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1.
Targeted Medical Therapies for Hypertrophic Cardiomyopathy.
Fumagalli, C, De Gregorio, MG, Zampieri, M, Fedele, E, Tomberli, A, Chiriatti, C, Marchi, A, Olivotto, I
Current cardiology reports. 2020;(2):10
Abstract
PURPOSE OF REVIEW The management of hypertrophic cardiomyopathy (HCM) has changed considerably over the years, although molecular therapies targeting core mechanisms of the disease are still lacking. This review provides an overview of the contemporary medical approach to patients with HCM, and of promising novel developments hopefully soon to enter the clinical arena. RECENT FINDINGS Our perception of therapeutic targets for medical therapy in HCM is rapidly evolving. Novel approaches include myocardial metabolic modulation, late sodium current inhibition, and allosteric myosin inhibition, actively pursued to reduce and hopefully prevent the development of severe HCM phenotypes, improve symptom control, and preserve patients from disease-related complications. Clinical management of patients with HCM should be guided by in-depth knowledge of the complex mechanisms at the energetic, metabolic, and electrophysiologic level. Until new experimental therapies become available, tailored management of modifiable disease manifestations should be pursued, including lifestyle counseling and prevention of comorbidities.
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2.
Efficacy and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonist (VKA) among patients with atrial fibrillation and hypertrophic cardiomyopathy: a systematic review and meta-analysis.
Rujirachun, P, Charoenngam, N, Wattanachayakul, P, Winijkul, A, Owattanapanich, W, Ungprasert, P
Acta cardiologica. 2020;(8):724-731
Abstract
Background/objectives: Long-term oral anticoagulant therapy is recommended for patients with hypertrophic cardiomyopathy (HCM) who develop atrial fibrillation (AF) to prevent cardioembolic complications. In patients with non-valvular AF, direct oral anticoagulants (DOACs) has been proved to be non-inferior to adjusted-dose vitamin K antagonist (VKA). However, the role of DOACs in patients with AF in the setting of HCM has not been fully established.Methods: A comprehensive literature review was conducted by searching for published articles indexed in MEDLINE and EMBASE databases from inception through 1 May 2019. Eligible studies must start with recruitment of patients with AF in the setting of HCM who received either DOACs or VKA. The studies must follow them for the occurrence of ischaemic stroke. Hazard ratio (HR) and confidence interval (CI) of developing ischaemic stroke between the two groups must be reported. Pooled HR was calculated using a random-effect, generic inverse variance method of DerSimonian and Laird.Results: A total of three retrospective cohort studies with 4,418 participants met the eligibility criteria and were included into the meta-analysis. A significantly lower risk of all-cause death was observed in the DOACs group than in the VKA group with the pooled HR of 0.43 (95% CI, 0.33-0.58, I2 = 0%). However, the risk of ischaemic stroke among patients with AF and HCM who received DOACs was not significantly different from those who received VKA with the pooled HR of 0.95 (95% CI, 0.73-1.22, I2 = 0%). Both major bleeding and intracranial bleeding were also not significantly different between those who received DOACs versus those who received VKA with the pooled HR of 0.94 (95% CI, 0.70-1.26, I2 = 0%) and 0.61 (95% CI, 0.27-1.37, I2 = 0%), respectively.Conclusions: The current study found that the risk of all-cause death was significantly reduced but the risk of ischaemic stroke, major bleeding and intracranial bleeding were not significantly different between patients with AF and HCM who had received DOACs and those who received VKA.
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3.
Novel Pharmacotherapy for Hypertrophic Cardiomyopathy.
Wong, TC, Martinez, M
Cardiology clinics. 2019;(1):113-117
Abstract
Medical therapy for hypertrophic cardiomyopathy (HCM) has focused on minimizing the impact of symptoms due to left ventricular outflow tract obstruction and diastolic dysfunction. This article briefly discusses currently available therapy and focuses on both clinically available medications with novel applications for HCM as well as novel medications under development with specific indication for HCM. Finally, a brief summary of the current gaps and potential targets for pharmacotherapy is discussed.
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4.
Lifestyle Modification and Medical Management of Hypertrophic Cardiomyopathy.
