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Clinical Cardiology Jan 2024Hypertrophic cardiomyopathy (HCM) is a common contemporary, treatable, genetic disorder that can be compatible with normal longevity. While current medical therapies are... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a common contemporary, treatable, genetic disorder that can be compatible with normal longevity. While current medical therapies are ubiquitous, they are limited by a lack of solid evidence, are often inadequate, poorly tolerated, and do not alter the natural disease course. As such, there has long been a need for effective, evidence-based, and targeted disease-modifying therapies for HCM. In this review, we redefine HCM as a treatable condition, evaluate current strategies for therapeutic intervention, and discuss novel myosin inhibitors. The majority of patients with HCM have elevated left ventricular outflow tract gradients, which predicts worse symptoms and adverse outcomes. Conventional pharmacological therapies for symptomatic HCM can help improve symptoms but are often inadequate and poorly tolerated. Septal reduction therapies (surgical myectomy and alcohol septal ablation) can safely and effectively reduce refractory symptoms and improve outcomes in patients with obstructive HCM. However, they require expertise that is not universally available and are not without risks. Currently, available therapies do not alter the disease course or the progressive cardiac remodeling that ensues, nor subsequent heart failure and arrhythmias. This has been regarded as an unmet need in the care of HCM patients. Novel targeted pharmacotherapies, namely cardiac myosin inhibitors, have emerged to reverse key pathophysiological changes and alter disease course. Their favorable outcomes led to the early Food and Drug Administration approval of mavacamten, a first-in-class myosin modulator, changing the paradigm for the pharmacological treatment of HCM.
Topics: United States; Humans; Cardiomyopathy, Hypertrophic; Heart; Disease Progression; Heart Failure; Myosins
PubMed: 38269637
DOI: 10.1002/clc.24207 -
The American Journal of Cardiology Jan 2024We aimed to assess the overall clinical impact of cardiac myosin inhibitors in hypertrophic cardiomyopathy (HCM). We performed a meta-analysis of published trials... (Meta-Analysis)
Meta-Analysis
We aimed to assess the overall clinical impact of cardiac myosin inhibitors in hypertrophic cardiomyopathy (HCM). We performed a meta-analysis of published trials assessing the effect of cardiac myosin inhibitors (mavacamten and aficamten) on resting and Valsalva left ventricular outflow tract (LVOT) gradients and functional capacity in symptomatic HCM. The co-primary outcomes were mean percent change (mean difference [MD]) from baseline in LVOT gradient at rest and Valsalva LVOT gradient and the proportion of patients achieving New York Heart Association class improvement ≥1. The secondary outcomes included the mean percent change from baseline N-terminal pro-B-type natriuretic peptide, troponin I, and left ventricular ejection fraction (LVEF). A total of 4 studies (all randomized controlled trials, including 3 mavacamten-focused and 1 aficamten-focused trials) involving 463 patients were included in the meta-analysis. Compared with placebo, the cardiac myosin inhibitor group demonstrated statistically significant differences in the baseline percent change in mean LVOT gradient at rest (MD -62.48, confidence interval [CI] -65.44 to -59.51, p <0.00001) and Valsalva LVOT gradient (MD -54.21, CI -66.05 to -42.36, p <0.00001) and the proportion of patients achieving New York Heart Association class improvement ≥1 (odds ratio 3.43, CI 1.90 to 6.20, p <0.0001). Regarding the secondary outcomes, the intervention group demonstrated statistically significant reductions in mean percent change from baseline in N-terminal pro-B-type natriuretic peptide (MD -69.41, CI -87.06 to -51.75, p <0.00001), troponin I (MD, -44.19, CI -50.59 to -37.78, p <0.00001), and LVEF (MD -6.31, CI -10.35, -2.27, p = 0.002). In conclusion, cardiac myosin inhibitors may confer clinical and symptomatic benefits in symptomatic HCM at the possible expense of LVEF. Further trials with large sample sizes are needed to confirm our findings.
Topics: Humans; Natriuretic Peptide, Brain; Stroke Volume; Troponin I; Ventricular Function, Left; Cardiomyopathy, Hypertrophic; Cardiac Myosins; Randomized Controlled Trials as Topic
PubMed: 37884110
DOI: 10.1016/j.amjcard.2023.10.059 -
Indian Heart Journal 2022To assess the safety and efficacy of omecamtiv mecarbil compared with placebo in heart failure (HF) patients. (Meta-Analysis)
Meta-Analysis Review
AIM
To assess the safety and efficacy of omecamtiv mecarbil compared with placebo in heart failure (HF) patients.
METHODS
We searched PubMed, Web of Science, Cochrane Library, and SCOPUS until August 15th, 2021. We included all randomized controlled studies comparing omecamtiv mecarbil with placebo in heart failure patients. The meta-analysis was carried out using Rev Man software V5.4.
RESULTS
A total of eight studies were included in our systematic review. Pooled analysis showed that omecamtiv mecarbil is not associated with increased incidence of death, any adverse events, hypotension, heart failure, ventricular tachyarrhythmia, dyspnea, dizziness, and serious adverse events. Regarding the efficacy, omecamtiv mecarbil significantly reduced heart rate with some studies demonstrating its significant improvement in left ventricular ejection fraction and systolic function.
CONCLUSION
Omecamtiv mecarbil is a well-tolerated drug in heart failure patients. The limited data regarding the efficacy suggested that it may improve ejection fraction and systolic function.
