Reduction Therapy Research Articles

Managing Intracranial Pressure Crisis.

The objective of this review is to provide a comprehensive management protocol for the treatment of intracranial pressure (ICP) crises based on the latest evidence. The review discusses updated information on various aspects of critical care management in patients experiencing ICP crises, including mechanical ventilation, fluid therapy, hemoglobin targets, and hypertonic saline infusion, the advantages of ICP monitoring, the critical ICP threshold, and bedside neuromonitoring. All aspects of critical care treatment, including hemodynamic and respiratory support and adjustment of ICP reduction therapy, may impact patient outcomes. ICP monitoring allows ICP values, trends, waveforms, and CPP calculation, which are helpful to guide patient care. Advanced neuromonitoring devices are available at the bedside to diagnose impaired intracranial compliance and intracranial hypertension, assess brain function, and optimize cerebral perfusion. Future research should focus on developing appropriate intervention protocols for both invasive and noninvasive neuromonitoring in managing ICP crisis patients.

A Novel Injectable Polypeptide Nanoparticle Encapsulated siRNA Targeting TGF-β1 and COX-2 for Localized Fat Reduction II: Phase I Clinical Trial.

Rising demand for non-invasive body contouring is driven by aesthetics and the obesity epidemic. Deoxycholic acid (DCA) is the only FDA-approved injectable for fat reduction but can cause side effects and significant local skin reactions (LSR). RNA interference, using small interfering RNA (siRNA) molecules, offers targeted fat reduction by silencing genes involved in fat maintenance. STP705, a siRNA injectable targeting TGF-β1 and COX-2, has shown promising preclinical results both invitro and in animal models. To evaluate the safety and tolerability of STP705 for localized fat reduction in subjects undergoing abdominoplasty. This phase I dose-ranging, randomized, vehicle-controlled trial involved eight females undergoing abdominoplasty who received subcutaneous STP705 injections at varying concentrations and volumes in designated abdominal zones. Safety assessments, including physical exams, lab tests, ECGs, and local skin reactions (LSRs), were conducted at baseline and follow-ups. Histopathologic evaluations of biopsies collected during abdominoplasty assessed adipocyte apoptosis and tissue remodeling. STP705 demonstrated a favorable safety profile with no clinically significant changes in lab values, vital signs, or ECGs. Adverse events (AEs) were rare and transient. The incidence, intensity, and duration of LSRs were low throughout the study. Histological analysis revealed adipocyte destruction, fat remodeling, and necrosis. STP705 was safe and very well-tolerated and showed preliminary efficacy in inducing adipocyte apoptosis and tissue remodeling, suggesting a safer alternative or adjunct to existing fat reduction therapies. These findings support further trials to establish the safety and efficacy of STP705 for targeted fat reduction and body contouring. ClinicalTrials.gov identifier: NCT05422378.

A Triple Threat: A Case Report Detailing Surgical Management for Hypertrophic Cardiomyopathy, Flail Mitral Valve and Severe Pulmonary Hypertension

The combination of hypertrophic cardiomyopathy with outflow tract obstruction, severe pre-capillary and post-capillary pulmonary hypertension, and severe primary mitral regurgitation is rare and presents distinct management challenges. Background and Clinical Significance: Pulmonary hypertension is an independent predictor of all-cause mortality in patients with hypertrophic cardiomyopathy managed medically and often precludes patients from undergoing cardiopulmonary bypass due to increased surgical morbidity and mortality. In studies specifically evaluating surgical myectomy, however, survival is favorable in patients with moderate-to-severe pulmonary hypertension. Case Presentation: We present a case of a 74-year-old male with six months of dyspnea with minimal exertion. A diagnostic work-up with transthoracic echocardiogram showed asymmetric left ventricular hypertrophy, left ventricular outflow tract obstruction with a peak gradient of 200 mmHg, right ventricular systolic pressure of 99 mmHg, systolic anterior motion of the mitral valve and flail anterior mitral leaflet. The patient was evaluated by a multi-disciplinary team and underwent extended septal myectomy and mitral valve repair with significant improvement in functional capacity post-operatively. Conclusions: While pulmonary hypertension increases the risk of morbidity and mortality during cardiopulmonary bypass, moderate-to-severe pulmonary hypertension in hypertrophic cardiomyopathy with outflow tract obstruction is a unique indication for septal reduction therapy that may not be associated with higher surgical mortality.