Heitner, SB, Fischer, KL
Cardiology clinics. 2019;(1):45-54
Abstract
Hypertrophic cardiomyopathy is a heterogenous condition associated with a myriad of symptoms. Just as in other disease states, the aim of medical therapy is the alleviation of suffering, improvement of longevity, and the prevention of complications. This article focuses on the associated comorbidities seen in patients with hypertrophic cardiomyopathy, potential lifestyle interventions, and conventional medical treatments for symptomatic hypertrophic cardiomyopathy.
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5.
Novel Pharmacotherapy in Hypertrophic Cardiomyopathy.
Andries, G, Yandrapalli, S, Naidu, SS, Panza, JA
Cardiology in review. 2018;(5):239-244
Abstract
Hypertrophic cardiomyopathy (HCM) is an inherited disease characterized by unexplained left ventricular hypertrophy. Although it is estimated to affect 1 out of 500 people, the HCM gene carrier prevalence is much more common, probably as high as 1 in 200 people. Most affected individuals have a normal life expectancy, whereas some patients may develop sudden cardiac death or end-stage heart failure. Despite significant developments in the treatment of HCM with surgical, interventional, and device-based procedures, the main focus of current pharmacological therapy has not evolved from the basic objectives of relief of symptoms and improvement in functional capacity. To date, no medical treatment has been shown to prolong survival or reduce the risk of sudden cardiac death. In recent decades, research focus in HCM has shifted to identify the treatments which are able to alter the natural pathophysiological process of this disease. This article reviews the currently recommended and frequently used medications (beta-blockers, nondihydropyridine calcium channel blockers, and disopyramide) and emerging pharmacological treatment options in the management of HCM. The mechanism of action and latest clinical trials of the novel agents are discussed in greater detail.
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6.
Impact of Demographic Features, Lifestyle, and Comorbidities on the Clinical Expression of Hypertrophic Cardiomyopathy.
Finocchiaro, G, Magavern, E, Sinagra, G, Ashley, E, Papadakis, M, Tome-Esteban, M, Sharma, S, Olivotto, I
Journal of the American Heart Association. 2017;(12)
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7.
Emerging pharmacologic and structural therapies for hypertrophic cardiomyopathy.
Philipson, DJ, DePasquale, EC, Yang, EH, Baas, AS
Heart failure reviews. 2017;(6):879-888
Abstract
Hypertrophic cardiomyopathy is the most common inherited heart disease. Although it was first described over 50 years ago, there has been little in the way of novel disease-specific therapeutic development for these patients. Current treatment practice largely aims at symptomatic control using old drugs made for other diseases and does little to modify the disease course. Septal reduction by surgical myectomy or percutaneous alcohol septal ablation are well-established treatments for pharmacologic-refractory left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients. In recent years, there has been a relative surge in the development of innovative therapeutics, which aim to target the complex molecular pathophysiology and resulting hemodynamics that underlie hypertrophic cardiomyopathy. Herein, we review the new and emerging therapeutics for hypertrophic cardiomyopathy, which include pharmacologic attenuation of sarcomeric calcium sensitivity, allosteric inhibition of cardiac myosin, myocardial metabolic modulation, and renin-angiotensin-aldosterone system inhibition, as well as structural intervention by percutaneous mitral valve plication and endocardial radiofrequency ablation of septal hypertrophy. In conclusion, while further development of these therapeutic strategies is ongoing, they each mark a significant and promising advancement in treatment for hypertrophic cardiomyopathy patients.
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8.
Implantable Cardioverter-defibrillator Therapy for Hypertrophic Cardiomyopathy: Usefulness in Primary and Secondary Prevention.
