not been documented yet. AIMS: In the present study, we investigated the short-term effects of radiofrequency catheter ablation (RFCA) of outflow tract PVCs on atrial electromechanical delay (EMD). METHODS: A total of 71 subjects with idiopathic outflow tract PVCs who underwent RFCA were included. Interatrial and intra-atrial EMDs were measured by tissue Doppler imaging before and 3 months after catheter ablation. RESULTS: The study population was divided into normal ejection fraction (EF) and low-EF subgroups according to their LVEF. In all study groups, substantial improvement was found in lateral electromechanical coupling time (PA), septal PA, right ventricular PA, interatrial EMD, left-sided intra-atrial EMD, and right-sided intra-atrial EMD. No treatment heterogeneity was observed when comparing low-EF and normal-EF subgroups with respect to atrial EMDs (interatrial EMD, interaction p = .29; left-sided intra-atrial EMD, interaction p = .13; right-sided intra-atrial EMD, interaction p = .88). CONCLUSION: RFCA of outflow tract PVC has a favorable early effect on intra- and inter-atrial EMDs irrespective of preprocedural LVEF.

A novel index combining diastolic and systolic tissue Doppler parameters for predicting cardiac resynchronization therapy response.

OBJECTIVE: Identification of patients who are nonresponders to cardiac resynchronization therapy (CRT) with the use of simple and objective parameters may be helpful in tailoring treatment. The aim of this study is to investigate whether E/(Ea × Sa) could be a predictor of CRT nonresponders (E = early diastolic transmitral velocity, Ea = early diastolic mitral annular velocity, Sa = systolic mitral annular velocity). METHODS: In total, 53 heart failure patients were evaluated for this study, and 33 patients were included according to the study criteria. Before and 6 months after CRT-D(CRT with a defibrillator) implantation, E, Ea, and Sa were determined at the medial and lateral mitral annular sites, and the average values were obtained. E/(Ea × Sa) was calculated (medial, lateral, average). The patients were followed for 6 months to monitor their CRT response. A responder was defined as a patient with a reduction in end-systolic volume of ≥15% and an increase in 6-minute walking distance of 50 m. RESULTS: At a 6-month follow-up, 24 (72.7%) of the 33 patients responded to CRT. At the 6-month follow-up, in the responder group, the E/Ea ratio, lateral mitral, and average E/(Ea × Sa) indices were significantly reduced (P < .01 for all). The baseline lateral mitral, medial mitral, and average E/(Ea × Sa) indices were significantly lower in the responder group than in the nonresponder group (P ≤ .01 for all). The receiver operating characteristic analysis showed that all the E/(Ea × Sa) indices predict the CRT nonresponder patients. The AUC values were 0.89 (lateral E/(Ea × Sa)), 0.85 (average E/(Ea × Sa)), and 0.77 (medial E/(Ea × Sa)) (P ≤ .01 for all). CONCLUSION: We found that the E/(Ea × Sa) index is a novel predictor of CRT nonresponder patients.

Successful cryoablation of atrial fibrillation from jugular approach in patient with interrupted inferior vena cava and azygos continuation.

We herein report successful cryoablation of paroxysmal atrial fibrillation via right jugular vein in a patient with interrupted inferior vena cava. We preferred cryoablation instead of radiofrequency ablation in the treatment of our patient. For stronger support in aiming the Brockenbrough needle toward the septum, we manuallly curved the needle with a 120° angle about 6 cm proximal to the tip. After successful transseptal puncture, we performed balloon dilatation in the septal puncture zone to facilitate passage. Cryoablation has theoretical advantage, particularly in challenging anatomies, in which it eliminates the need for point-by-point ablation around the pulmonary vein.

Left Atrial Function Is Improved in Short-Term Follow-Up after Catheter Ablation of Outflow Tract Premature Ventricular Complexes.