An Overview of Gaucher Disease

Background: Gaucher disease (GD) is a rare autosomal recessive disorder caused by mutations in the GBA1 gene that lead to a deficiency in the glucocerebrosidase gene. This deficiency results in the accumulation of glucocerebrosides in macrophages, primarily affecting the liver, spleen, and bone marrow. Focusing on the Mexican population, this study aims to review GD’s epidemiology, clinical manifestations, and treatment options to enhance early diagnosis and optimize treatment outcomes. Methods: This study is a comprehensive literature review analyzing epidemiological data, clinical presentations, and current therapeutic approaches for Gaucher disease, including enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Conclusions: Early diagnosis and individualized treatment, primarily through enzyme replacement therapy, significantly improve the prognosis of patients with Gaucher disease, particularly type 1. Continued research is required to enhance therapeutic approaches for the neuropathic types and better understand the disease’s epidemiology in Mexico. These efforts will contribute to improved clinical outcomes and quality of life for patients.

EFFECTIVENESS OF POSITIVE REMINISCENCE GROUP THERAPY ON DEPRESSION, SELF-ESTEEM AND LONELINESS AMONG ELDERS

Background of the studyThe increase in the relative and absolute number of older people in our society has posed a major challenge for both individual and collective levels in the study of aging. It had appeared various contributions, at the individual level, extending the biological perspective of disease and disability with a more positive and comprehensive one, covering the social and behavioral sciences to reduce the risk of adverse events and improve the resilience of the seniors and make changes in their immediate surroundings.At the population level, aging is seen as a challenge that involves, in addition, challenges such as the double burden of disease, increased risk of disability, having to provide adequate care for the aging population, addressing inequalities, economic challenges, and having a different view of aging and old age.Methodology:The study method included quantitative research, Quasi experimental design where Pre and post-test with equivalent control group design, a population comprises all elderly people residing in the selected old age homes, 400 samples chosen for the study, and a purposive sampling methodology was utilized for the study. Three tools were used to evaluate depression, loneliness and self-esteem among elders. Before data collection, the tool was tested and certified by seven professionals. Permission was taken from concern old age homes and consent was taken from elders. Elderly were asked to rate items against depression, self-esteem and loneliness questions followed by positive reminiscencegroup therapy went on for a month and post was conducted after one month. ResultsElderly from experimental group in depression score pretest 14.45 and posttestmean 9.58 and mean difference was 3.304. The obtained t- test value was 21.576 which shows statistical significance at p<0.05. in self esteem score pretest 22.6 and posttest mean 30.26 and mean difference was 7.66. The obtained t- test value was 28.247 which shows statistical significance at p<0.05. in loneliness score pretest 30.73 and posttest mean 20.86 and mean difference was 9.87. The obtained t- test value was 24.717which shows statistical significance at p<0.05.In experimental group, in depression in post test maximum were 110 (55) mild depression, in self esteem maximum 164 (52) moderate self esteem, in loneliness maximum were 105 (52.5) moderate loneliness. In correlation there is weak positive correlation found between depression and self-esteem, Strong Positive correlation found between depression and loneliness and similarly Very strong positive correlation found between self-esteem and Loneliness. ConclusionReminiscence group therapy is an effective therapy for reduction of depression and loneliness and elevation of self-esteem in elderly. Further research and an improvement in methodological quality, such as using qualitative and mixed methods approaches, is recommended to help establish an evidence base and provide better understanding of the effectiveness of group reminiscence therapynical ventilation period of the patients hospitalized in the ICU had a positive effect on physiological responses..

Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers.

MYBPC3 founder variants cause hypertrophic cardiomyopathy leading to heart failure and malignant ventricular arrhythmias. Exercise is typically regarded as a risk factor for disease expression although evidence is conflicting. Stratifying by type of exercise may discriminate low- from high-risk activities in these patients. Here, we evaluate the effects of exercise, stratified by high-static and high-dynamic components, on the risk of major cardiomyopathy-related events (MCEs) and cardiomyopathy penetrance among MYBPC3 founder variant carriers. We interviewed 188 carriers (57.4% male; aged 43.0±15.0 years) on exercise participation since the age of 10 years. The exercise was quantified as the metabolic equivalent of task-h/wk before the presentation. MCE was defined as a composite of malignant ventricular arrhythmia (sustained ventricular tachycardia/fibrillation), heart failure (heart failure hospitalizations or transplantation), and septal reduction therapy. Static and dynamic exercises were defined per the Bethesda classification. Associations of exercise with MCE and cardiomyopathy penetrance were adjusted for sex and assessed using Cox regression. Overall, 43 (22.9%) subjects experienced MCE and 139 (73.9%) were diagnosed with cardiomyopathy. No association was found between overall physical activity and high-static activity with MCE (P=0.587 overall; P=0.322 high static) or cardiomyopathy penetrance (P=0.317 overall; P=0.623 high static). In contrast, high-dynamic activity was associated with malignant ventricular arrhythmia (dichotomized at the 75th percentile: adjusted hazard ratio, 3.26 [95% CI, 1.26-8.44]; P=0.015). Overall exercise participation does not generally increase the risk of adverse events among MYBPC3 founder variant carriers. Nonetheless, an increased risk of malignant ventricular arrhythmia was observed among those engaged in the highest quartile of high-dynamic sports, suggesting that high-level high-intensity exercise activities should be entertained with caution.

