Role of open access echocardiography in detection of cardiac structural and functional abnormalities

PurposeTo evaluate the prevalence and incidence of significant structural heart disease in targeted patients with cardiac symptoms referred by general practitioners (GPs) using open access echocardiography, without prior clinical evaluation by a cardiologist.DesignData were derived from 488 subjects who underwent transthoracic echocardiography between January and April 2018. Patients were referred directly by GPs in East Berkshire, South England, through an online platform. Echocardiography was performed within 4–6 weeks of referral and all reports were assessed by a consultant cardiologist with expedited follow-up facilitated pro re nata. Results were analysed to determine the frequency of detection of structural abnormalities, particularly of the left ventricle and cardiac valves.ResultsEchocardiography was prospectively performed in consecutive subjects (50% male, mean (±SD) age 68.5±22 years; 50% female; mean (±SD) 64.6 (±19.1)). At least one abnormality likely to change management was found in 133 (27.3%) of all open access echocardiograms. Clinical heart failure with left ventricular systolic dysfunction (LVSD) and diastolic dysfunction was confirmed in 46 (9%) and 69 (14%), respectively. Of the 46 patients with LVSD, 33 were new diagnoses. Significant cardiac valve disease was found in 42 (8.6%) patients. 12 of these had known valvular disease or previous valvular surgery, and 30 were new diagnoses.ConclusionMajor structural and functional cardiac abnormalities are common in late middle-aged patients who present to GPs with cardiac symptoms and signs. Reported, unrestricted open access echocardiography enables early detection of significant cardiac pathology and timely intervention may improve cardiovascular outcomes.

Clinical and event-based outcomes of patients with mucopolysaccharidosis VI receiving enzyme replacement therapy in Turkey: a case series

Background The objective of this study was to describe clinical manifestations and events of patients with mucopolysaccharidosis (MPS) VI in Turkey who are treated with galsulfase enzyme replacement therapy (ERT). Clinical data of 14 children with MPS VI who were followed up at the Department of Pediatrics of the Gazi University Faculty of Medicine in Ankara, Turkey were retrospectively collected from the patients’ medical records. Patients were selected based on availability of a pre-ERT baseline and follow-up clinical data for a similar period of time (1.9–3.2 years). Event data (occurrence of acute clinical events, onset of chronic events, surgeries) collected during hospital visits and telemedicine were available for up to 10 years after initiation of ERT (2.5–10 years). Results Age at initiation of ERT ranged from 2.8 to 15.8 years (mean age 7.5 years). All patients presented with reduced endurance and skeletal abnormalities (dysostosis multiplex) on radiography. Other common clinical manifestations were cardiac valve disease (N = 13), short stature (N = 11), cranial abnormalities on MRI (N = 10), spinal abnormalities on MRI (N = 7), and mild cognitive impairment (N = 6). School attendance was generally poor, and several patients had urinary incontinence. After 1.9 to 3.2 years of ERT, most patients showed improvements in endurance in the 6-min walk test and 3-min stair climb tests; the frequency of urinary incontinence decreased. ERT did not seem to prevent progression of cardiac valve disease, eye disorders, hearing loss, or bone disease. Long-term event-based data showed a high incidence of respiratory tract infections, adenotonsillectomy/adenoidectomy, reduced sleep quality, sleep apnea, and depression before initiation of ERT. The number of events tended to remain stable or decrease in all patients over 2.5–10 years follow-up. However, the nature of the events shifted over time, with a reduction in the frequency of respiratory tract infections and sleep problems and an increase in ophthalmologic events, ear tube insertions, and depression. Conclusions This case series shows the high disease burden of the MPS VI population in Turkey and provides a unique insight into their clinical journey based on real-life clinical and event-based data collected before and after initiation of ERT.