Background: Association of premature ventricular complexes (PVC) with left ventricular systolic dysfunction (LVSD) and efficacy of catheter ablation treatment have been demonstrated in studies. The role of left atrial (LA) mechanics in the etiopathogenesis of PVC-induced cardiomyopathy (PVC-CMP) as well as changes in LA mechanics with catheter ablation have not been studied before. Methods: A total number of 61 patients (Mean Age 43 ± 3) with idiopathic outflow tract (OT) PVCs undergoing radiofrequency catheter ablation (RFCA) were enrolled. ECG, 24 h Holter, and echocardiographic evaluation with left ventricular (LV) diastolic functions and LA volumetric assessments were performed before and three months after RFCA. Results: Along with a marginal increase in left ventricle ejection fraction (LVEF), improvement in diastolic functions and left atrial mechanics were observed in the study (LVEF 53 ± 7 versus 57 ± 6, p < 0.01) in short-term follow-up. The frequency of LV diastolic dysfunction (LVDD) decreased with catheter ablation (n = 5 to 0, p = 0.02). The overall LA function improved. Left atrium passive and overall emptying fraction (LAEF) increased significantly (0.32 ± 0.04 to 0.41 ± 0.04, p < 0.05 and 0.62 ± 0.04 to 0.65 ± 0.004, p < 0.05, respectively). Active LAEF decreased significantly (0.29 ± 0.005 to 0.24 ± 0.006, p < 0.05). Conclusions: The results of this study are indicative of "PVC-induced atriomyopathy" which responds to RFCA in short-term follow-up. Atrial dysfunction might play a role in symptoms and etiopathogenesis of LVSD.

Hourglass-shaped right ventricle and localized constrictive pericarditis.

Constrictive pericarditis is characterized by thick pericardial fibrosis and frequent calcification that progressively impairs diastolic filling of the heart. The diagnosis of constrictive pericarditis has been challenging even though multiple diagnostic modalities have been developed. The diagnosis of constructive pericarditis is especially difficult in localized constrictive pericarditis which is extremely rare. We report a case of localized constrictive pericarditis with a 3D multislice cardiac computed tomography (CT) finding of the constrictive band causing strangulation and hourglass shaping of the right ventricle.

A Novel Index Combining Diastolic and Systolic Tissue Doppler Parameters for Prediction of Atrial Fibrillation Recurrence.

OBJECTIVE: Identification of patients at risk for atrial fibrillation (AF) recurrence with using simple and objective parameters may be helpful in tailoring the treatment. In this study, we investigated whether E/(Ea×Sa) and Ea/(Aa×Sa) could be a predictor of AF recurrence after cardioversion. (E = early diastolic transmitral velocity, Ea = early diastolic mitral annular velocity, Aa = late diastolic mitral annular velocity, Sa = systolic mitral annular velocity). METHODS: In total, 127 patients with persistent AF were evaluated for this study and 73 patients were included according to the study criteria. Sinus rhythm (SR) was achieved for 70 patients after electrical direct-current cardioversion. E, Sa, Ea, and Aa were determined at mitral medial and lateral site and average values obtained. E/(Ea×Sa) and Ea/(Aa×Sa) were calculated (medial, lateral, average). Heart rate and rhythm were followed with an electrocardiography (ECG) monitor and 12-lead ECG at first week and first month. RESULTS: At one month, 53 patients (75.7%) were in SR, whereas 17 patients (24.3%) reverted to AF. According to precardioversion E/(Ea×Sa) lateral, E/(Ea×Sa) medial, E/(Ea×Sa) average (P ≤ 0.01 for all the indices), 24-hour echocardiographic evaluation E/(Ea×Sa) lateral, E/(Ea×Sa) medial, E/(Ea×Sa) average, Ea/(Aa×Sa) lateral, Ea/(Aa×Sa) medial, and Ea/(Aa×Sa) average (P ≤ 0.01 for all the indices), indices were significantly higher in the AF recurrence group than in the SR group. Furthermore, the ROC analysis showed that all the E/(Ea×Sa) and Ea/(Aa×Sa) parameters predict the AF recurrence. The AUC values range from 70% to 81% (P ≤ 0.01 for all the parameters). In subgroup analysis of the patients, precardioversion mitral medial E/Ea ratio was between 8 and 15, and the ROC analysis showed that the novel indices predict the AF recurrence. The AUC values range from 72% to 86% (P ≤ 0.02 for all the parameters). CONCLUSIONS: We found that E/(Ea×Sa) and Ea/(Aa×Sa) indices are novel predictors of AF recurrence.

