Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models.

BACKGROUND: We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed. RESULTS: We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts. CONCLUSIONS: For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype.

Atorvastatin Effect on Aortic Dilatation and Valvular Calcification Progression in Bicuspid Aortic Valve (BICATOR): A Randomized Clinical Trial.

BACKGROUND: Ascending aorta dilation and aortic valve degeneration are common complications in patients with bicuspid aortic valve. Several retrospective studies have suggested the benefit of statins in reducing these complications. This study aimed to determine whether atorvastatin treatment is effective in reducing the growth of aortic diameters in bicuspid aortic valve and if it slows the progression of valve calcification. METHODS: In a randomized clinical trial, 220 patients with bicuspid aortic valve (43 women; 46±13 years of age) were included and treated with either 20 mg of atorvastatin per day or placebo for 3 years. Inclusion criteria were ≥18 years of age, nonsevere valvular dysfunction, nonsevere valve calcification, and ascending aorta diameter ≤50 mm. Computed tomography and echocardiography studies were performed at baseline and after 3 years of treatment. RESULTS: During follow-up, 28 patients (12.7%) discontinued medical treatment (15 on atorvastatin and 13 taking placebo). Thus, 192 patients completed the 36 months of treatment. Low-density lipoprotein cholesterol levels decreased significantly in the atorvastatin group (median [interquartile range], -30 mg/dL [-51.65 to -1.75 mg/dL] versus 6 mg/dL [-4, 22.5 mg/dL]; P<0.001). The maximum ascending aorta diameter increased with no differences between groups: 0.65 mm (95% CI, 0.45-0.85) in the atorvastatin group and 0.74 mm (95% CI, 0.45-1.04) in the placebo group (P=0.613). Similarly, no significant differences were found for the progression of the aortic valve calcium score (P=0.167) or valvular dysfunction. CONCLUSIONS: Among patients with bicuspid aortic valve without severe valvular dysfunction, atorvastatin treatment was not effective in reducing the progression of ascending aorta dilation and aortic valve calcification during 3 years of treatment despite a significant reduction in low-density lipoprotein cholesterol levels. REGISTRATION: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001808-57; URL: https://www.clinicaltrials.gov; Unique identifier: NCT02679261.

TAV-in-TAV in patients with prosthesis embolization: Impact of commissural alignment and global outcomes.

BACKGROUND: Optimal strategies to manage embolization of transcatheter aortic valve implantation (TAVI) devices are unclear; valve-in-valve (ViV) is often used. We aimed to describe through one-single center experience its rate, causes, consequences, and management as well as the rate and relevance of commissural alignment (CA) in this context. METHODS: We identified across 1038 TAVI cases, those cases requiring ViV for the management of first device embolization. CA (absence or mild misalignment) after first and second device was assessed by CT or fluoroscopy. RESULTS: A total of 23 cases (2.2%) were identified, 52.3% embolized towards the aorta and 47.7% towards the ventricle. Suboptimal implant height (38%) and embolization at the time of post-dilation (23%) were the most frequent mechanisms together with greater rate of bicuspid valve (p < 0.001) and a trend to greater annular eccentricity. Procedural and 1-year death occurred in 13% and 34%, respectively (vs. 1.1% and 7.8% in the global cohort, p < 0.001). CA was present in 76.9% of the prostheses initially implanted but was only spontaneously achieved in 30.8% of the second ViV device. Adequate CA of both prostheses was identified in only two cases (8.7%). There were no cases of coronary obstruction. CONCLUSIONS: TAVI device embolization mechanisms can often be predicted and prevented. Mortality following bail-out ViV is higher than in regular TAVI procedures but 2/3 of these patients survived beyond 1-year follow-up. In them, valve degeneration or coronary re-access might be particularly challenging since CA was rarely achieved with both devices suggesting that greater efforts should be made in this regard.

Onasemnogene Abeparvovec Administration via Peripherally Inserted Central Catheter: A Case Report.

