Circulation : Clinical Summaries

Abstract

HomeCirculationVol. 129, No. 19Circulation: Clinical Summaries Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation: Clinical SummariesOriginal Research Put Into Perspective for the Practicing Clinician Originally published13 May 2014https://doi.org/10.1161/CIR.0000000000000057Circulation. 2014;129:1903–1904STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naive Pediatric Pulmonary Arterial HypertensionPulmonary arterial hypertension causes significant morbidity and mortality; therapy for pulmonary arterial hypertension rarely has been tested in controlled clinical studies in pediatric patients. In the first randomized, double-blind study in children (aged 1–17 years) with pulmonary arterial hypertension (Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension [STARTS-1]), the safety and efficacy of thrice-daily oral sildenafil therapy was assessed over 16 weeks. Importantly, 3 doses of sildenafil were evaluated (low, medium, and high), with actual dose received based on patient weight (range, 10–80 mg 3 times a day). Although the primary comparison of percent change in peak oxygen consumption for the 3 sildenafil groups combined was only marginally statistically significant, improved exercise capacity, functional class, and hemodynamic parameters were observed in patients who received medium and high doses of sildenafil compared with placebo. In this continuation study (STARTS-2), patients had the potential to receive ≥3 years of sildenafil treatment. Patients who had received sildenafil in STARTS-1 continued their sildenafil dose; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Children randomized to the high-dose sildenafil group had an unexplained increased mortality compared with the lower-dose sildenafil groups. However, multiple analyses raised uncertainty about the survival/dose relationship. All dose groups displayed favorable survival for children with pulmonary arterial hypertension. Combined with STARTS-1 efficacy results, the long-term survival rates favor use of lower sildenafil doses. After interim STARTS-2 survival data were reviewed, a recommendation was issued to downtitrate all patients remaining in the study to lower sildenafil doses. See p 1914.Experimentally Increasing Titin Compliance in a Novel Mouse Model Attenuates the Frank-Starling Mechanism But Has a Beneficial Effect on DiastoleIn patients who have heart failure with a preserved ejection fraction, titin’s protein kinase A/protein kinase G sites are hypophosphorylated and this increases the passive stiffness of cardiomyocytes beyond that of control cells. This finding led to the recent clinical PhosphodiesteRasE-5 Inhibition to Improve CLinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial that evaluated whether elevating protein kinase G activity through blocking cGMP breakdown might relieve symptoms in patients who have heart failure with a preserved ejection fraction, but the result showed no significant improvement. Experimentally upregulating compliant titins has been suggested as an alternative therapeutic for lowering pathological diastolic stiffness levels. Here, we investigate the effect of experimentally upregulating compliant titins on diastolic and systolic function in a novel mouse model that we made with a genetically altered titin splicing factor (RBM20). Results show that upregulating compliant titin isoforms reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Our work suggests that therapeutic manipulation of the RBM20-based splicing system and careful dosing might be able to minimize the effects on fibrosis and systolic function while improving diastolic function of patients who have heart failure. Considering the high prevalence of the heart failure with preserved ejection fraction syndrome and the current lack of effective therapies for lowering pathological stiffness levels, new insights provided by our study should be extended with a goal to relieve the symptoms of heart failure with a preserved ejection fraction by manipulating titin splicing and improving diastolic compliance. See p 1924.Postmortem Cardiovascular Magnetic Resonance Imaging in Fetuses and Children: A Masked Comparison Study With Conventional AutopsyAutopsy has an undisputed role in confirming or refuting antemortem diagnosis and in identifying a cause of death. Cardiac abnormalities are found in ≤35% of fetal autopsies and ≈10% of sudden deaths in infants; however, only 40% to 50% are detected antenatally or before death. Thus, fetal and pediatric cardiac autopsies have a crucial role in counseling parents with regard to both the cause of death and the implications of such findings for future pregnancies, as well as for quality assurance of antenatal screening programs and antemortem diagnostic procedures. Despite this, there has been a global reduction in fetal and pediatric autopsies in the last decade; in the United Kingdom, fetal autopsy rates are <50% and neonatal autopsy rates <20%. Several researchers have suggested using postmortem magnetic resonance imaging as an alternative to conventional autopsy over the last decade; however, the published data on postmortem cardiovascular magnetic resonance imaging have been poor. In this large, blinded study of 400 cases, we have shown that 3-dimensional, postmortem cardiovascular magnetic resonance imaging can provide equivalent structural information to that of conventional autopsy in the majority of larger fetuses, newborns, and children (sensitivity and negative predictive value, 100%). This technique may have a major role in developing less invasive autopsy methods that offer parents and medical professionals a more acceptable method of assessing the