Efficacy and safety of nebulized glycopyrrolate for administration using a high efficiency nebulizer in patients with chronic obstructive pulmonary disease.

AIMS: To establish the dose-response for pharmacodynamics (bronchodilatation), safety and pharmacokinetics for a nebulized formulation of the long acting muscarinic antagonist glycopyrrolate (EP-101) with a high efficiency nebulizer in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients with moderate to severe COPD (GOLD II/III), with reversible lung function, were enrolled into this randomized, double-blind, placebo-controlled, six period crossover study (n = 42). Patients received single doses of EP-101 (12.5-400 µg) and placebo via a high efficiency nebulizer (eFlow® PARI nebulizer), with washout between treatments. Plasma pharmacokinetics were assessed in a subset of patients (n = 11). RESULTS: All treatments were well tolerated with similar adverse event rates reported with placebo and at all doses. There were no clinically relevant changes in heart rate, systolic and diastolic blood pressure or in ECG parameters including QTc interval. Following treatment with EP-101 at all doses there was a rapid bronchodilator response within 5 min. Significant improvements in mean change from baseline FEV1 at 24 h were reported at doses ≥ 50 µg compared with placebo, with a clear dose-response relationship. Mean changes in FEV1 were 0.10 l (95% CI 0.06, 0.14) and 0.12 l (95% CI 0.08, 0.16) for 100 µg and 200 µg, respectively. CONCLUSION: Single doses of EP-101 ranging from 12.5 µg to 400 µg were well tolerated. EP-101 delivered by high efficiency nebulizer device produced a rapid onset of bronchodilatation with clinically meaningful improvements in lung function maintained over a 24 h period at all doses >50 µg.

Effects of off-pump versus on-pump coronary artery bypass grafting: apoptosis, inflammation, and oxidative stress.

BACKGROUND: It has been suggested that off-pump coronary artery bypass grafting (CABG) surgery reduces myocardial ischemia-reperfusion injury, postoperative systemic inflammatory response, and oxidative stress. The aim of this study was to measure serum malondialdehyde (MDA), high-sensitivity C-reactive protein (hs-CRP), M30, and M65 levels and to investigate the relationship between M30 levels and oxidative stress and inflammation in patients undergoing on-and off-pump CABG surgery. METHODS: Fifty patients were randomly assigned to on-pump or off-pump CABG surgery (25 patients off-pump and 25 on-pump CABG surgery), and blood samples were collected prior to surgery, and 30 minutes, 60 minutes, 6 hours, and 24 hours after CABG surgery. RESULTS: Compared to the on-pump group, serum MDA levels at 30 minutes, 60 minutes, 6 hours, and 24 hours after the CABG surgery were significantly lower in the off-pump group (P=.001, P=.001, P=.001, and P=.001, respectively). Serum M30 levels were found to be elevated in both groups, returning to baseline at 24 hours. When compared to baseline, the hs-CRP level reached its peak at 24 hours at 13.28±5.32 mg/dL in the on-pump group, and 15.44±4.02 mg/dL in the off-pump group. CONCLUSION: CABG surgery is associated with an increase in inflammatory markers and serum M30 levels, indicating epithelial/endothelial apoptosis in the early period.

Predictive Value of C2HEST Score for Atrial Fibrillation Recurrence Following Successful Cryoballoon Pulmonary Vein Isolation in Paroxysmal Atrial Fibrillation.