Meta-Analysis on the Racial Disparity of Outcomes Following Alcohol Septal Ablation in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a prevalent cardiac condition that often leads to heart failure, exertional syncope, and sudden cardiac death. Despite the availability of various treatments for HCM, such as septal reduction therapy through surgical septal myectomy or alcohol septal ablation (ASA), disparities in access to care and treatment outcomes persist, particularly among marginalized racial and ethnic groups. These disparities underscore the importance of understanding the influence of race, ethnicity, and regional factors on the management and outcomes of HCM, necessitating a closer examination of whether access to ASA and its associated benefits is equitably distributed across diverse populations. A comprehensive literature search was conducted on various electronic databases aimed to identify studies evaluating the odds of undergoing ASA in HCM in racial subgroups and outcomes like all-cause mortality and stroke. Three studies were included in this meta-analysis with a total sample size of 24,939 HCM patients. Adjusted odds ratio (OR) or pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random-effects model. Blacks were significantly less likely to undergo ASA for HCM (OR, 0.64; 95% CI, 0.57-0.72; P < 0.01) as compared to white patients; however, no differences in all-cause mortality (RR, 0.97; 95% CI, 0.54-1.75) and stroke (RR, 1.29; 95% CI, 0.76-2.18) were noted. In conclusion, this meta-analysis highlights a significant association between race and the likelihood of undergoing ASA among patients with HCM, with minority racial groups potentially facing barriers to accessing this advanced treatment.

Vagal Nerve Stimulation in the Pediatric Population and Correlation between Family and Treatment Team Perspectives: Single-Center Experience.

Vagal nerve stimulation (VNS) is an adjunctive therapy to pharmacologic treatment in patients with drug-resistant epilepsy. This study aimed to assess the efficacy of VNS therapy for seizure frequency reduction and improving the quality-of-life (QOL) measures in children with refractory epilepsy and to evaluate the correlation between the perspectives of families and those of the treating team. This was a prospective cohort study conducted at Abha Maternity and Children's Hospital, Saudi Arabia, from 2018 to 2022. A total of 21 pediatric patients who completed 1 year of follow-up after VNS implantation were included. Patients were aged between 2 and 14 years, with a mean age of 8.14 ± 3.92 years; 11 (52.4%) patients were females. Family and physician assessments were collected blinded to each other using the Clinical Global Impression of Improvement (CGI-I) scores and QOL assessments to evaluate the correlation between the families' and treating team's perspectives on VNS outcomes. In this study, VNS showed significant efficacy in reducing the frequency of seizures. VNS significantly reduced the number of seizures per week from a baseline median of 35 to a median of 0.25 at the end of the follow-up period, representing a dramatic reduction of 99.3% (p < 0.001). The number of emergency department visits per year decreased from a baseline median of 12 to a median of 2, a reduction of 83.3% (p < 0.001), while the number of hospital admissions per year decreased from a baseline median of 3 to a median of 1, a 66.7% decrease (p < 0.001). The number of antiepileptic medications taken decreased from a median of four to three (p < 0.001). Notably, 28.57% of the patients achieved complete seizure freedom, and 38% exhibited significant improvement, with at least 50% reduction in seizure frequency. Importantly, none of the patients experienced an increase in seizure frequency following VNS treatment. The family and physician assessments showed varying degrees of alignment in perceptions, with "concentration" exhibiting a significant positive correlation (r = 0.498, p = 0.022), indicating noteworthy agreement, whereas verbal communication did not show a substantial correlation (r = - 0.062, p = 0.791), indicating a divergence of views. VNS is a promising and well-tolerated therapy for individuals with intractable seizures, offering clinical benefits and potential enhancements in various aspects of QOL. The varying perceptions between family and physician assessments highlight the importance of considering multiple perspectives when evaluating treatment outcomes.

Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 128 Results from VALOR-HCM

Background: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), VALOR-HCM trial (Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy [URL: https://clinicaltrials.gov; Unique identifier: NCT04349072]) reported that mavacamten reduced the short-term need for septal reduction therapy (SRT). The current report examined the longer-term effect of mavacamten through end of treatment at week 128. Methods: A double-blind randomized placebo-controlled multicenter trial at 19 sites in the United States included symptomatic obstructive HCM patients referred for SRT (enrollment July 2020 through October 2021). The group initially randomized to mavacamten continued the drug for 128 weeks and the placebo to mavacamten group from week 16 to 128 (112-week exposure). Dose titrations were performed using echocardiographic left ventricular outflow tract gradient and left ventricular ejection fraction measurements. The principal end point was proportion of patients proceeding with SRT or remaining guideline-eligible at week 128. Results: At week 128, 17 of 108 (15.7%) patients in the total study sample met the composite end point (7 underwent SRT, 1 was SRT-eligible, and 9 SRT-status unevaluable). Additionally, 87 of 108 (80.5%) patients demonstrated ≥1 New York Heart Association class improvement by week 128, and 52 of 108 (48.1%) demonstrated ≥2, with a sustained reduction in resting and Valsalva left ventricular outflow tract gradients of 38.2 mm Hg and 59.4 mm Hg, respectively. Ninety-five of 108 (88%) patients transitioned to commercial mavacamten. Overall, 15 of 108 (13.8%) patients (5.41 per 100 patient-years) had an left ventricular ejection fraction &lt;50% (2 with left ventricular ejection fraction ≤30%; 1 death). Of these, 12 of 15 (80%) continued treatment. New-onset atrial fibrillation occurred in 11 (10.2%) patients (4.55 per 100 patient-years). Conclusions: In severely symptomatic obstructive HCM patients, sustained freedom from SRT was observed at 128 weeks, with nearly 90% patients remaining on long-term mavacamten.

Recent Therapeutic Advancements for Gaucher Disease

AbstractGaucher Disease (GD) is a well‐known lysosomal storage disease resulting from mutations in the GBA1 gene. GD exhibits a range of clinical manifestations, each with unique symptoms and severity levels. This review explores the genetic foundations of GD, highlighting the significance of Glucocerebrosidase (GCase) deficiency, resulting in the skeletal complications associated with GD, such as osteonecrosis, fractures, and bone pain, all of which significantly negatively influence the quality of life for patients. Over 700 mutations in the GBA1 gene are found to cause variations in gene expression in GD, indicating the disease's complexity and the need for continued research. Early diagnosis and prognosis evaluation depend heavily on diagnostic approaches integrating laboratory assessments, genetic testing, and clinical symptoms. Treatment strategies like enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) have advanced, but issues like high costs and invasiveness still exist. This review focuses on novel therapeutic approaches that show promise in treating GD, including gene and cell‐based therapies, pharmacological chaperone therapy (PCT), and drug delivery via nanoparticles. Finally, discussions on current clinical trials, limitations of the advanced therapies, and future scope are summarized.

Abstract 4137810: Association of Sociodemographic Characteristics on Costs of Care in Patients with Obstructive Hypertrophic Cardiomyopathy

Introduction: No evidence exists on the impact of sociodemographic characteristics on costs of care for obstructive hypertrophic cardiomyopathy (oHCM). Therefore, we evaluated 5-year cumulative costs by age, sex, and race/ethnicity. Methods: Retrospective cohort study of adults diagnosed with oHCM (January 2013 to December 2021) using Optum claims and electronic medical record data. Patients with ≥2 claims for HCM (ICD-9 and-10) at least 30 days apart (index date = earliest oHCM claim) with ≥1 additional oHCM claim or septal reduction therapy, 6-months pre-index and 5-year post-index continuous enrollment were included. HCM-related cumulative costs (2022 CPI adjusted) were reported for medical (ambulatory [AB]: office [OV] visits, outpatient [OP] visits); emergency room [ER] visits; inpatient admissions (IP); and pharmacy (Rx). Results: Among 5,129 patients with oHCM, 52% were female (mean age 63.9 ± 14.3 years; 77.6% non-Hispanic White; 40% Medicare). Compared to females (Table), male patients had greater costs including total ($71,581 vs $63,710, p= 0.014), medical ($70,395 vs $62,455, p= 0.013), ambulatory ($16,024 vs $10,776, p&lt;0.001), OV ($1,906 vs $1,573, p&lt;0.001), and OP ($14,118 vs $9,202, p&lt;0.001). Compared with White patients, Black patients had significantly greater IP costs ($54,572 vs $42,686, p= 0.01), Hispanic patients had greater ER costs ($1,724 vs $791, p&lt;0.001), and Asian patients had greater OV costs ($2,094 vs $1,800, p&lt;0.001). Patients aged 18-39 years had greater costs across all categories (p&lt;0.001; IP=NS), except Rx. Patients aged 40-54 years had the highest Rx costs ($1,557, p&lt;0.001), followed by 18-39, 55-64, 65-74, 75+ years ($1,528; $1,329; $1,197; $867), respectively. Conclusions: For oHCM patients , being male and age 18-39 years was associated with increased HCM-related healthcare costs. Differences in cost across race/ethnicity exist, including greater IP and ER costs for Black and Hispanic patients, respectively. Future research is required to understand the source of these differences among oHCM patients.