Topics: Cardiac Myosins; Heart Failure; Humans; Stroke Volume; Urea; Ventricular Function, Left
PubMed: 35301008
DOI: 10.1016/j.ihj.2022.03.005 -
International Journal of Molecular... Oct 2022Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform.... (Review)
Review
Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform. Muscle fibre-specific gene expression and proportions of muscle fibre types change during development and in response to exercise, chronic electrical stimulation, or inactivity. To identify genes whose gain or loss-of-function alters type 1, 2A, 2X, or 2B muscle fibre proportions in mice, we conducted a systematic review of transgenic mouse studies. The systematic review was conducted in accordance with the 2009 PRISMA guidelines and the PICO framework. We identified 25 "muscle fibre genes" (, , , , , , , , , , , , , , , , , , , , , , , and ) whose gain or loss-of-function significantly changes type 1, 2A, 2X or 2B muscle fibre proportions in mice. The fact that 15 of the 25 muscle fibre genes are transcriptional regulators suggests that muscle fibre-specific gene expression is primarily regulated transcriptionally. A reanalysis of existing datasets revealed that the expression of and increases and decreases after exercise, respectively. This suggests that these genes help to regulate the muscle fibre adaptation to exercise. Finally, there are many known DNA sequence variants of muscle fibre genes. It seems likely that such DNA sequence variants contribute to the large variation of muscle fibre type proportions in the human population.
Topics: Adult; Mice; Animals; Humans; Muscle Fibers, Skeletal; Myosin Heavy Chains; Protein Isoforms; Electric Stimulation; Muscle, Skeletal; RNA-Binding Proteins; Forkhead Transcription Factors; Nuclear Receptor Co-Repressor 1
PubMed: 36361732
DOI: 10.3390/ijms232112933 -
Otology & Neurotology : Official... Mar 2022To review the characteristics and progression of hearing loss in MYH9-related disease (MYH9-RD) patients and present a unique case of bilateral non-simultaneous sudden...
OBJECTIVES
To review the characteristics and progression of hearing loss in MYH9-related disease (MYH9-RD) patients and present a unique case of bilateral non-simultaneous sudden sensorineural hearing loss (SNHL) in an MYH9-RD patient. MYH9-RD is a rare autosomal dominant platelet disorder. Patients with this disorder have a variable risk of developing SNHL.
METHODS
A comprehensive literature search for scientific articles in PubMed, Scopus, and Web of Science that reported hearing loss outcomes in MYH9-RD patients.
RESULTS
Initial search yielded 270 studies. Eight studies with a total of 23 patients met inclusion criteria and were used for data analysis. MYH9-RD patients typically present with progressive bilateral SNHL affecting predominantly the high frequencies. Mean age of hearing loss onset was 17.1 years, progressing to severe-profound SNHL over a mean period of 14.4 years. Seventeen of the 23 patients received cochlear implant (CI) at a mean age of 37.9 years. In comparison, the study patient presented initially with bilateral progressive SNHL as a teenager and developed bilateral non-simultaneous sudden SNHL, first in her right ear at the age of 31 and 7 months later in her left ear at the age of 32. She is now a successful bilateral CI user.
CONCLUSIONS
This is the first systematic investigation of the relationship between MYH9-RD patients and SNHL. Hearing loss in MYH9-RD patients is generally characterized as progressive SNHL. However, the study patient presented with the unique feature of bilateral non-simultaneous sudden SNHL, potentially expanding the hearing loss sequela associated with this disorder.
Topics: Adolescent; Adult; Cochlear Implantation; Deafness; Female; Hearing Loss, Sensorineural; Hearing Loss, Sudden; Humans; Myosin Heavy Chains; Thrombocytopenia
PubMed: 35147601
DOI: 10.1097/MAO.0000000000003450 -
Journal of Applied Physiology... Aug 2020As studies examining the hypertrophic effects of resistance training (RT) at the cellular level have produced inconsistent results, we performed a systematic review and... (Meta-Analysis)
Meta-Analysis
As studies examining the hypertrophic effects of resistance training (RT) at the cellular level have produced inconsistent results, we performed a systematic review and meta-analysis to investigate muscle fiber size before and after a structured RT intervention in older adults. A random-effects model was used to calculate mean effect size (ES) and 95% confidence intervals (CI). Thirty-five studies were included (age range: 59.0-88.5 yr), and 44 and 30 effects were used to estimate RT impact on myosin heavy chain (MHC) I and II fiber size. RT produced moderate-to-large increases in MHC I (ES = +0.51, 95%CI +0.31 to +0.71; < 0.001) and II (ES = +0.81, 95%CI +0.56 to +1.05; < 0.001) fiber size, with men and women having a similar response. Age was negatively associated with change in muscle fiber size for both fiber types (MHC I: = 0.11, β = -0.33, = 0.002; MHC II: = 0.10, β = -0.32, = 0.04), indicating a less robust hypertrophic response as age increases in older adults. Unexpectedly, a higher training intensity (defined as percentage of one-repetition maximum) was associated with a smaller increase in MHC II fiber size ( = 15.09%, β = -0.39, = 0.01). Notably, MHC II fiber subtypes (IIA, IIX, IIAX) were examined less frequently, but RT improved their size. Overall, our findings indicate that RT induces cellular hypertrophy in older adults, although the effect is attenuated with increasing age. In addition, hypertrophy of MHC II fibers was reduced with higher training intensity, which may suggest a failure of muscle fibers to hypertrophy in response to high loads in older adults.
Topics: Aged; Aged, 80 and over; Female; Humans; Hypertrophy; Male; Middle Aged; Muscle Fibers, Skeletal; Muscle, Skeletal; Myosin Heavy Chains; Resistance Training
PubMed: 32702280
DOI: 10.1152/japplphysiol.00170.2020 -
Haemophilia : the Official Journal of... Mar 2021
Topics: Female; Hearing Loss, Sensorineural; Humans; Molecular Motor Proteins; Myosin Heavy Chains; Thrombocytopenia
PubMed: 32997874
DOI: 10.1111/hae.14147