The C2HEST score ((coronary artery disease (CAD) or chronic obstructive pulmonary disease (COPD) [C2, 1 point each]; hypertension [H, 1 point]; elderly [E, age ≥75 years, 2 points]; systolic heart failure [S, 2 points]; thyroid disease [T, hyperthyroidism, 1 point]) has been validated for predicting incidental atrial fibrillation (AF) in both the general population and patients with ischemic stroke. The present study evaluated the performance of this score in predicting AF recurrence in 252 patients following cryoballoon ablation (CRYO) for paroxysmal AF. The AF recurrence rate in 3-12 months following CRYO was 20,2%. The predictive value of the C2HEST score was significantly better than that of the CHA2DS2-VASc score ((congestive heart failure, hypertension, age (>65 = 1 point, >75 = 2 points), diabetes, previous stroke/transient ischemic attack (2 points), vascular disease, age 65-74 years, and sex category)) (area under curve [AUC]: .881 vs .741; P = .0017). C2HEST score of ≥2, increased atrial diameter, and E/e' ratio as well as, the presence of COPD and systolic heart failure (SHF) were independent predictors for AF recurrence (P < .05). In patients undergoing CRYO for paroxysmal AF, the C2HEST, a simple clinical score, could be useful to assess the risk of AF recurrence.

Successful radiofrequency catheter ablation of idiopathic premature ventricular complexes originating from the outflow tract improves heart failure-related quality of life.

BACKGROUND: To investigate the effect of successful RFCA in patients with idiopathic outflow tract PVCs (OT-PVC) on left heart functions, neurohormonal activation, functional status, and heart failure-related quality of life (HFQoL), with an integrated approach. METHODS: Patients with frequent OT-PVCs, determined by 12-lead surface ECG who underwent radiofrequency catheter ablation (RFCA) with an acute success, were prospectivelly enrolled. Left heart functions were evaluated with the use of transthoracic echocardiography, neurohormonal activation with N-terminal Pro-brain natriuretic peptide (BNP), functional class with New York Heart Association (NYHA) and 6-min walking distance (6MWD), and HFQoL with Minnesota Living with Heart Failure Questionnaire (MLHFQ), at baseline and at 6 months. RESULTS: A total of 108 patients were included in this study (43 ± 12 years old, 56% male). Majority of the OT-PVCs originated from aortic valve and right ventricle outflow tract (44% and 37%, respectively). Total RF time was 216 ± 87 s. Major complication rate was 0.9%. Left ventricle (LV) ejection fraction increased from 47 ± 8 to 53 ± 6% at 6 months (p < 0.001). Neurohormonal activation was suppressed significantly (104 ± 69 to 83 ± 42, p < 0.001). Functional class improved with %NYHA-I patients increasing from 54 to 89% (p < 0.001) and 6MWD from 293 ± 73 to 335 ± 59 m (p < 0.001). MLHFQ score improved from 32 ± 9 to 23 ± 5 p < 0.001. In multivariable analysis, LV end-systolic diameter (LVESD) and 6MWD were independent predictors of improvement in MLHFQ (for LVESD Uß: - 0.26, 95%CI [0.44-0.09], p < 0.004 and for 6MWD: 0.04, 95%CI [0.03-0.06], p < 0.001). CONCLUSIONS: RFCA of OT-PVCs is associated with improved well-being of patients, determined by left heart functions, neurohormonal activation, functional class, and HFQoL.

A New Perspective for Isolated Coronary Artery Ectasia: Cystatin C.

Introduction The pathophysiology of isolated coronary artery ectasia (iCAE) has not been clearly identified, although multiple abnormalities, including arteritis, endothelial dysfunction, and vascular destruction, have been reported. In this study, we aimed to analyze serum cystatin C concentrations in patients with iCAE and controls. Methods Forty-seven patients with iCAE (mean age: 55.9 ± 11.5) and 32 individuals with normal coronary angiography (mean age: 57.8.1 ± 9.6) were included in the study. Plasma cystatin C levels were measured by using the principle of particle-enhanced turbidimetric immunoassay (PETIA). Results Serum cystatin C concentrations were significantly lower in patients with iCAE compared with the control group (0.98 ± 0.17 mg/L versus 1.17 ± 2.6 mg/L, p-value = 0.001). A significantly positive relationship was found between serum cystatin C levels and creatinine and high-sensitivity C-reactive protein (hs-CRP) levels in both groups (r-value = 0.288, p-value = 0.005, r-value = 0.143, p-value = 0.007, respectively). In multivariate logistic regression analysis, serum cystatin C level found to be a significant predictor for the presence of iCAE (OR: 0.837, CI: 95% (0.341 - 1.637), p-value = 0.013). Receiver operating characteristic (ROC) analysis determined that a cystatin C value < 1.02 mg/L had a sensitivity of 56% and a specificity of 78% for the prediction of ectasia. Conclusion We conclude that cystatin C independently can be a useful predictor for the presence of iCAE.

