Resolution of dynamic left ventricular outflow tract obstruction and reversible left ventricular hypertrophy in 4 cats.

This case series describes spontaneous resolution of systolic anterior motion of the mitral valve, cessation of a dynamic left ventricular outflow tract obstruction, and reverse cardiac remodeling in 4 young cats. Following initial presentation with or without congestive heart failure, subsequent rechecks documented resolution of systolic anterior motion of the mitral valve and normalization of left heart dimensions. Those cats originally presented with congestive heart failure were successfully weaned off diuretic medications. Atenolol was prescribed to all 4 cats, and all remained on oral atenolol through the final recheck. There was no documented recurrence of progressive heart disease and heart failure in any of the cats. Consideration is given to transient myocardial thickening, spontaneous resolution of mitral valve dysplasia, and response to beta-1 adrenergic antagonism as possible underlying mechanisms. Key clinical message: When presented with young cats with hypertrophic obstructive cardiomyopathy, veterinarians should consider multiple differential diagnoses, as lifespan in these cases may be longer than typically expected for cats with primary hypertrophic cardiomyopathy, even with concurrent congestive heart failure.

Résolution d'une obstruction dynamique de la voie d'éjection du ventricule gauche et d'une hypertrophie réversible du ventricule gauche chez 4 chatsCette série de cas décrit la résolution spontanée du mouvement antérieur systolique de la valve mitrale, la cessation d'une obstruction dynamique de la voie d'éjection du ventricule gauche et le remodelage cardiaque inverse chez 4 jeunes chats. Après une présentation initiale avec ou sans insuffisance cardiaque congestive, des vérifications ultérieures ont documenté la résolution du mouvement antérieur systolique de la valve mitrale et la normalisation des dimensions du cœur gauche. Les chats initialement présentés avec une insuffisance cardiaque congestive ont été sevrés avec succès des médicaments diurétiques. De l'aténolol a été prescrit aux 4 chats, et tous sont restés sous aténolol oral jusqu'au dernier contrôle. Aucune récidive de maladie cardiaque progressive et d'insuffisance cardiaque n'a été documentée chez aucun des chats. L'épaississement transitoire du myocarde, la résolution spontanée de la dysplasie de la valve mitrale et la réponse à l'antagonisme bêta-1 adrénergique sont pris en compte comme mécanismes sous-jacents possibles.Message clinique clé :Lorsqu'ils sont confrontés à de jeunes chats atteints de cardiomyopathie hypertrophique obstructive, les vétérinaires doivent envisager plusieurs diagnostics différentiels, car la durée de vie dans ces cas peut être plus longue que celle généralement attendue pour les chats atteints de cardiomyopathie hypertrophique primaire, même en cas d'insuffisance cardiaque congestive concomitante.(Traduit par Dr Serge Messier).

Serial Changes in Ventricular Strain in Symptomatic Obstructive Hypertrophic Cardiomyopathy Treated With Mavacamten: Insights From the VALOR-HCM Trial.

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain. METHODS: VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-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: At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were -14.7%, -22.2%, and -16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 (P=0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (-11.4%), with no significant worsening from baseline through week 56 (P=0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 (P=0.62 and P=0.56, respectively). CONCLUSIONS: In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04349072.

Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state. Binding to an allosteric site on the myosin catalytic domain distinct from mavacamten, aficamten prevents the conformational changes necessary to enter the strongly actin-bound force-generating state. In doing so, aficamten reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state provides a basis for understanding its selectivity over smooth and fast skeletal muscle. Furthermore, in cardiac myocytes and in mice bearing the hypertrophic R403Q cardiac myosin mutation, aficamten reduces cardiac contractility. Our findings suggest aficamten holds promise as a therapy for HCM.

Innovative pharmacological approaches to hypertrophic cardiomyopathy: The emerging role of Aficamten.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), which can lead to left ventricular outflow tract (LVOT) obstruction. Traditional treatments often provide limited symptom relief and may not adequately reduce the LVOT gradient. Myosin inhibitors, such as Aficamten , offer a new therapeutic approach by modulating myocardial contractility and improving symptoms. This paper evaluated the efficacy and safety of Aficamten in patients with symptomatic HCM. We conducted a comprehensive literature review of studies evaluating Aficamten for symptomatic HCM, including clinical trials and observational studies up to July 2024. Data on efficacy, safety, and patient outcomes were extracted and analyzed from a total of 10 studies involving 1,067 patients. Aficamten demonstrated substantial efficacy in reducing the LVOT gradient, with dose-dependent reductions ranging from 3.6 % to 48.6 %. It also improved symptoms, with 82.3 % of patients experiencing reduced left ventricular ejection fraction (LVEF) and notable improvements in New York Heart Association (NYHA) functional class. Exercise capacity was enhanced, as indicated by increased peak oxygen uptake. Safety profiles were generally favorable, though some serious adverse events, such as atrial fibrillation and cardiac dysfunction, were reported. Aficamten was well-tolerated overall, with manageable dose-dependent adverse effects. Aficamten represents a promising advance in the management of symptomatic HCM, offering significant reductions in LVOT gradient and improvement in symptoms and exercise capacity. Its safety profile is generally favorable, although ongoing monitoring is necessary to manage potential adverse effects. Future research should focus on long-term outcomes, comparative effectiveness, and real-world evidence.

