Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension.

BACKGROUND: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. METHODS: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. RESULTS: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. CONCLUSIONS: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.

Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies.

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Anatomical characterization of pulmonary artery and implications to pulmonary artery pressure monitor implantation.

In patients with heart failure, guideline directed medical therapy improves outcomes and requires close patient monitoring. Pulmonary artery pressure monitors permit remote assessment of cardiopulmonary haemodynamics and facilitate early intervention that has been shown to decrease heart failure hospitalization. Pressure sensors implanted in the pulmonary vasculature are stabilized through passive or active interaction with the anatomy and communicate with an external reader to relay invasively measured pressure by radiofrequency. A body mass index > 35 kg/m2 and chest circumference > 165 cm prevent use due to poor communication. Pulmonary vasculature anatomy is variable between patients and the pulmonary artery size, angulation of vessels and depth of sensor location from the chest wall in heart failure patients who may be candidates for pressure sensors remains largely unexamined. The present study analyses the size, angulation, and depth of the pulmonary artery at the position of implantation of two pulmonary artery pressure sensors: the CardioMEMS sensor typically implanted in the left pulmonary artery and the Cordella sensor implanted in the right pulmonary artery. Thirty-four computed tomography pulmonary angiograms from patients with heart failure were analysed using the MIMICS software. Distance from the bifurcation of the pulmonary artery to the implant site was shorter for the right pulmonary artery (4.55 ± 0.64 cm vs. 7.4 ± 1.3 cm) and vessel diameter at the implant site was larger (17.15 ± 2.87 mm vs. 11.83 ± 2.30 mm). Link distance (length of the communication path between sensor and reader) was shorter for the left pulmonary artery (9.40 ± 1.43 mm vs. 12.54 ± 1.37 mm). Therefore, the detailed analysis of pulmonary arterial anatomy using computed tomography pulmonary angiograms may alter the choice of implant location to reduce the risk of sensor migration and improve readability by minimizing sensor-to-reader link distance.

Lacticaseibacillus rhamnosus FM9 and Limosilactobacillus fermentum Y57 Are as Effective as Statins at Improving Blood Lipid Profile in High Cholesterol, High-Fat Diet Model in Male Wistar Rats.

Elevated serum cholesterol is a major risk factor for coronary heart diseases. Some Lactobacillus strains with cholesterol-lowering potential have been isolated from artisanal food products. The purpose of this study was to isolate probiotic Lactobacillus strains from traditional yoghurt (dahi) and yogurt milk (lassi) and investigate the impact of these strains on the blood lipid profile and anti-obesity effect in a high cholesterol high fat diet model in Wistar rats. Eight candidate probiotic strains were chosen based on in vitro probiotic features and cholesterol reduction ability. By 16S rDNA sequencing, these strains were identified as Limosilactibacillus fermentum FM6, L. fermentum FM16, L. fermentum FM12, Lacticaseibacillus rhamnosus FM9, L. fermentum Y55, L. fermentum Y57, L. rhamnosus Y59, and L. fermentum Y63. The safety of these strains was investigated by feeding 2 × 108 CFU/mL in saline water for 28 days in a Wistar rat model. No bacterial translocation or any other adverse effects were observed in animals after administration of strains in water, which indicates the safety of strains. The cholesterol-lowering profile of these probiotics was evaluated in male Wistar rats using a high-fat, high-cholesterol diet (HFCD) model. For 30 days, animals were fed probiotic strains in water with 2 × 108 CFU/mL/rat/day, in addition to a high fat, high cholesterol diet. The cholesterol-lowering effects of various probiotic strains were compared to those of statin. All strains showed improvement in total cholesterol, LDL, HDL, triglycerides, and weight gain. Serum cholesterol levels were reduced by 9% and 8% for L. rhamnosus FM9 and L. fermentum Y57, respectively, compared to 5% for the statin-treated group. HDL levels significantly improved by 46 and 44% for L. rhamnosus FM9 and L. fermentum Y57, respectively, compared to 46% for the statin-treated group. Compared to the statin-treated group, FM9 and Y57 significantly reduced LDL levels by almost twofold. These findings show that these strains can improve blood lipid profiles as effectively as statins in male Wistar rats. Furthermore, probiotic-fed groups helped weight control in animals on HFCD, indicating the possible anti-obesity potential of these strains. These strains can be used to develop food products and supplements to treat ischemic heart diseases and weight management. Clinical trials, however, are required to validate these findings.

A Plum On Thumb: A Rare Presentation Of Synovial Sarcoma.