A pulmonary arteriovenous malformation treated with percutaneous intervention.

A pulmonary arteriovenous malformation (PAVM) is a rare anomaly that may have significant clinical complications. PAVMs are commonly seen in patients with hereditary hemorrhagic telangiectasia, while some 10% of PAVMs may be idiopathic. PAVMs can cause cyanosis, fatigue, polycythemia, and paradoxical thromboembolic complications. The diagnosis and treatment of a PAVM should be performed with great care, as the disorder may be fatal if not properly treated. Percutaneous closure (such as embolization) can be very beneficial. Presently described is the case of a 23-year-old man with an idiopathic PAVM who was treated percutaneously with 3 vascular plugs.

Effect of Echocardiographic Epicardial Adipose Tissue Thickness on Success Rates of Premature Ventricular Contraction Ablation

Background: Idiopathic premature ventricular contractions are frequently detected ventricular arrhythmias, and radiofrequency ablation is an effectively treatment for improving symptoms and eliminating premature ventricular contractions. Studies have reported a relationship between an elevated epicardial adipose tissue thickness and myocardial structural pathologies. However, the association between epicardial adipose tissue thickness and success rates of premature ventricular contraction ablation has not yet been investigated. Aims: To assess the relationship between epicardial adipose tissue thickness and success rates of premature ventricular contraction ablation. Study Design: Retrospective case-control study. Methods: This study enrolled a total of 106 consecutive patients who have had a high premature ventricular contraction burden of >10,000/24-h assessed using ambulatory Holter monitorization and underwent catheter ablation. A frequency of premature ventricular contractions of more than 10,000/day was defined as frequent premature ventricular contraction. Epicardial adipose tissue thickness was measured using 2D transthoracic echocardiography. A successful ablation was defined as >80% decrease in pre-procedural premature ventricular contraction attacks with the same morphology during 24-h Holter monitorization after a 1-month follow-up visit from an ablation procedure. Results: Successful premature ventricular contraction ablation was achieved in 87 (82.1%) patients. Epicardial adipose tissue thickness was significantly higher in patients with unsuccessful ablation (p<0.001). Procedure time, total fluoroscopy time, and radiofrequency ablation time were statistically higher in the unsuccessful group (p<0.001). Stepwise multivariate logistic regression analysis showed that epicardial adipose tissue thickness and pseudo-delta wave time were independently associated with procedural success (both p values <0.001). In the receiver-operating curve analysis, epicardial adipose tissue thickness was found to be an important predictor for procedural success (area under the receiver-operating characteristic curve= 0.85, p=0.001), with a cutoff value of 7.7 mm, a sensitivity of 92%, and a specificity of 68%. Conclusion: Epicardial adipose tissue thickness is higher in patients with premature ventricular contraction ablation failure, which may be indicative of procedural success.

Transcatheter closure of atrial septal defect with atrial septal occluder in a patient with nickel allergy.

Presently described is transcatheter closure of atrial septal defect with atrial septal occluder (ASO) device in a patient with nickel allergy. Patients with metal allergy who will undergo nitinol device implantation should be tested for possible nickel hypersensitivity. ASO device and treatment strategy (percutaneous or surgical) should be selected according to allergy test result.

The impact of cardiac rhythm on the mitral valve area and gradient in patients with mitral stenosis.