Sarrias, A, Galve, E, Sabaté, X, Moya, À, Anguera, I, Núñez, E, Villuendas, R, Alcalde, Ó, García-Dorado, D
Revista espanola de cardiologia (English ed.). 2015;(6):492-6
Abstract
INTRODUCTION AND OBJECTIVES Hypertrophic cardiomyopathy is a frequent cause of sudden death. Clinical practice guidelines indicate defibrillator implantation for primary prevention in patients with 1 or more risk factors and for secondary prevention in patients with a history of aborted sudden death or sustained ventricular arrhythmias. The aim of the present study was to analyze the follow-up of patients who received an implantable defibrillator following the current guidelines in nonreferral centers for this disease. METHODS This retrospective observational study included all patients who underwent defibrillator implantation between January 1996 and December 2012 in 3 centers in the province of Barcelona. RESULTS The study included 69 patients (mean age [standard deviation], 44.8 [17] years; 79.3% men), 48 in primary prevention and 21 in secondary prevention. The mean number of risk factors per patient was 1.8 in the primary prevention group and 0.5 in the secondary prevention group (P=.029). The median follow-up duration was 40.5 months. The appropriate therapy rate was 32.7/100 patient-years in secondary prevention and 1.7/100 patient-years in primary prevention (P<.001). Overall mortality was 10.1%. Implant-related complications were experienced by 8.7% of patients, and 13% had inappropriate defibrillator discharges. CONCLUSIONS In patients with a defibrillator for primary prevention, the appropriate therapy rate is extremely low, indicating the low predictive power of the current risk stratification criteria.
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9.
Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA).
Guttmann, OP, Pavlou, M, O'Mahony, C, Monserrat, L, Anastasakis, A, Rapezzi, C, Biagini, E, Gimeno, JR, Limongelli, G, Garcia-Pavia, P, et al
European journal of heart failure. 2015;(8):837-45
Abstract
AIMS: Atrial fibrillation (AF) and thrombo-embolism (TE) are associated with reduced survival in hypertrophic cardiomyopathy (HCM), but the absolute risk of TE in patients with and without AF is unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Exploratory analyses were performed to determine predictors of TE, the performance of the CHA2 DS2 -VASc score, and outcome with vitamin K antagonists (VKAs). METHODS AND RESULTS A retrospective, longitudinal cohort of seven institutions was used to develop multivariable Cox regression models fitted with pre-selected predictors. Bootstrapping was used for validation. Of 4821 HCM patients recruited between 1986 and 2008, 172 (3.6%) reached the primary endpoint of cerebrovascular accident (CVA), transient ischaemic attack (TIA), or systemic peripheral embolus within 10 years. A total of 27.5% of patients had a CHA2 DS2 -VASc score of 0, of whom 9.8% developed TE during follow-up. Cox regression revealed an association between TE and age, AF, the interaction between age and AF, TE prior to first evaluation, NYHA class, left atrial (LA) diameter, vascular disease, and maximal LV wall thickness. There was a curvilinear relationship between LA size and TE risk. The model predicted TE with a C-index of 0.75 [95% confidence interval (CI) 0.70-0.80] and the D-statistic was 1.30 (95% CI 1.05-1.56). VKA treatment was associated with a 54.8% (95% CI 31-97%, P = 0.037) relative risk reduction in HCM patients with AF. CONCLUSIONS The study shows that the risk of TE in HCM patients can be identified using a small number of simple clinical features. LA size, in particular, should be monitored closely, and the assessment and treatment of conventional vascular risk factors should be routine practice in older patients. Exploratory analyses show for the first time evidence for a reduction of TE with VKA treatment. The CHA2 DS2 -VASc score does not appear to correlate well with the clinical outcome in patients with HCM and should not be used to assess TE risk in this population.
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10.
The myosin-activated thin filament regulatory state, M⁻-open: a link to hypertrophic cardiomyopathy (HCM).
Lehrer, SS, Geeves, MA
Journal of muscle research and cell motility. 2014;(2):153-60
Abstract
This review proposes a link between the hypertrophic (HCM) and restrictive cardiomyopathies caused by mutations in several sarcomeric thin filament proteins, and the open state of the three-state muscle regulation theory. The three characteristics of various muscle systems reconstituted from HCM mutated proteins (increased Ca(2+)-sensitivity, increased basal activity in the absence of Ca(2+), and decreased cooperativity) can be explained by the contribution of a myosin-induced open state (M (-) ), which elevates the basal activity and competes with the normal Ca(2+)-activated pathway. A model based on the three-state theory of regulation, shows how a change in the closed/blocked equilibrium caused by a mutation that weakens the binding of troponin I to tropomyosin-actin can produce the characteristics of HCM. This review also shows that in the M (-) state, Ca(2+) can shift the closed-open equilibrium of the N-terminal hydrophobic region of troponin C without affecting activity.