Abstract MP235: PROX1 Contributes To Cardiac Valve Disease

Background: Heart valves regulate the unidirectional forward flow and prevent retrograde backflow of blood during the cardiac cycle. Cardiac valve disease (CVD) is observed in approximately 2.5% of the general population and the incidence increases to ~10% in elderly people. Patients with severe CVD require surgery and effective pharmacological treatments are currently not available. PROX1 is a transcription factor that regulates the development of lymphatic, venous, and lymphovenous valves (vascular valves). We identified that PROX1 is also expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 regulates cardiac valve development and disease is not known. Method and Results: We have discovered that mice lacking Prox1 in their VECs ( Prox1 ΔVEC ) develop enlarged aortic and mitral valves in which the expression of proteoglycans is increased (control, N=10; Prox1 ΔVEC , N=9, p <0.05). Echocardiography revealed moderate to severe stenosis of aortic valves of Prox1 ΔVEC mice (control, N=5; Prox1 ΔVEC , N=9, p <0.05). PROX1 regulates the expression of the transcription factor FOXC2 in the vascular valves. Similarly, we have found that the expression of FOXC2 is downregulated in the VECs of Prox1 ΔVEC mice. Specific knockdown of FOXC2 in VECs results in the thickening of aortic valves (control, N=10; shFoxc2 ΔVEC , N=8, p <0.05). Furthermore, restoration of FOXC2 expression in VECs ( Foxc2 OE-VEC ) ameliorates the thickening of the aortic valves of Prox1 ΔVEC mice ( Prox1 ΔVEC , N=9; Foxc2 OE-VEC ; Prox1 ΔVEC , N=8, p <0.05). We have also determined that the expression of platelet-derived growth factor-B ( Pdgfb ) is increased in the valve tissue of Prox1 ΔVEC mice and in PROX1 deficient sheep mitral valve VECs (MVECs) (siCtrl , N=4; siProx1 , N=4, p <0.05). Additionally, hyperactivation of PDGF-B signaling in mice results in a phenotype that is similar to Prox1 ΔVEC mice (control , N=4; Pdgfb GOF , N=3, p <0.05). Conclusion: Together these data suggest that PROX1 maintains the extracellular matrix composition of cardiac valves by regulating the expressions of FOXC2 and PDGF-B in VECs.

Development of an effective therapy for alkaptonuria – Lessons for osteoarthritis

Osteoarthritis (OA) is one of the major causes of disability and pain worldwide, yet despite a massive international research effort, no effective disease-modifying drugs have been identified to date. In this review, we put forward the proposition that greater focus on rarer forms of OA could lead to a better understanding of the pathogenesis of more common OA. We have investigated the severe osteoarthropathy of the ultra-rare disease alkaptonuria (AKU). In addition to the progress made in finding a treatment for AKU, our research has revealed important lessons for more common OA, including the identification of high-density mineralized protrusions (HDMPs), new pathoanatomical structures which may play an important role in joint destruction and pain in AKU and in OA. AKU is an inherited disorder of tyrosine metabolism, caused by genetic lack of the enzyme homogentisate 1,2 dioxygenase (HGD), which leads to failure to breakdown homogentisic acid (HGA). While most HGA is excreted over time, some of it is deposited as a pigment in connective tissues, a process described as ochronosis. Ochronotic pigment alters the mechanical properties of tissues, leading to inevitable joint destruction and frequently to cardiac valve disease. Until recently, there was no effective therapy for AKU, but preclinical studies demonstrated that upstream inhibition of tyrosine metabolism by nitisinone, a drug previously used in hereditary tyrosinaemia 1 (HT1), completely prevented ochronosis in AKU mice. This was followed by successful clinical trials which have resulted in nitisinone being approved for therapy of AKU by the European Medicines Agency, making AKU the only cause of OA for which there is an effective therapy to date. Study of other rare causes of OA should be a higher priority for researchers and funders to ensure further advances in understanding and eventual therapy of OA.

Feasibility of CT-derived myocardial strain measurement in patients with advanced cardiac valve disease

To explore the feasibility of CT-derived myocardial strain measurement in patients with advanced cardiac valve disease and to compare it to strain measurements derived from transthoracic echocardiography (TTE). 43 consecutive patients with advanced cardiac valve disease and clinically indicated retrospectively gated cardiac CTs were retrospectively analyzed. The longitudinal, circumferential as well as radial systolic strain were determined in all patients utilizing a commercially available CT strain software. In 36/43 (84%) patients, CT-derived longitudinal strain was compared to speckle-tracking TTE. Pearson’s correlation coefficients as well as Bland–Altman analysis were used to compare the CT-derived strain measurements to TTE. The intra- and inter-reader-reliability of the CT-derived strain measurements were assessed by intra-class correlation coefficients (ICCs). Strain measurements were feasible in all patients. CT-derived global longitudinal strain (GLS) correlated moderately with TTE-derived GLS (r = 0.6, p < 0.001). A moderate correlation between CT-derived GLS and CT-derived left ventricular ejection fraction was found (LVEF, r = − 0.66, p = 0.036). Bland–Altman analysis showed a systematic underestimation of myocardial strain by cardiac CT compared to TTE (mean difference: − 5.8%, 95% limit of agreement between − 13.3 and 1.8%). Strain measurements showed an excellent intra- and inter-reader-reliability with an intra-reader ICC of 1.0 and an inter-reader ICC of 0.99 for GLS measurements. CT-derived myocardial strain measurements are feasible in patients with advanced cardiac valve disease. They are highly reproducible and correlate with established parameters of strain measurements. Our results encourage the implementation of CT-derived strain measurement into clinical routine.