Abstract 4135259: Coronary Artery Anomalies Induce Myocardial Ischemia in Hypertrophic Cardiomyopathy

Background: Myocardial ischemia is a frequent finding in hypertrophic cardiomyopathy (HCM) and is often attributed to microvascular disease, extravascular compressive forces, reduced coronary flow reserve, hemodynamic abnormalities, and concomitant atherosclerotic coronary artery disease (CAD). The potential contribution of congenital coronary artery anomaly (CCAA) to myocardial ischemia in HCM has not been systematically explored. Research Question: We aimed to evaluate the spectrum and potential contribution of CCAA to myocardial ischemia in HCM. Methods: From June 1991 to March 2023 a total of 35 CCAA were reported in 29 adults [age 18-87 (47.9±19.9; 59% male; 35% obstructive, 21% apical variant). Clinical data on presence or absence of myocardial ischemia, mode of therapy, and outcomes of the patients were reviewed. Results: The individual CCAAs were graphically reproduced [Figure] and were categorized based on the number of coronary ostia present in the aorta [single ostium (n=11; 38%); 2 ostia (n=13; 45%); 3 ostia (n=4; 14%); 4 ostia (n=1; 3%)]. The anomalous coronary artery was the left main in 6 (17%); left anterior descending in 6 (17%); left circumflex in 8 (23%); right in 14 (40%) or the ramus intermedius in 1 (3%). Two patients (7%) with apical variant HCM also had coronary artery fistulae in a non-anomalous coronary artery. Of all 29 patients who presented, 12 (41%) showed objective evidence of myocardial ischemia and of those, a total of 6 (50%) had an anomalous coronary artery coursing between the great vessels. In addition, 1 of 5 patients with sudden cardiac arrest had a high-risk coronary anomaly. Pharmacologic treatment was offered to 11 (38%) patients and 3 (10%) patients underwent coronary artery surgery (bypass grafting in 2 and unroofing in 1). Septal reduction therapy was performed in 8 (28%). Follow up data was available in 14 patients including 2 of the 3 who underwent surgical correction. Symptomatic improvement was noted in all 14. Conclusion: Congenital coronary artery anomalies may be present in patients with HCM and may contribute to myocardial ischemia. Treatment options depend on the type of anomaly and presence of objective evidence of myocardial ischemia.

Abstract 4126581: COVID-19 Impacted Septal Reduction Therapies in Hypertrophic Cardiomyopathy

Background: Coronavirus Disease-19 (COVID-19) pandemic had a significant impact on emergent and elective treatment strategies in patients with cardiovascular disease. We aimed to examine the impact of COVID-19 on septal reduction therapy (SRT) in hypertrophic cardiomyopathy (HCM). Methods: National Inpatient Sample 2019-2021 was queried to identify patients with HCM and SRT using appropriate ICD codes. Temporal trends for SRT were obtained before and after COVID-19 outset. Results: There was a significant decline in the number of SRT from 2019 to 2020 (1505 vs. 1180, p&lt;0.001) with partial recovery in 2021 (1250 vs. 1180, p&lt;0.001). Geographic differences existed with differential decrease in number of SM in midwestern and Western Unites States. In addition, the proportion of patients who underwent surgical myectomy (SM) decreased in 2020 (44.6 vs. 48.7%, p=0.008) in favor of alcohol septal ablation (ASA). Patients undergoing SRT in 2020 had higher prevalence of heart failure (39.5 vs. 29%, p=0.002). In-hospital complication rates for cardiogenic shock, bleeding requiring transfusion, acute kidney injury and admission to the critical care unit were higher in 2020 compared to 2019. Hospital length of stay (LOS) was not significantly different however there was an overall increase in LOS in septal myectomy group from 2019 to 2021 (9.1 vs. 10 days, p=0.028). The overall proportion of comorbidities and other in-hospital complications remain unchanged during this study period. Conclusions: Our data indicates that COVID-19 resulted in a significant decrease in total number of SRTs and a shift from surgical to percutaneous septal reduction therapy. Partial recovery of procedure numbers were noted in the year following the pandemic outset.