Synovial sarcoma (SS) is a rare and aggressive mesenchymal tumour accounting for around 5-10% soft tissue neoplasms usually found in joints of upper and lower extremities. A 35years old healthy looking male patient from Afghanistan presented with swelling on palmar side of base of thumb from last one year. Seven months back excisional biopsy was taken report of which showed neurofibroma/dermatofibroma with. No evidence of malignancy seen. From last 5months mass reappeared and gradually increased in size with itching sensation and mild pain. On local examination there was 5×4×5 cm reddish mass on palmar surface of base of thumb with extension into mid thenar eminence with diffuse margins. X-ray showed soft tissue density mass with spikes of calcification. Ultrasound showed 4.2×4×4.5 cm heterogeneous solid lesion on anteromedial surface of root of right thumb without any remarkable intralesional calcification and remarkable intralesional vasculature. MRI reported lobulated well defined soft tissue mass eliciting low to intermediate signal on T1 and WIs and bright signal on T2and STIR Vividly enhancing mass. Case was operated mass was excised and biopsy sent. Post op status was unremarkable. Biopsy reported poorly differentiated biphasic synovial sarcoma. No recurrence seen till 3months.

Left ventricular blood flow kinetic energy is associated with the six-minute walk test and left ventricular remodelling post valvular intervention in aortic stenosis.

BACKGROUND: Left ventricular (LV) kinetic energy (KE) assessment by four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) may offer incremental value over routine assessment in aortic stenosis (AS). The main objective of this study is to investigate the LV KE in patients with AS before and after the valve intervention. In addition, this study aimed to investigate if LV KE offers incremental value for its association to the six-minute walk test (6MWT) or LV remodelling post-intervention. METHODS: We recruited 18 patients with severe AS. All patients underwent transthoracic echocardiography for mean pressure gradient (mPG), CMR including 4D flow and 6MWT. Patients were invited for post-valve intervention follow-up CMR at 3 months and twelve patients returned for follow-up CMR. KE assessment of LV blood flow and the components (direct, delayed, retained and residual) were carried out for all cases. LV KE parameters were normalised to LV end-diastolic volume (LVEDV). RESULTS: For LV blood flow KE assessment, the metrics including time delay (TD) for peak E-wave from base to mid-ventricle (14±48 vs. 2.5±9.75 ms, P=0.04), direct (4.91±5.07 vs. 1.86±1.72 µJ, P=0.01) and delayed (2.46±3.13 vs. 1.38±1.15 µJ, P=0.03) components of LV blood flow demonstrated a significant change between pre- and post-valve intervention. Only LV KEiEDV (r=-0.53, P<0.01), diastolic KEiEDV (r=-0.53, P<0.01) and Ewave KEiEDV (r=-0.38, P=0.04) demonstrated association to the 6MWT. However, Pre-operative LV KEiEDV (r=0.67, P=0.02) demonstrated association to LV remodelling post valve intervention. CONCLUSIONS: LV blood flow KE is associated with 6MWT and LV remodelling in patients with AS. LV KE assessment provides incremental value over routine LV function and pressure gradient (PG) assessment in AS.

An exercise-based cardiac rehabilitation programme for AF patients in the NHS: a feasibility study.

There is increasing evidence for the role of exercise-based cardiac rehabilitation in the management of patients with atrial fibrillation (AF). However, this intervention has not yet been widely adopted within the National Health Service (NHS). We performed a feasibility study on the utilisation of an established NHS cardiac rehabilitation programme in the management of AF, and examined the effects of this intervention on exercise capacity, weight, and psychological health. We then identified factors that might prevent patients from enrolling on our programme. Patients with symptomatic AF were invited to participate in an established six-week exercise-based cardiac rehabilitation programme, composed of physical activity and education sessions. At the start of the programme, patients were weighed and measured, performed the six-minute walk test (6MWT), completed the Generalised Anxiety Disorder Questionnaire (GAD-7), and the Patient Health Questionnaire (PHQ-9). Measurements were repeated on completion of the programme. Over two years, 77 patients were invited to join the programme. Twenty-two patients (28.5%) declined participation prior to initial assessment and 22 (28.5%) accepted and attended the initial assessment, but subsequently withdrew from the programme. In total, 33 patients completed the entire programme (63.9 ± 1.7 years, 58% female). On completion, patients covered longer distances during the 6MWT, had lower GAD-7 scores, and lower PHQ-9 scores, compared with their baseline results. Compared with patients that completed the entire programme, those who withdrew from the study had, at baseline, a significantly higher body mass index (BMI), covered a shorter distance during the 6MWT, and had higher PHQ-9 and GAD-7 scores. In conclusion, enrolling patients with AF into an NHS cardiac rehabilitation programme is feasible, with nearly half of those invited completing the programme. In this feasibility study, cardiac rehabilitation resulted in an improved 6MWT, and reduced anxiety and depression levels, in the short term. Severe obesity, higher anxiety and depression levels, and lower initial exercise capacity appear to be barriers to completing exercise-based cardiac rehabilitation. These results warrant further investigation in larger cohorts.

Cardiac Magnetic Resonance in Pulmonary Hypertension-an Update.