fetus, newborn, and child after death. See p 1937.Electronic Cigarettes in North America: History, Use, and Implications for Smoking CessationElectronic cigarettes (e-cigarettes) are currently not licensed to be sold as smoking cessation aids in either the United States or Canada. However, e-cigarettes are rapidly growing in popularity among smokers attempting to quit. We reviewed the available data on the efficacy and safety of e-cigarettes for smoking cessation and considered issues relevant to the context in which they are used, including product awareness and attitudes. Most research findings revealed a reduction in cigarette consumption with e-cigarette use, regardless of nicotine content. However, studies had various limitations, including very small sample sizes and short follow-up periods (eg, 1 day), or included smokers not motivated to quit. The authors of one randomized controlled trial concluded that e-cigarettes may be as effective as the nicotine patch. However, methodological considerations, including an underpowered primary analysis, limit the robustness of these results. In addition, there remains a lack of data regarding the long-term safety of e-cigarette use. Until results from large, generalizable, randomized controlled trials become available, the efficacy and safety of e-cigarettes for smoking cessation remain uncertain, particularly in light of variable product restrictions and regulations. Clinicians who are asked to comment on the efficacy of e-cigarettes for smoking cessation should err on the side of caution and recommend proven smoking cessation therapies, including nicotine replacement therapies, bupropion, and varenicline. See p 1945.Echocardiographic Screening for Rheumatic Heart Disease in High and Low Risk Australian ChildrenRheumatic heart disease (RHD) affects ≈20 million people worldwide, and whilst disease burden is highest in developing countries, it remains a significant cause of morbidity and mortality in the Australian Indigenous population. Over the past decade, there has been increasing interest in echocardiographic screening for RHD, in the hope that earlier detection and instigation of secondary prophylaxis will improve patient outcome. However, methodologies and echocardiographic definitions have varied, making comparisons between studies difficult. In 2012, the World Heart Federation published evidence-based guidelines for the echocardiographic diagnosis of RHD, but these criteria have not yet been applied to a screened cohort. Our study is the first to apply these criteria to a large cohort of Indigenous Australian children at high risk for RHD, providing the first cross-sectional prevalence data in our population. In addition, we included a cohort of non-Indigenous children at low risk for RHD, providing detailed information about normal echocardiographic findings in children and allowing some assessment of the performance of the World Heart Federation criteria when applied to these 2 different risk groups in a blinded, standardized fashion. Our results suggest that that children meeting World Heart Federation criteria for definite RHD are likely to have true disease, but that the borderline RHD group is likely to include children with echocardiographic findings in the upper range of normal. Longitudinal follow-up is essential to establish the clinical significance of borderline RHD in particular. We propose that the World Heart Federation criteria be adopted internationally in future echocardiographic screening studies to allow meaningful comparisons between populations and recruitment of children with similar echocardiographic findings to follow-up studies. See p 1953.CCBE1 Enhances Lymphangiogenesis via A Disintegrin and Metalloprotease With Thrombospondin Motifs-3–Mediated Vascular Endothelial Growth Factor-C ActivationThere has been substantial progress in the understanding of the hereditary lymphedemas. However, the molecular mechanism is not always obvious, even when the genetic lesion has been identified. In 2009, Alders et al established the link between mutations in the CCBE1 gene and Hennekam lymphangiectasia–lymphedema syndrome, a human hereditary condition with lymphedema as a characteristic feature. Later, genetic experiments in zebrafish and mice indicated that the CCBE1 gene interacts with the lymphangiogenic vascular endothelial growth factor (VEGF)-C receptor-3 pathway, but the nature of the interaction remained elusive. In this article, Jeltsch et al show that the activity of VEGF-C is regulated by collagen- and calcium-binding epidermal growth factor domains 1 (CCBE1), which facilitates the proteolytic activation of a latent “pro” form of VEGF-C by the A disintegrin and metalloprotease with thrombospondin motifs-3 (ADAMTS3) metalloproteinase via a novel mode of growth factor activation. The in vivo data in the article show that CCBE1 is a potential therapeutic tool for the modulation of lymphangiogenesis and angiogenesis in a variety of diseases that involve the lymphatic system, such as lymphedema or lymphatic metastasis. In particular, application of VEGF-C has been scheduled for clinical trials to improve the incorporation of lymph node transplants into the lymphatic vascular system after mastectomy and axillary lymph node surgery. CCBE1 is a powerful activator of VEGF-C that can facilitate therapeutic lymphangiogenesis. CCBE1 and ADAMTS3 could also provide new targets for inhibition of tumor angiogenesis, lymphangiogenesis, and metastasis. See p 1962. Previous Back to top Next FiguresReferencesRelatedDetails May 13, 2014Vol 129, Issue 19 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIR.0000000000000057 Originally publishedMay 13, 2014 PDF download Advertisement