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27ЛЕЧЕНИЕ ГИПЕРТРОФИЧЕСКОЙ КАРДИОМИОПАТИИ:
НОВЫЕ МЕТОДЫ
Касимова Нихола Кадировна
Андижанский государственный медицинский институт
Гипертрофическая кардиомиопатия (ГКМП) — заболевание, характеризующееся аномальным утолщением сердечной мышцы (гипертрофией). Утолщенная сердечная мышца может ухудшить работу сердца. Гипертрофическая кардиомиопатия часто не диагностируется, потому что многие люди с этим заболеванием имеют меньше симптомов и могут жить нормальной жизнью без значительных проблем. Однако у небольшого числа людей с ГКМП утолщение сердечной мышцы может привести к одышке, болям в груди или проблемам с биотоксической системой сердца, что может привести к опасным для жизни нарушениям сердечного ритма (аритмиям) или внезапной смерти. В настоящее время учеными проводится ряд исследований и разрабатываются новые методы лечения этого заболевания. Мы обсудим это в этой статье.
Ключевые слова: гипертрофическая кардиомиопатия, биотоковая система сердца, аритмии.
GIPERTROFIK KARDIOMIOPATIYANI DAVOLASH: YANGI METODLAR
Gipertrofik kardiomiyopatiya (HCM) yurak mushagining g'ayritabiiy qalinlashishi (gipertrofiya) bilan kechadigan kasallikdir. Qalinlashgan yurak mushagi yurakning funksiyalarini qiyinlashtirishi mumkin. Gipertrofik kardiomiyopatiyada ko'pincha tashxis qo'yilmaydi, chunki kasallikka chalingan ko'plab odamlarda kam simptomlar kuzatiladi va sezilarli muammolarsiz normal hayot kechirishi mumkin. Lekin HCM bilan og'rigan kam sonli odamlarda qalinlashgan yurak mushaklari nafas qisilishi, ko'krak qafasidagi og'riqlar yoki yurakning biotok tizimidagi muammolarga olib kelishi mumkin, bu esa hayot uchun xavfli anormal yurak ritmlariga (aritmiya) yoki to'satdan o'limga olib kelishi mumkin. Hozirgi kunda olimlar tomonidan bir qancha izlanishlar olib borilmoqda va ushbu kasallikni davolashning yangi metodlari ishlab chiqilmoqda. Ushbu maqolada buni muhokama qilamiz.
Kalit so'zlar: Gipertrofik kardiomiyopatiya, yurakning biotok tizimi, aritmiyalar.
TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY: NEW METHODS
Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle becomes abnormally thick (hypertrophied). The thickened heart muscle can make it harder for the heart to pump blood. Hypertrophic cardiomyopathy often goes undiagnosed because many people with the disease have few, if any, symptoms and can lead normal lives with no significant problems. However, in a small number of people with HCM, the thickened heart muscle can cause shortness of breath, chest pain or problems in the heart's electrical system, resulting in life-threatening abnormal heart rhythms (arrhythmias) or sudden death. Currently, a number of studies are being conducted by scientists and new methods of treating this disease are being developed. We will discuss this in this article.
Keywords: Hypertrophic cardiomyopathy, the heart's electrical system, arrhythmias.
Introduction: Hypertrophic cardiomyopathy is most often caused by abnormal genes in the heart muscle. These genes cause the walls of the heart chamber (left ventricle) to contract harder and become thicker than normal. The thickened walls become stiff. This reduces the amount of blood taken in and pumped out to the body with each heartbeat. Hypertrophic cardiomyopathy (HCM) is a common myocardial disease characterized by otherwise unexplained left ventricular hypertrophy. The main cause of disabling symptoms in patients with HCM is left ventricular outflow tract (LVOT) obstruction. This phenomenon is multifactorial, determined both by anatomical and functional abnormalities: myocardial hypercontractility is believed to represent one of its major determinants. The anatomical anomalies are targeted by surgical interventions, whereas attenuating hypercontractility is the objective of old and new drugs including the novel class of allosteric myosin inhibitors. This review summarizes the current treatment modalities and discusses the emerging therapeutical opportunities focusing on the recently developed cardiac myosin ATPase inhibitors Mavacamten and CK-274. Novel surgical and interventional approaches are also discussed.
In obstructive HCM, the wall (septum) between the two bottom chambers of the heart thickens. The walls of the pumping chamber can also become stiff. It may block or reduce the blood flow from the left ventricle to the aorta. Most people with HCM have this type. In nonobstructive HCM, the heart's main pumping chamber still becomes stiff. This limits how much blood the ventricle can take in and pump out, but blood flow is not blocked. A wealth of novel information regarding the molecular mechanisms associated with the clinical phenotype and natural history of HCM have been developed over the last two decades. Such advances have only recently led to a number of controlled randomized studies, often limited in size and fortune. Recently, however, the allosteric inhibitors of cardiac myosin adenosine triphosphatase, countering the main pathophysiological abnormality associated with HCM-causing mutations, i.e. hypercontractility, have opened new management perspectives. Mavacamten is the first drug specifically developed for HCM used in a successful phase 3 trial, with the promise to reach symptomatic obstructive patients in the near future. In addition, the fine characterization of cardiomyocyte electrophysiological remodelling has recently highlighted relevant therapeutic targets [1].