Diagnosis and management of hypertrophic cardiomyopathy: European vs. American guidelines.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, affecting 1:200 to 1:500 individuals worldwide. Guidelines on the diagnosis and management of HCM have been recently published by the European Society of Cardiology (ESC) and American societies. The ESC guidelines cover a broad range of cardiomyopathies, including HCM, with 119 recommendations, whereas the American guidelines focus exclusively on HCM with 141 specific recommendations. Both guidelines emphasize a comprehensive diagnostic approach, including imaging and genetic testing, but differ in some specific aspects. For example, sudden cardiac death (SCD) risk assessment is a primary point of divergence. The ESC guidelines advocate for the use of a validated Risk-SCD calculator, while the American guidelines rely on specific risk markers for individualized risk evaluation. Management strategies also vary: both guidelines prioritize beta-blockers and calcium channel blockers in patients with resting or provocable left ventricular outflow tract (LVOT) obstruction. If beta-blockers (or verapamil/diltiazem) are ineffective, either disopyramide or the myosin inhibitor mavacamten may be an option with slightly different indications among the two guidelines. Septal reduction therapy is recommended in ESC guidelines for symptomatic patients with significant LVOT gradients, while American guidelines suggest earlier myectomy for certain clinical factors and emphasize shared decision-making. The ESC guidelines recommend sequential atrioventricular pacing and dual-chamber defibrillators for reducing LVOT gradients. The American guidelines focus on genetic testing for risk assessment and suggest periodic cardiac magnetic resonance imaging. This paper provides a detailed comparison of these guidelines, highlighting key differences and areas needing further research and expert debate.

The Clinical Trajectory of NYHA Functional Class I Patients With Obstructive Hypertrophic Cardiomyopathy.

An improved understanding of the natural history in NYHA functional class I patients with obstructive hypertrophic cardiomyopathy (oHCM) is needed. Using a multicenter registry (SHaRe [Sarcomeric Human Cardiomyopathy Registry]), this study described the natural history in patients with oHCM who were classified as NYHA functional class I at the initial visit compared with patients classified as NYHA functional class II and reported baseline characteristics associated with incident clinical events. Incident events assessed included a composite of NYHA functional class III to IV symptoms, left ventricular ejection fraction<50%, atrial fibrillation, stroke, ventricular arrhythmias, septal reduction therapy, ventricular assist device or transplantation, or death. Factors associated with incident events were determined using Kaplan-Meier, Cox proportional hazards, and restricted cubic spline models. Of 7,964 patients with HCM in SHaRe, 1,239 patients with oHCM met inclusion criteria; 598 were in NYHA functional class I at the initial visit (age 48 ± 17 years; 31.1% female; peak gradient, 75 ± 40mmHg). At 5-year follow-up, the composite event rate of NYHA functional class I patients was 28% compared with 44% (P< 0.001) in 641 NYHA functional class II patients with oHCM (age 54 ± 16 years; 46.5% female; peak gradient, 83 ± 39mmHg). Left atrial (LA) diameter≥45mm (HR: 1.56 [95%CI: 1.14-2.12]; P = 0.005), female sex (HR: 1.61 [95%CI: 1.16-2.24]; P = 0.003), and older age (HR: 1.21 per 10 years [95%CI: 1.09-1.34]; P< 0.001), but not the magnitude of left ventricular outflow tract obstruction, were associated with a higher risk of the composite outcome in NYHA functional class I patients. Although NYHA functional class I patients with oHCM fared better than NYHA functional class II patients, more than one-fourth experienced adverse events over 5-year follow-up, especially if they were older, female, and/or had LA enlargement. Strategies to reduce the rate of clinical outcomes in NYHA functional class I patients warrant further study.

Neurological manifestations of lysosomal storage diseases.

Lysosomal storage diseases (LSDs) encompass a group of rare inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes, leading to multisystemic manifestations, including profound neurological involvement. This article provides a concise overview of the neurological manifestations of LSDs, with a focus on central nervous system (CNS) involvement and treatment strategies. While the paper intricacies of each LSD subtype and its associated CNS manifestations, it aims to provide a summary of the essential findings and implications. The neurological manifestations of LSDs encompass a spectrum of symptoms, including cognitive impairment, motor dysfunction, seizures, and sensory deficits, which significantly impact patients' quality of life and pose therapeutic challenges. Current treatment strategies primarily aim to alleviate symptoms and slow disease progression, with limited success in reversing established neurological damage. Enzyme replacement therapy, substrate reduction therapy, and emerging gene therapies hold promise for addressing CNS involvement in LSDs. However, challenges such as blood-brain barrier penetration and long-term efficacy remain. In addition to discussing treatment modalities, this article highlights the importance of early diagnosis, multidisciplinary care, and patient advocacy in optimizing outcomes for individuals affected by LSDs. Ethical considerations are also addressed, including equitable access to emerging treatments and integrating personalized medicine approaches. Overall, this article underscores the complex interplay between genetics, neuroscience, and clinical care in understanding and managing the neurological manifestations of LSDs while emphasizing the need for continued research and collaboration to advance therapeutic interventions and improve patient outcomes.