Onasemnogene abeparvovec (OA) is the approved intravenous gene therapy for the treatment of spinal muscular atrophy (SMA). A functional copy of the human SMN1 gene was inserted into the target motor neuron cells via a viral vector, AAV9. In clinical trials, OA was infused through a peripheral venous catheter, and no data are available on central catheter use. Recently, we had a case where OA was administered directly into the right atrium via a peripherally inserted central catheter (PICC) instead of a peripheral line, as recommended. The patient was a female child aged 4 months, diagnosed as SMA type I. For practical reasons, a dose of OA according to the weight of the patient (1.1 × 1014 vectorial genomes/kg) was administered via PICC in 1 h, as the product information recommends. The drug was well tolerated, with no hypersensitivity reactions or initial elevation of transaminases or other adverse effects. To our knowledge, this is the first case reported where OA was administered via a central line. This type of administration is not contraindicated, but it is not specifically contemplated or recommended. It is unknown whether central line administration could have any implications for transduction efficiency and immunogenicity. Future studies should clarify these aspects, as each gene therapy has a specific optimal dose recorded that depends on the site and route of administration of the drug, the AAV variant and the transgene.

Evolution and Prognostic Significance of Patient-Reported Symptoms After Intervention in Severe Aortic Stenosis.

OBJECTIVE: To describe the evolution of symptoms in patients with symptomatic severe aortic stenosis (sSAS) undergoing valve replacement, the predictors of the persistence of these symptoms, and their prognostic significance. The evolution of symptoms after intervention in sSAS and their association with outcome are unknown. PATIENTS AND METHODS: Data from patients with sSAS who underwent intervention were collected. All-cause mortality and cardiovascular mortality were considered events. The evolution of symptoms and their association with events were studied. RESULTS: In this study, 451 consecutive patients with sSAS and no other valvular or coronary disease who were alive 30 days after intervention were included. Before valve replacement, 133 of the 451 patients (29.5%) had congestive heart failure requiring hospitalization. Of the remaining 318 patients, 287 (90.2%) had dyspnea on effort, 129 (40.6%) had angina, and 59 had syncope (18.6%). Symptoms disappeared after intervention in 192 of the 451 patients (42.6%) and remained in 259 (57.4%): 193 dyspnea, 9 angina, 17 syncope, and 60 admission for heart failure. Syncope on effort persisted in 4 of 33 patients (12.1%) and at rest in 11 of 20 (55.0%; P<.001). Age, body mass index, previous admission for heart failure, and chronic obstructive pulmonary disease were independently related to persistence of symptoms. Over a median follow-up of 56 months in our cohort of 451 patients, 129 deaths were registered (28.6%), 40 of which were cardiovascular (8.9%). Age, chronic obstructive pulmonary disease, chronic kidney disease, atrial fibrillation, heart failure, and persistence of symptoms were independently associated with all-cause mortality. CONCLUSION: Symptoms attributed to SAS remain after intervention in a high proportion of patients, particularly dyspnea on effort and syncope at rest. The persistence of symptoms after intervention identifies patients with poor outcome.

Expanding the Clinical Spectrum of DRP2-Associated Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.

Real life experience of tafamidis for the treatment of Spanish patients with Val30Met transthyretin amyloidosis with polyneuropathy.

INTRODUCTION: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain. METHODS: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed. RESULTS: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability. CONCLUSIONS: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.

Safety and Efficacy of Nipocalimab in Patients With Generalized Myasthenia Gravis: Results From the Randomized Phase 2 Vivacity-MG Study

BACKGROUND AND OBJECTIVES: To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups. RESULTS: Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend). DISCUSSION: Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG. TRIAL REGISTRATION INFORMATION: Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.

Different prognostic significance of coronary artery and aortic valve calcium in patients with chest pain.

