Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5′-triphosphate (ATP) turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase®, Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients’ responses.

BackgroundJuvenile Idiopathic Arthritis (JIA) can cause long-term cardiovascular complications. There are non-invasive, validated, easy to perform methods for cardiovascular testing, such as: carotid intimal-media thickness (cIMT), and measurement of arterial rigidity through carotid distensibility, carotid-femoral pulse wave velocity (cfPWV) and the augmentation index (AIx).ObjectivesTo compare the main hemodynamics measurements (cIMT, carotid distensibility, cfPWV and AIx) between JIA and non-JIA subjects.MethodsAnalytical cross-sectional study in subjects 5 to 16 years of age. Two groups: patients with JIA according to the ILAR classification without any other condition vs healthy children. Measurements: somatometry, laboratory (glucose, creatinine, lipid profile), disease activity index (JADAS-27) and hemodinamic variables (cIMT, carotid distensibility, cfPWV and AIx).Results63 JIA subjects and 50 healthy controls were included, mean age 11.5 ± 2.8 vs 10.7 ± 3.2 years (p = 0.17) and 70% vs 54% females, respectively. Both groups were also similar (p > 0.05) for nutritional state, sedentary lifestyle, smoking habits and family history of cardiovascular risk. Table 1 show lipid profile of both groups. Subtypes of JIA were: RF positive polyarthritis (29%), RF negative polyarthritis (29%), oligoarthritis (19%), enthesitis-related arthritis (14%) and systemic arthritis (9%). Mean time of disease evolution was 4 ± 3 años. There were no significant differences between groups in the main hemodinamic parameters (table 2). When comparing inactive vs active disease and active disease vs controls there were no differences either, we found a discrete trend to less carotid distensibility and higher cfPWV in patients with active disease compared to controls [0.63 ± 0.17 mm vs 0.66 ± 0.15 mm (p = 0.94) and 6.12 ± 2.88 m/s vs 5.42 ± 0.75 m/s (p = 0.33), respectively]. 59% of subjects with JIA were inactive according to JADAS-27. When considering time of disease evolution, children with 0-4 years vs children with >4 years and children with >4 years vs controls, we found differences in cIMT [0.41 ± 0.62 mm vs 0.44 ± 0.50 mm (p = 0.02) and 0.44 ± 0.50 mm vs 0.40 ± 0.70 mm (p = 0.01), respectively]. Finally, cfPWV was higher in patients with 0-4 years than in patients with >4 years of evolution (p = 0.01).TABLE 1 LIPID PROFILELIPIDJIACONTROLS p†Triglicerides94 ± 5685 ± 360.22Total cholesterol141 ± 27152 ± 260.06HDL cholesterol45 ± 1247 ± 100.36LDL cholesterol77 ± 2187 ± 220.01VLDL cholesterol18 ± 1117 ± 70.52†Mann-Whitney U test.TABLE 2 HEMODINAMIC MEASUREMENTSMEASUREMENTJIACONTROLS p†cIMT (mm)0.42 ± 0.590.40 ± 0.700.11Carotid distensibility (mm)0.64 ± 0.160.66 ± 0.150.78cfPWV (m/s)5.77 ± 25.42 ± 0.750.66AIx (%)69 ± 1569 ± 120.64†Mann-Whitney U test.ConclusionWe found a tendency to increased cardiovascular risk when the disease has more than 4 years of evolution, specially in patients with persistent active disease. Traditional and non-traditional cardiovascular risk factors add up in this population. We need longterm follow-up stu...