Exploring Gaucher disease: A pediatric case of severe dyslipidemia and unique symptoms

Introduction: Gaucher disease is a rare inherited lysosomal storage disorder caused by mutations in the GBA gene, leading to glucocerebrosidase deficiency. This results in the accumulation of glucocerebroside in macrophages, forming "Gaucher cells" that infiltrate various tissues, primarily affecting the liver, spleen, bone marrow, and nervous system. The disease manifests in three types, with Type 1 being the most common and devoid of neurological symptoms. Diagnosis involves enzyme level testing, genetic screening, and imaging, while treatment primarily consists of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Case-Report: A one-year-old girl presented with weakness, irritability, and recurrent fever over six months, previously misdiagnosed with malaria and respiratory infections. Physical examination revealed pallor, hepatosplenomegaly, and cherry-red spots on fundoscopy. Laboratory findings indicated anemia, leukocytosis, and severe dyslipidemia, highlighting atypical features for Gaucher disease. Discussion: This case emphasizes the diagnostic challenges in pediatric Gaucher disease, especially with nonspecific symptoms. The combination of cherry-red spots and dyslipidemia suggests a unique variant or severity of the disease, underlining the necessity for heightened awareness among healthcare providers for prompt diagnosis. Conclusion: Gaucher disease should be considered in pediatric patients with unexplained systemic symptoms. Early detection and ERT initiation can significantly improve clinical outcomes. The case illustrates the variability in clinical presentations, emphasizing the need for comprehensive diagnostic evaluation.

Serial changes in left and right ventricular global longitudinal strain in symptomatic obstructive hypertrophic cardiomyopathy treated with mavacamten: insights from VALOR-HCM trial

Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM phase 3 randomized, double-blind, placebo-controlled clinical trial demonstrated that mavacamten, reduces the need for septal reduction therapy with sustained improvement in left ventricular outflow tract gradients and symptoms. As a cardiac myosin inhibitor, mavacamten’s mechanism of action reduces myocardial hypercontractility. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function and can complement left ventricular ejection fraction (LVEF). Objective We sought to assess serial changes in LV and right ventricular (RV)-GLS in patients enrolled in the VALOR-HCM study. Methods VALOR-HCM included 112 symptomatic obstructive HCM patients (mean 60 years, 51% male, LVEF 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo crossed over to mavacamten (n=52) from week 16-56 (40-week exposure). LV and RV-GLS assessment was performed according to the current American and European guideline recommendations using a vendor-neutral post processing software. Non-foreshortened apical (4, 3 and 2-chamber) views were used to obtain peak value of LV-GLS. For RV-GLS, RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. Results Serial changes in LVEF, average LV-GLS, and RV-GLS (4-chamber and free wall) from baseline to week 56 are shown in the Figure. Despite preserved LVEF at baseline, average baseline LV-GLS was abnormal. There were significant and continued improvements in LV-GLS in the total group from baseline to week 56. 12 patients had transient reduction in LVEF (&amp;lt;50%) requiring temporary drug interruption (permanent discontinuation in 3). The LV-GLS in this subgroup was worse at baseline compared to the total study population, with no significant worsening from baseline through week 56. In the overall population, excluding these 12 patients, LV-GLS demonstrated an improvement sustained through week 56. Both free wall and 4-chamber RV-GLS were abnormal at baseline and remained unchanged from baseline to week 56. Conclusions In the VALOR-HCM trial, despite hypercontractile LVEF at baseline, average baseline LV-GLS was worse than normal reference values. Treatment with mavacamten resulted in an improvement in LV-GLS from baseline through Week 56 (with no significant worsening of LV-GLS in the subgroup who experienced any reduction in LVEF &amp;lt;50%), suggesting a favorable long-term impact on regional LV systolic function due to the reduction of cardiac hypercontractility. Additionally, there was no significant detrimental impact on RV systolic function on serial GLS assessment.Serial changes in LV and RV GLS in VALOR

Serial changes in left atrial strain in symptomatic obstructive hypertrophic cardiomyopathy treated with mavacamten: insights from VALOR-HCM trial

Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM phase 3 randomized, double-blind, placebo-controlled clinical trial demonstrated that mavacamten, a cardiac myosin inhibitor, reduces the eligibility for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Mavacamten also resulted in favorable cardiac remodeling, including improvement in left atrial volume index (LAVI), LV diastolic function, and biomarkers (NT-proBNP and troponin T). However, the impact of mavacamten on LA function is not known. Objective We sought to assess serial changes in LA strain measures in patients enrolled in the VALOR-HCM trial. Methods VALOR-HCM included 112 symptomatic obstructive HCM patients (mean age 60 years, 51% male). Patients assigned to mavacamten at baseline (n=56) continued therapy for 56 weeks and those assigned to placebo crossed over to mavacamten (n=52) from week 16-56 (40-week exposure). Echocardiographic LA strain assessment was performed according to the current American and European guideline recommendations, using a vendor-neutral post processing software. For assessment of LA strain components (reservoir, conduit, and contraction), the non-foreshortened apical 4-chamber view was utilized. The zero reference was set at end-diastole. Results Serial changes in LAVI and all components of mean LA strain from baseline to week 56 are shown in the Figure. At baseline, LAVI and all mean LA strain values were worse than reported normal mean thresholds. There was a continued and significant improvement in all 3 LA strain values, from baseline to week 56, along with a significant reduction in LAVI. Improvement in LAVI was seen earlier than improvements in LA strain. There was a significant inverse correlation between change in mean LAVI and LA reservoir strain from baseline to week 56 (r= -0.42, p&amp;lt;0.001). Conclusions In the VALOR-HCM trial, average LAVI and baseline LA strain values were significantly worse than reported normal thresholds. Treatment with mavacamten resulted in an improvement in LAVI and LA strain values from baseline through week 56 suggesting a sustained favorable impact on cardiac remodeling. The advantageous cardiac remodeling associated with long-term treatment with mavacamten may in turn have a favorable impact on the observed high burden of atrial tachyarrhythmias in HCM.Serial changes in LA strain in VALOR-HCM

Is unsatisfactory outcome of alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy predictable?

Abstract Background Alcohol septal ablation (ASA) has been introduced for left ventricular outflow tract gradient (LVOTG) reduction in patients with hypertrophic obstructive cardiomyopathy (HOCM). However, some patients may not profit from ASA. Thus, we identified characteristics of patients with unsatisfactory outcome of ASA in a large single-center cohort. Methods Consecutive ASAs between 1997 and 2023, performed at our institution, were retrospectively enrolled. Those ASAs performed in patients with missing follow-up (FU), previous septal reduction therapy (SRT), and atypical HOCM were excluded. Patients with unsatisfactory outcome (PUO) were defined as continuing to meet the guideline criteria for SRT (NYHA ≥III or NYHA ≥II with exertional syncope and resting/exercise-induced LVOTG ≥50mmHg). PUO were compared to patients with good outcome (PGO). Results are expressed in % or median and interquartile range (IQR). Pre-procedural predictors of poor hemodynamic outcome were identified using logistic regression analysis. Results 65 of 1003 patients were PUO (6.5%). Those were younger (48.0 years [40.5-61.8] vs. 57.0 years [IQR 47.0-67.0] in PGO; p=0.0030), more often reported syncope at baseline (35.4% vs. 22.2% in PGO; p=0.0214), and had lower body-mass-index (26.4kg/m2 [23.8-29.2] vs. 27.7kg/m2 [25.2-23.1] in PGO; p=0.0160). In PUO, resting LVOTG was higher at baseline (53.0mmHg [24.5-82.0]) than in PGO (40.0mmHg [22.0-75.0]; p=0.0292; Table 1). Differences in sex, family history of sudden cardiac death, dyspnoea, medication, and interventricular septum diameter (IVSD) were not observed at baseline (all p&amp;gt;0.05; Table 1). Age (OR 1.023; CI: 1.005-1.042; p=0.0129), syncope at baseline (OR 1.890; CI: 1.049-3.324; p=0.0296), and BMI (OR 1.072; CI: 1.007-1.145; p=0.0355) were found to independently influence poor hemodynamic response to ASA using multiple logistic regression controlling for confounders. However, sex, baseline IVSD, and LVOTG were not found to influence poor hemodynamic outcome (p&amp;gt;0.05). There were no differences with regard to the number of embolized branches (1 in both groups), the size of the balloon used to cover the septal branch (1.5mm in both groups), the volume of ethanol (PUO: 1.4ml [1.0-2.0]; PGO: 1.5ml [1.2-2.0]), or creatine kinase release (PUO: 879.0U/l [375.0-1187.0]; PGO: 842.0U/l [501.5 - 1234]) (all p&amp;gt;0.05). At 6-months-FU, PUO had significantly higher IVSD (18.0mm [13.5-22.0] vs. 16.0mm [12.0-19.0] in PGO; p=0.008), higher resting LVOTG (31.0mmHg [20.0-55.5] vs. 14.0mmHg [10.0-22.0] in PGO; p&amp;lt;0.0001) and higher exercise-induced LVOTG (105.0mmHg [84.5-143.0] vs. 35.0mmHg [22.0-64.0] in PGO; p&amp;lt;0.0001). Conclusion ASA was overall effective with only few patients experiencing unsatisfactory outcome. Syncope, age, and BMI were found predicting poor hemodynamic outcome.Baseline characteristics