Mavacamten for Obstructive Hypertrophic Cardiomyopathy: Rationale for Clinically Guided Dose Titration to Optimize Individual Response.

Mavacamten is the first and only cardiac myosin inhibitor approved in 5 continents for the treatment of adults with symptomatic New York Heart Association class II and III obstructive hypertrophic cardiomyopathy. An evidence-based rationale was used to develop individualized mavacamten dosing, guided by commonly used clinical parameters. Echocardiography is recommended as part of routine clinical assessment of patients with hypertrophic cardiomyopathy, and left ventricular (LV) outflow tract gradient and LV ejection fraction are parameters that can be readily assessed and monitored by echocardiography. Therefore, an echocardiography-based, clinically guided dose-titration strategy was developed to optimize patient benefit from mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy while minimizing the risk of LV ejection fraction reduction. Results from clinical trials paired with extensive modeling and simulation analyses support a dose-titration and monitoring strategy based on serial echocardiographic measures of Valsalva LV outflow tract gradient and LV ejection fraction. This dosing approach allows for the identification of the lowest individualized mavacamten dose and exposure required to provide improvements in LV outflow tract obstruction, functional capacity, and symptoms. Mavacamten is primarily metabolized by CYP2C19 (cytochrome P450 2C19), and CYP2C19 metabolizer phenotype has an effect on mavacamten exposure. Therefore, this approach has also been demonstrated to provide a favorable safety profile irrespective of patients' CYP2C19 metabolizer status. The dose-titration strategy includes additional considerations for the potential onset of systolic dysfunction in the context of intercurrent illness, and for the potential of drug-drug interactions with inhibitors and substrates of cytochrome P450 enzymes. This posology is reflected in the mavacamten US prescribing information.

Quality of Life and Exercise Capacity in Early Stage and Subclinical Hypertrophic Cardiomyopathy: A Secondary Analysis of the VANISH Trial.

BACKGROUND: The health-related quality of life (HRQOL) and cardiopulmonary exercise testing (CPET) performance of individuals with subclinical and early stage hypertrophic cardiomyopathy (HCM) have not been systematically studied. Improved understanding will inform the natural history of HCM and factors influencing well-being. METHODS: VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) participants with early stage sarcomeric HCM (primary analysis cohort) and subclinical HCM (sarcomere variant without left ventricular hypertrophy comprising the exploratory cohort) who completed baseline and year 2 HRQOL assessment via the pediatric quality of life inventory and CPET were studied. Metrics correlating with baseline HRQOL and CPET performance were identified. The impact of valsartan treatment on these measures was analyzed in the early stage cohort. RESULTS: Two hundred participants were included: 166 with early stage HCM (mean age, 23±10 years; 40% female; 97% White; and 92% New York Heart Association class I) and 34 subclinical sarcomere variant carriers (mean age, 16±5 years; 50% female; and 100% White). Baseline HRQOL was good in both cohorts, although slightly better in subclinical HCM (composite pediatric quality of life score 84.6±10.6 versus 90.2±9.8; P=0.005). Both cohorts demonstrated mildly reduced functional status (mean percent predicted peak oxygen uptake 73±16 versus 78±12 mL/kg per minute; P=0.18). Percent predicted peak oxygen uptake and peak oxygen pulse correlated with HRQOL. Valsartan improved physical HRQOL in early stage HCM (adjusted mean change in pediatric quality of life score +4.1 versus placebo; P=0.01) but did not significantly impact CPET performance. CONCLUSIONS: Functional capacity can be impaired in young, healthy people with early stage HCM, despite New York Heart Association class I status and good HRQOL. Peak oxygen uptake was similarly decreased in subclinical HCM despite normal left ventricular wall thickness and excellent HRQOL. Valsartan improved physical pediatric quality of life scores but did not significantly impact CPET performance. Further studies are needed for validation and to understand how to improve patient experience. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.