OBJECTIVE: The aim of this study was to evaluate the effect of cardiac rhythm on the echocardiographic mitral valve area (MVA) and transmitral gradient calculation in relation to net atrioventricular compliance (Cn). METHODS: Patients (n=22) with mild or moderate pure rheumatic mitral stenosis (MS) (MVA <2 cm2 and MVA >1 cm2) and atrial fibrillation (AF) were evaluated. All patients underwent transthoracic electrical DC cardioversion under amiodarone treatment. Nineteen of the 22 patients were successfully converted to sinus rhythm (SR). The patients were evaluated with transthoracic echocardiography before and two to three days after DC cardioversion. In order to deal with variable R-R intervals, the measurements were averaged on five to eight consecutive beats in AF. Cn was calculated with a previously validated equation [Cn (mL/mm Hg)=1.270 x MVA/E-wave downslope]. The Cn difference between AF and SR was calculated as follows: [(AF Cn-SR Cn)/AF Cn] x 100. The percentage gradient (mean or maximal) difference between AF and SR was calculated as follows: [AF gradient (mean or maximal) - SR gradient (mean or maximal)]/[AF gradient (mean or maximal)] x 100. RESULTS: The MVA was lower (MVA planimetric; 1.62±0.29 vs. 1.54±0.27; p=.003, MVA PHT; 1.66±0.30 vs. 1.59±0.26; p=0.01) but transmitral gradient (mean gradient; 6.49±2.51 vs. 8.89±3.52; p=0.001, maximal gradient: 16.94±5.11 vs. 18.57±4.54; p=0.01) and Cn values (5.37±0.77 vs. 6.26±0.64; p<0.001) were higher in the AF than SR. There was a significant correlation between Cn difference and transmitral gradient difference (mean and maximal) (Cn difference-mean gradient difference; r=0.46; p=0.05; Cn difference-maximal gradient difference; r=0.72; p=0.001). CONCLUSION: Cardiac rhythm has a significant impact on echocardiographic evaluation of MVA, transmitral gradient, and Cn in patients with MS.

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.

BACKGROUND: Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. METHODS: This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. FINDINGS: Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. INTERPRETATION: This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation. FUNDING: Patara Pharma.

A Very Rare Coronary Artery Anomaly: Two Circumflex Arteries Originating From Both Right and Left Coronary Sinuses of Valsalva.

Coronary anomalies are found in less than 1% of diagnostic coronary angiograms. The clinical importance of coronary anomalies varies from insignificant to life-threatening. We report a very rare case of a patient with two circumflex arteries originating from both right and left coronary sinuses of Valsalva.

Evaluation of Tp-Te Interval and Tp-Te/QT Ratio in Patients with Coronary Slow Flow Tp-Te/QT Ratio and Coronary Slow Flow.

OBJECTIVE: Coronary slow flow (CSF) phenomenon is described by angiographically normal coronary arteries with delayed opacification of the distal vasculature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-Te) may correspond to the transmural dispersion of the repolarization and that increased Tp-Te interval and Tp-Te/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate the ventricular repolarization by using Tp-Te interval and Tp-Te/QT ratio in patients with CSF. MATERIALS AND METHODS: This study included 50 CSF patients (40 male, mean age 48.6±12.5 years) and 40 control individuals (23 male, mean age 47.8±12.5 years). Tp-Te interval and Tp-Te/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared in groups. RESULTS: Baseline characteristics of the study groups were comparable. In electrocardiographic parameters analysis, QT and corrected QT were similar in CSF patients compared to the controls (357±35.2 vs 362±38.0 milliseconds and 419±25.8 vs 430±44.2 milliseconds, all p value >0.05). Tp-Te interval, Tp-Te/QT and Tp-Te/QTc ratio were significantly higher in CSF patients (85±13.7 vs 74±9.9 milliseconds and 0.24±0.03 vs 0.20±0.02 and 0.20±0.03 vs 0.17±0.02 all p value <0.001). CONCLUSION: Our study revealed that QTd, Tp-Te interval and Tp-Te/QT ratio are prolonged in patients with CSF.