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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.
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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3.
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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4.
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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5.
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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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.
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.
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8.
Mutation of mitochondrial DNA G13513A presenting with Leigh syndrome, Wolff-Parkinson-White syndrome and cardiomyopathy.
Wang, SB, Weng, WC, Lee, NC, Hwu, WL, Fan, PC, Lee, WT
Pediatrics and neonatology. 2008;(4):145-9
Abstract
Mutation of mitochondrial DNA (mtDNA) G13513A, encoding the ND5 subunit of respiratory chain complex I, can cause mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) and Leigh syndrome. Wolff-Parkinson-White (WPW) syndrome and optic atrophy were reported in a high proportion of patients with this mutation. We report an 18-month-old girl, with an 11-month history of psychomotor regression who was diagnosed with WPW syndrome and hypertrophic cardiomyopathy, in association with Leigh syndrome. Supplementation with coenzyme Q10, thiamine and carnitine prevented further regression in gross motor function but the patient's heart function deteriorated and dilated cardiomyopathy developed 11 months later. She was found to have a mutation of mtDNA G13513A. We suggest that mtDNA G13513A mutation is an important factor in patients with Leigh syndrome associated with WPW syndrome and/or optic atrophy, and serial heart function monitoring by echocardiography is recommended in this group of patients.
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9.
Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a review of the literature.
Veselka, J
Medical science monitor : international medical journal of experimental and clinical research. 2007;(4):RA62-8
Abstract
Hypertrophic obstructive cardiomyopathy (HOCM) is a common inheritable cardiac disorder that can lead to symptoms of dyspnea, angina pectoris, and syncope. Symptomatic patients are usually treated with negatively inotropic agents, such as beta-blockers, calcium channel blockers, or disopyramide. However, up to 10% of patients with outflow pressure gradient are unresponsive to medical therapy. Until the early 1990s, surgical myectomy represented the standard treatment for patients with HOCM and drug-refractory symptoms. More than one decade ago, alcohol septal ablation (ASA) was introduced as a less invasive alternative therapy for symptomatic HCM patients with obstruction. ASA is performed through a percutaneous approach, in which 1-3 ml of absolute alcohol is introduced into the septal branch to create a controlled septal infarction of the basal interventricular septum. This procedure results in relief of symptoms, a decrease in the pressure gradient, and improvement in left ventricular diastolic function. A randomized controlled trial is needed to compare ASA and surgical myectomy in order to determine which technique provides maximal benefit.
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10.
[Diabetic cardiomyopathy].
Podleśny, M
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2003;(89):476-9
Abstract
In the last decades, due to the growing number of new cases of diabetes and its cardiovascular complications, much attention has been paid to diabetic cardiomyopathy. The studies on the etiology of this condition have confirmed the role of advanced glycation end products, lipoprotein a Lp(a), apolipoprotein B (apo B) and the changes in the intracellular calcium levels. An insight in the natural history of left ventricular diastolic and systolic dysfunction in diabetes has been made possible thanks to the widespread availability of echocardiography. Diastolic dysfunction, characteristic of diabetes, precedes the onset of systolic dysfunction, which reveals at a later stage, first as exercise-induced abnormalities. The influence of diabetes on morphology of the heart manifests as hypertrophy of the left ventricle, especially in non-insulin-dependent diabetes and enlargement of the left atrial chamber. The results of the studies are not decisive as to the possible correlation between the severity of the diastolic dysfunction and the duration of diabetes or the quality of metabolic control. The presence of significant coexisting conditions, including hypertension and the complications of diabetes such as autonomic neuropathy is associated with more pronounced symptoms of diastolic dysfunction and higher values of corrected QT interval and dispersion which are considered to be the most important predictors of mortality in diabetic patients.