Comparison of Drug Therapy Efficacy in Patients With Hypertrophic Cardiomyopathy: A Network Meta-Analysis.

The aim of this network meta-analysis was to compare the efficacy of various commonly used drugs in treating patients with hypertrophic cardiomyopathy (HCM). Randomized controlled trials on drugs for HCM treatment were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (search cutoff: January 10, 2024). Quality assessment was performed using the risk of bias tool, and data analysis used R software. Seventeen studies (1,133 patients with HCM) were included. The network meta-analysis indicated that mavacamten and perhexiline improved peak oxygen consumption compared with placebo. Mavacamten reduced N-terminal pro-B-type natriuretic peptide, left ventricular mass index, left atrial volume index, and septal E/e' ratio. Losartan decreased systolic blood pressure, whereas candesartan, mavacamten, and valsartan reduced maximum wall thickness. Perhexiline had better efficacy in increasing peak oxygen consumption, and candesartan in reducing maximum wall thickness. No drug significantly improved left ventricular ejection fraction compared with placebo. In conclusion, on the basis of current studies, commonly used drugs may effectively improve some of the outcome measures in patients with HCM, whereas the novel drug mavacamten showed significant therapeutic effects in most of the remaining outcome measures except for left ventricular ejection fraction.

Hypertrophic Cardiomyopathy: From Medical Treatment to Advanced Heart Failure Therapies.

PURPOSE OF REVIEW: There has been much debate surrounding novel medical therapies and heart transplantation listing challenges in patients with hypertrophic cardiomyopathy (HCM). RECENT FINDINGS: Recent clinical trials led to FDA approval of mavacamten (a cardiac myosin inhibitor), offering symptom relief and potentially delaying/avoiding invasive septal reduction therapies for some patients with HCM and left ventricular outflow obstruction (LVOTO). For those with refractory symptoms and end-stage heart failure, heart transplantation remains the gold standard. However, the concern for the organ allocation system failing to prioritize those individuals persists. HCM is a heterogeneous genetic condition with variable penetration and clinical presentation. Even though a large portion of patients remain asymptomatic, an important minority develops debilitating symptoms refractory to medical therapy. Post-HT short- and long-term outcomes are favorable. However, HT waitlist mortality remains high. For highly selected patients with HCM, a left ventricular assist device is a viable option.

Clinical signs associated with severe ST segment elevation in three cats with a hypertrophic cardiomyopathy phenotype.

Three cats were presented for unusual collapsing episodes. Echocardiography revealed a hypertrophic cardiomyopathy (HCM) phenotype in each cat. Continuous electrocardiographic monitoring showed that the clinical signs coincided with periods of severe ST-segment elevation in each cat. The first cat was treated with amlodipine and diltiazem but did not improve and was euthanized due to poor quality of life. Postmortem examination revealed cardiac lymphoma without obstructive coronary disease. The second cat was thought to have cardiac lymphoma, based on pericardial effusion cytology, and was euthanized before starting therapy. The third cat was diagnosed with HCM and left ventricular outflow tract obstruction and was treated with atenolol and diltiazem. This treatment reduced the frequency of episodic clinical signs, but the cat subsequently developed congestive heart failure and was euthanized. This case series describes clinical signs associated with severe ST elevation in cats with an HCM phenotype, and their outcomes. Continuous electrocardiographic monitoring was necessary to detect transient ST elevation in each case.

Novel Cardiac Myosin Inhibitor Therapy for Hypertrophic Cardiomyopathy in Adults: A Contemporary Review.

Hypertrophic cardiomyopathy (HCM) affects as many as 1 in 200 people in the adult population globally. Patients may present with exertional dyspnea, presyncope or syncope, atrial and ventricular arrhythmias, heart failure, and even sudden cardiac death. Current guideline-based therapy involves medical therapy for treatment of symptoms in milder forms of the disease and surgical or catheter-based septal reduction therapies in obstructive HCM. Until recently, there has existed a gap between these two approaches that is now being filled by a new class of drugs, cardiac myosin inhibitors, which directly target the underlying disease process in HCM. Current investigations examine the effects of two cardiac myosin inhibitors on reported symptoms, echocardiographic evidence of disease, and the associated need for septal reduction. This paper reviews the contemporary evidence for the use of cardiac myosin inhibitors in HCM in adults and highlights future directions for this exciting field of cardiovascular medicine.

Two cardiac myosin inhibitors in the treatment of obstructive hypertrophic cardiomyopathy.