OBJECTIVES: Coronary artery calcification (CorCa) identifies high cardiovascular risk in the general population. In this setting, aortic valve calcification (AoCa) showed contradictory results. Our goal has been to assess the prognostic power of CorCa and AoCa in patients with chest pain who underwent an ECG-gated cardiac multidetector CT (cardiac-MDCT). METHODS: A total of 528 patients without previous known coronary artery disease, with chest pain who underwent a cardiac-MDCT multidetector, were retrospectively recruited. The primary endpoint included death, acute coronary syndrome, stroke, and heart failure. RESULTS: A total of 61 patients (11.6%) had an event during a mean follow-up of almost 6 years (5.95 ± 2.98). The most frequent event was acute coronary syndrome (6.4%). Total mortality was 4.5%. Patients with CorCa > 0 had more events than those without CorCa (17.3% versus 4.3%; p < 0.001). Likewise, when only patients without AoCa were considered (n = 118), clinical events were more frequent in those with CorCa (12.7% versus 3.6%; p = 0.004). After excluding patients with coronary artery disease, events were more frequent in those with CorCa (12.6% versus 4.3%; p = 0.004). The higher the Agatston score, the more frequent the events. Patients with AoCa > 0 had more events than those without (16.5% versus 7.3%; p < 0.001), but in patients without CorCa, no difference in events was seen (6.2% versus 3.6%; p = 0.471). A Cox regression analysis showed age, smoking, prior stroke, and CorCa but not AoCa to be independently related to events. CONCLUSIONS: In summary, CorCa, but not AoCa, is related to cardiovascular events in patients with chest pain who undergo a cardiac-MDCT. CLINICAL RELEVANCE STATEMENT: We show that coronary artery calcification, but not aortic valve calcification, detected in a coronary CT scan is tightly related to cardiovascular events. Although this is a message already shown by other groups in the general population, we do believe that this work is unique because it is restricted to patients with chest pain sent to coronary CT. In other words, our work deals with what we face in our routine everyday practice. KEY POINTS: • The presence and the amount of coronary artery calcification are associated with cardiovascular events in patients with chest pain. • Aortic valve calcification is not associated with cardiovascular events in patients with chest pain.

Sex Differences in Clinical Outcomes after Aortic Valve Intervention for Isolated Severe Aortic Stenosis.

There are known pathophysiologic and clinical differences according to sex in patients with aortic stenosis (AS). To evaluate if these differences persist after valve replacement, we conducted an observational study including 451 patients with symptomatic AS who survived aortic valve intervention (AVI) in two centers. Clinical data and mortality were evaluated at a mean follow-up of 5 years. 56% of patients were women. At baseline, women were older (80.6 vs. 78 years, p = 0.013), presented higher mean gradient (48 vs. 45 mmHg, p = 0.023), lower aortic valve area (0.70 vs. 0.74 cm2, p = 0.002) and higher systolic pulmonary artery pressure (36 vs. 33 mmHg, p = 0.016). They underwent percutaneous aortic valve replacement more frequently than men (47 vs. 35.9%, p = 0.017). At 5 years follow-up, women required more admissions due to heart failure (23 vs. 9%, p = 0.046) but they did not present higher cardiovascular nor overall mortality (27.7% vs. 29.8%, p = 0.741; 11.1 vs. 10.1%, p = 0.619, respectively). Female sex was an independent predictor of heart failure hospitalization at follow-up (HR 95% 1.16-4.22, p = 0.016). Women undergo AVI at a more advanced stage than men, resulting in a higher frequency of readmissions due to heart failure during the follow-up period, but not in higher mortality.

Msi2 enhances muscle dysfunction in a myotonic dystrophy type 1 mouse model.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3' untranslated region of the DM1 protein kinase gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an MSI2>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy. Because the DM1 HSALR mouse model expressing expanded CUG repeats shows weak muscle-wasting phenotypes, we hypothesized that MSI2 overexpression was sufficient to promote muscle dysfunction in vivo. METHODS: By means of recombinant AAV murine Msi2 was overexpressed in neonates HSALR mice skeletal muscle to induce DM1-like phenotypes RESULTS: Sustained overexpression of the murine Msi2 protein in HSALR neonates induced autophagic flux and expression of critical autophagy proteins, increased central nuclei and reduced myofibers area, and weakened muscle strength. Importantly, these changes were independent of Mbnl1, Mbnl2, and Celf1 protein levels, which remained unchanged upon Msi2 overexpression. CONCLUSIONS: Globally, molecular, histological, and functional data from these experiments in the HSALR mouse model confirms the pathological role of Msi2 expression levels as an atrophy-associated component that impacts the characteristic muscle dysfunction symptoms in DM1 patients.