Genome-wide association meta-analysis supports genes involved in valve and cardiac development to associate with mitral valve prolapse

Objective. Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous GWAS have identified six risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding a dataset from the UK Biobank. Approaches and Results. We re-analyzed 1,007/1,469 cases and 479/862 controls from the MVP-France study and the MVP-Nantes study, respectively. We re-imputed genotypes using HRC and TOPMed, and found this latter to perform better in terms of accuracy in the lower ranges of minor allele frequency (MAF) below 0.1. We then incorporated 434 MVP cases and 4,527 controls from the UKBiobank and conducted a meta-analysis GWAS including ~2000 MVP cases and over 6,800 controls for ~8 million genotyped or imputed common SNPs (MAF>0.01). We replicated the association on chr2 and now provide a finer association map near TNS1. We identified three suggestive risk loci, all driven by common variants on Chr1 (SYT2), Chr8 (MSRA), and Chr19 (FBXO46). Gene-based association using MAGMA revealed 15 risk genes for MVP including GLIS1, TGFB2, ID2, TBX5, MSRA, and DMPK. Extensive functional annotation showed that genes associated with MVP are highly expressed in cardiovascular tissues, especially heart, and are involved in cardiac development and potentially aging. Conclusions. We report an updated meta-analysis GWAS for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

MON-282 Treatment of Hyperprolactinemia with Ropinirole: An Open-Label Dose Escalation Study

Purpose Treatment of hyperprolactinemia and prolactinomas with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. Ropinirole (ROP) is a low cost selective D2/D3 receptor non-ergot DA, approved for treatment of Parkinson’s disease and Restless Leg Syndrome, that has been shown to acutely lower prolactin levels (PRL). This study investigated the efficacy and tolerability of long-term ROP therapy in patients with hyperprolactinemia. Methods & Results Ten healthy women (21-45 yrs) with hyperprolactinemia were treated with ROP (0.25-6.0mg/d) for 6 months in an open-label dose escalation study. Clinical and biochemical status was assessed monthly and ROP doses were up-titrated to achieve normal PRL levels, restore menses, and eliminate galactorrhea. Two subjects had macroprolactinomas, 7 had microprolactinomas, and 1 had idiopathic hyperprolactinemia. 8/10 had previously been treated with cabergoline and/or bromocriptine. 5/10 were intolerant and 1/10 was resistant to ergot DAs. Pituitary MRIs were performed at baseline and 6 months.ROP was initiated at 0.25mg QHS in 9/10 subjects. One subject with severe DA intolerance was initiated on 0.125mg QHS. Subjects reaching a total daily dose (TDD) &gt; 2.0mg/d were transitioned to ROP extended release. At study completion, TDDs ranged from 1-6mg/d, with a median TDD of 2mg/d. Baseline PRL levels were 136 ± 49ng/ml (1.9-25ng/ml). Stable PRL normalization was achieved in 50% of subjects. Of the subjects achieving normal PRL, 4 had microadenomas and 1 had idiopathic hyperprolactinemia, and the median effective TDD was 1mg/d (1-4mg/d, range). Among those not achieving PRL normalization, PRL decreased 46 ± 5.4% (Mean ± SEM) from baseline, at a median TDD of 4.0mg/d (2-6mg/d, range). In the subject with documented resistance to ergot DAs, PRL decreased from 529 to 320ng/ml, after 3 months of ROP on the maximum dose studied (6mg/d), but rose to 690ng/ml at 6 months. During ROP treatment, menses normalized in 57%, and galactorrhea resolved in 67% of affected subjects. At study completion, tumor size was unchanged in 7/8 prolactinomas. A 20% decrease in tumor size was observed in one macroadenoma, accompanied by a 30% reduction in PRL levels. There were no changes in BP, HR, weight, renal or kidney function. Mild adverse effects (AEs) were recorded in 80% of subjects. Fatigue (60%), nausea (40%), and headache (20%) were most common. Reported AEs declined after month 1 and ROP was not discontinued due to intolerance. Conclusion These data provide support for the efficacy of ROP in the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia. While further study is needed, ROP treatment for hyperprolactinemia could be considered in patients with ergot DA intolerance or significant cardiac valve disease.