A key area of therapeutic progress in obstructive hypertrophic cardiomyopathy revolves around the emergence of cardiac myosin inhibitors, of which mavacamten and aficamten represent the first and second molecules. We summarize the key research evidence, including many similarities and potential differences between various clinical trials studying these molecules.

Eighteen-Month Real-World Experience Using Mavacamten for Treatment of Obstructive Hypertrophic Cardiomyopathy in a Racially Diverse Population.

BACKGROUND: Patients with obstructive hypertrophic cardiomyopathy have increased symptomatic burden. Mavacamten was recently approved for treatment of obstructive hypertrophic cardiomyopathy based on 2 randomized controlled trials. However, its use under real-world conditions and in diverse populations is under-studied. METHODS AND RESULTS: This was a prospective observational cohort study of patients seen at the Johns Hopkins HCM center and prescribed mavacamten for obstructive hypertrophic cardiomyopathy between July 7, 2022 and January 6, 2024. Patients were followed longitudinally, with serial echocardiography and clinical evaluation as mandated by the risk evaluation and mitigation strategy program. Sixty-six patients received mavacamten (mean age 59 years, 47% male, 29% non-White [Black, Hispanic/Latino, Asian, Native Hawaiian or Pacific Islander], 47% obese). Before treatment, all patients had New York Heart Association class II (51.5%) or III (48.5%) heart failure symptoms. Initial maximum peak left ventricular outflow tract gradient was 107±46 mm Hg. Median treatment duration was 9 months. For patients on mavacamten after ≥6 months (n=43), symptoms improved by ≥1 New York Heart Association class in 72% of patients, and peak left ventricular outflow tract gradient decreased by 80±46 mm Hg, eliminating hemodynamically significant left ventricular outflow tract obstruction in 79.1% of patients. Mavacamten was temporarily discontinued in 3 patients due to left ventricular ejection fraction decrease <50%. There were no medication-related adverse events. Effectiveness and safety were similar between White and non-White patients, but symptomatic relief was attenuated in patients with body-mass index ≥35 kg/m2. CONCLUSIONS: Mavacamten was effective and safe when used under real-world conditions in a racially diverse population of symptomatic patients with obstructive hypertrophic cardiomyopathy. Patients with comorbid obesity were less likely to experience symptomatic improvement while on mavacamten.

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

How much protection does clopidogrel provide to cats with hypertrophic cardiomyopathy?

Cats with hypertrophic cardiomyopathy (HCM) have a risk of developing aortic thromboembolism (ATE). Clopidogrel reduces the risk of redeveloping ATE and delays recurrence of ATE in cats that have experienced an ATE episode. Consequently, cardiologists have recommended administering clopidogrel to cats as a primary preventative, suggesting that all cats with severe HCM be administered clopidogrel. However, clopidogrel is unpalatable in its manufactured format, making such administration problematic for many clients. Therefore, estimating the potential benefit of administration might help clinicians determine on a case-by-case basis the need to treat cats with clopidogrel. Relatively simple statistical analyses of currently available data, along with certain assumptions and extrapolations, allow such an estimation of benefit in terms of relative and absolute risk reduction conferred by clopidogrel. Using this approach, and provided certain assumptions are true, clopidogrel likely confers a reduction in risk of ATE in cats with moderate to severe HCM of approximately 3% to 4%. Given the difficulty of administering clopidogrel to cats, clinicians should weigh these relatively small potential benefits against the potential harms (difficulty of administration) and not necessarily insist that clients administer clopidogrel.

Forskolin is an effective therapeutic small molecule for the treatment of hypertrophic cardiomyopathy through ADCY6/cAMP/PKA pathway.

Hypertrophic cardiomyopathy (HCM) arises from a pathogenic variant in the gene responsible for encoding the myocardium-associated protein. Forskolin (FSK), a labdane diterpene isolated from Sphingomonas capillaris, exhibits diverse pharmacological effects, including bronchospasm relief, intraocular pressure reduction, and glaucoma treatment. However, whether FSK could regulate HCM and its associated mechanism remains unclear. Here, we discovered that FSK could mitigate cardiac hypertrophy in two HCM mouse models (Myh6R404Q and Tnnt2R109Q) in vivo. Additionally, FSK could prevent norepinephrine (NE)-induced cardiomyocyte hypertrophy in vitro. It reversed cardiac dysfunction, reduced enlarged cell size, and downregulated the expression of hypertrophy-related genes. We further demonstrated that FSK's mechanism in alleviating HCM relied on the activation of ADCY6. In conclusion, our findings demonstrate that FSK alleviates hypertrophic cardiomyopathy by modulating the ADCY6/cAMP/PKA pathway, suggesting that FSK holds promise as a therapeutic agent for HCM.