Recurrence of syncope after valve replacement in severe aortic stenosis.

OBJECTIVE: The recurrence of syncope after valve intervention in severe aortic stenosis (SAS) and its impact on outcome are unknown. We hypothesised that syncope on exertion will disappear after intervention, whereas syncope at rest might recur. Our aim has been to describe the recurrence of syncope in patients with SAS undergoing valve replacement and its impact on mortality. METHODS: Double-centre observational registry of 320 consecutive patients with symptomatic SAS without other valve disease and/or coronary artery disease who underwent valve intervention and were discharged alive. All-cause mortality and cardiovascular mortality were considered events. RESULTS: 53 patients (median age 81 years, 28 men) had syncope (29 on exertion, 21 at rest, 3 unknown). Clinical and echocardiographic variables were similar in patients with and without syncope (median vmax 4.44 m/s, mean gradient 47 mm Hg, valve area 0.7 cm2, left ventricular ejection fraction 62%). After a median follow-up of 69 months (IQR: 55-88), syncope on exertion did not recur in any patient. In contrast, 8 of the 21 patients with syncope at rest had postintervention syncope at rest (38%; p<0.001): 3 needed a pacemaker, 3 were neuromediated or hypotensive and 2 arrhythmic. Only recurrence of syncope was associated with cardiovascular mortality (HR 5.74; 95% CI 2.17 to 15.17; p<0.001). CONCLUSIONS: Syncope on exertion in patients with SAS did not recur after aortic valve intervention. Syncope at rest recurs in a high proportion of patients and identifies a population with increased mortality. According to our results, syncope at rest should be thoroughly evaluated before proceeding to aortic valve intervention.

Magnetic resonance analysis of ventricular volumes in bicuspid and trileaflet aortic regurgitation.

OBJECTIVE: To identify differences in left ventricular (LV) remodelling between patients with bicuspid aortic valve (BAV) and trileaflet aortic valve (TAV) with chronic aortic regurgitation (AR). METHODS: Retrospective cohort study of 210 consecutive patients undergoing cardiac magnetic resonance for AR evaluation. We divided the study population according to valvular morphology. Independent predictors of LV enlargement AR were evaluated. RESULTS: There were 110 patients with BAV and 100 patients with TAV. Patients with BAV were younger (mean age BAV vs TAV: 41±16 years vs 67±11 years; p<0.01), mostly male (% male BAV vs TAV: 84.5% vs 65%, p=0.01) and presented milder degrees of AR (median regurgitant fraction BAV vs TAV: 14 (6-28)% vs 22 (12-35)%, p=0.002). Both groups presented similar indexed LV volumes and ejection fraction. According to the degree of AR, at mild AR, patients with BAV presented larger LV volumes (BAV vs TAV: indexed end diastolic left ventricular volumes (iEDV): 96.5±19.7 vs 82.1±19.3 mL, p<0.01; indexed end systolic left ventricular volumes (iESV): 39.4±10.3 mL vs 33.2±10.5 mL, p=0.01). These differences disappeared at higher degrees of AR. Independent predictors of LV enlargement were regurgitant fraction (EDV: OR 1.118 (1.081-1.156), p<0.001; ESV: OR 1.067 (1.042-1.092), p<0.001), age (EDV: OR 0.940 (0.917-0.964), p<0.001, ESV: OR 0.962 (0.945-0.979), p<0.001) and weight (EDV: OR 1.054 (1.025-1.083), p<0.001). CONCLUSIONS: In chronic AR, LV enlargement is an early finding. LV volumes display a direct correlation with regurgitant fraction and an inverse association with age. Patients with BAV present larger ventricular volumes, especially at mild AR. However, these differences are attributable to demographic disparities; valve type is not independently associated with LV size.