PURPOSE OF REVIEW: This article reviews advances over the past 3 years in cardiac magnetic resonance (CMR) imaging in pulmonary hypertension (PH). We aim to bring the reader up-to-date with CMR applications in diagnosis, prognosis, 4D flow, strain analysis, T1 mapping, machine learning and ongoing research. RECENT FINDINGS: CMR volumetric and functional metrics are now established as valuable prognostic markers in PH. This imaging modality is increasingly used to assess treatment response and improves risk stratification when incorporated into PH risk scores. Emerging techniques such as myocardial T1 mapping may play a role in the follow-up of selected patients. Myocardial strain may be used as an early marker for right and left ventricular dysfunction and a predictor for mortality. Machine learning has offered a glimpse into future possibilities. Ongoing research of new PH therapies is increasingly using CMR as a clinical endpoint. SUMMARY: The last 3 years have seen several large studies establishing CMR as a valuable diagnostic and prognostic tool in patients with PH, with CMR increasingly considered as an endpoint in clinical trials of PH therapies. Machine learning approaches to improve automation and accuracy of CMR metrics and identify imaging features of PH is an area of active research interest with promising clinical utility.

Age-associated changes in 4D flow CMR derived Tricuspid Valvular Flow and Right Ventricular Blood Flow Kinetic Energy.

Assessment of right ventricular (RV) diastolic function is not routinely carried out. This is due to standard two-dimensional imaging techniques being unreliable. Four-dimensional flow (4D flow) derived right ventricular blood flow kinetic energy assessment could circumvent the issues of the current imaging modalities. It also remains unknown whether there is an association between right ventricular blood flow kinetic energy (KE) and healthy ageing. We hypothesise that healthy ageing requires maintaining normal RV intra-cavity blood flow as quantified using KE method. The main objective of this study was to investigate the effect of healthy ageing on tricuspid through-plane flow and right ventricular blood flow kinetic energy. In this study, fifty-three healthy participants received a 4D flow cardiovascular magnetic resonance (CMR) scan on 1.5 T Philips Ingenia. Cine segmentation and 4D flow analysis were performed using dedicated software. Standard statistical methods were carried out to investigate the associations. Both RV E-wave KEiEDV (r = -0.3, P = 0.04) and A-wave KEiEDV (r = 0.42, P < 0.01) showed an association with healthy ageing. Additionally, the right ventricular blood flow KEiEDV E/A ratio demonstrated the strongest association with healthy ageing (r = -0.53, P < 0.01) when compared to all RV functional and haemodynamic parameters. Furthermore, in a multivariate regression model, KEiEDV E/A ratio and 4D flow derived tricuspid valve stroke volume demonstrated independent association to healthy ageing (beta -0.02 and 0.68 respectively, P < 0.01). Ageing is independently associated with 4D flow derived tricuspid stroke volume and RV blood flow KE E/A ratio. These novel 4D flow CMR derived imaging markers have future potential for RV diastolic assessment.

Pulmonary embolism and infarction with a paradoxical thrombus visualised in both atria.

A 59-year-old woman presented with a sudden onset of breathlessness and chest pain. An echocardiography and CT scan showed pulmonary embolism and infarction with a paradoxical thrombus visualised in both atria. For haemodynamically stable patients, the optimal management strategy is poorly defined. Three main strategies were considered: surgical thrombectomy, thrombolysis and anticoagulation. Surgery with reversal of anticoagulation may lead to further coagulation and increased risk of bleeding complications. The significant pulmonary hypertension and right ventricular infarction raised the prospect of difficult weaning from cardiopulmonary bypass following thrombectomy. Thrombolysis, which has significant mortality rate, and systemic embolisation including pulmonary infarction with haemorrhagic transformation were also contraindications. A multidisciplinary approach was adopted and anticoagulation was therefore believed to be the safest and effective approach. Here, the use of anticoagulation alone was fortunately successful but could as easily end in disaster. This approach should be considered the ideal paradigm to yield optimum outcomes.

Clinical Characteristics and Outcomes of Moraxella Keratitis.

PURPOSE: Changing trends of infective keratitis have been identified worldwide. The aim of this study was to define the clinical associations, characteristics, and outcomes of patients with culture-proven Moraxella keratitis from a large tertiary corneal unit in the United Kingdom. METHODS: Patients with confirmed Moraxella isolates presenting between January 2004 and November 2016 were analyzed. Patient-related factors were examined, including patient demographics, date of presentation, clinical presentation, predisposing factors, best-corrected visual acuity (BCVA), treatment plans, and clinical outcomes. RESULTS: Eighty-six patients were identified, of whom 61 (70.9%) had at least one recognized predisposing factor. The median BCVA at presentation was 2.60 logarithm of the minimum angle of resolution (logMAR), which improved to median = 0.60 logMAR at final visit (P < 0.001). Visual improvement of more than 2 Snellen lines was achieved in 60.7% of eyes. A significant relationship (P = 0.003) between final vision and the presence of hypopyon was found, where for a fixed BCVA at presentation those with a hypopyon achieved a better final visual acuity of 0.69 logMAR. CONCLUSIONS: Our study showed that although most patients presented with at least one predisposing factor, some of the more traditionally perceived risk factors may need to be reconsidered. We have shown that with aggressive treatment, favorable visual outcomes can be achieved in most patients. Interestingly, the presence of hypopyon at presentation was linked to a better visual outcome, likely because such patients had more to gain in visual potential.