Some group scientists [2] say that hypertrophic cardiomyopathy is a complex cardiac disease with unique pathophysiologic characteristics and a great diversity of morphologic, functional, and clinical features. The heterogeneity of the disease is accentuated by the fact that it afflicts patients of all ages. During the past few years, technological developments in implantable defibrillators and pacemakers have provided new therapeutic options for patients with the disease. In addition, rapid advances in our knowledge of the molecular defects responsible for hypertrophic cardiomyopathy have deepened our understanding of the disorder and have suggested new approaches to the assessment of prognosis. These recent developments, however, have also generated considerable uncertainty and raised new questions about the optimal management of hypertrophic cardiomyopathy.
As for as some group scientists [13] go said that the stepped management proposed by the recent AHA/ACC guidelines defines the best of possible worlds in HCM, balancing risks and benefit in a long-term perspective [9]. In the light of new therapeutic approaches, a hypothetical prediction of how the algorithm may change, following the clinical introduction of Mavacamten (pending FDA approval) and CK-274 (still under investigation) is depicted in Figure 1. In patients with obstructive HCM, first line management with beta blockers or calcium channel blockers and, in case of unsatisfactory effect, disopyramide, is not expected to change. If the combination therapy results inadequate, a switch from disopyramide to a
myosin inhibitor might be considered. SRTs remain indicated in the presence of drug-refractory symptoms—hopefully less frequent with the introduction of the new agents. Surgical myectomy should be preferred over alcohol septal ablation (ASA) when local expertise is available. Atrioventricular (AV) sequential pacing may be considered in selected (generally older) patients, while the MitraClip and other percutaneous approaches have been attempted but should be considered investigational.
Figure 1. Possible treatment algorithm for obstructive Hypertrophic Cardiomyopathy therapy. HCM: Hypertrophic Cardiomyopathy. Mavacamten has been submitted for Food and Drugs administration approval. See the text for the flow chart description.
So they made a conclusion [13] that LVOT obstruction is the most prevalent cause of heart failure in patients with HCM, and its relief is a fundamental therapeutic aim requiring a concerted effort by physicians and surgeons, fulfilling the "HCM Heart Team" concept [14]. Ground-breaking advances in our understanding of HCM have led to the development of a revolutionary pharmacological approach involving allosteric myosin inhibitors. The pivotal results of EXPLORER-HCM justify cautious optimism for the future of HCM patients, despite the need for further evidence regarding long-term efficacy and safety of these agents. Whatever the outcome, a new and much awaited era has begun for our patients, likely to see the irresistible emergence of precision medicine in cardiomyopathies.
According to conclusion which is based on few scientists's some information [1], The last 60 years has brought unimaginable advances in our understanding of HCM. Only recently, however, drug development has started to exploit available knowledge and to provide innovative molecules addressing specific mechanisms of disease. In all likelihood, the present decade will witness a paradigm shift in targeted management of HCM patients, with implication potential reaching other fields of cardiovascular medicine overlapping this complex disease. Current treatment options for HCM do not address the genetic cause of the disease. HCM genes are induced by dominant mutations that manifest as late-onset adult disorders. Because of their delayed manifestation, these mutations escape natural selection and are often transmitted to the next generation. Thus, the development of novel strategies to prevent germline transmission of founder mutations is desirable. One approach for preventing second-generation transmission is preimplantation genetic diagnosis followed by selection of non-mutant embryos for transfer in the context of an in vitro fertilization. [3] Recent developments in precise genome-editing techniques and their successful applications in animal models have provided different option for correcting human germline mutations. A proof-of-concept study aimed to perform prezygotic correction of MYBPC3 mutation by using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/ clustered regularly interspaced short palindromic repeat- associated 9) technology. CRISPR-Cas9 is a versatile tool for recognizing specific genomic sequences and inducing double-strand breaks of deoxyribonucleic acid (DNA) at a desired genetic locus in the paternal allele, followed by intrinsic cellular repair using the homologous wild-type maternal gene to correct the MYBPC3 variant. [3] Allele-specific gene silencing is another gene-based therapeutic technology that holds promise for monogenic diseases. This typically involves gene silencing by short-interfering ribonucleic acid segments (RNAi) designed to suppress expression of a specific pathogenic allele. These RNAi are delivered by an adenovirus vector. [4] This approach is best suited to conditions caused by gain-of-function mutations, rather than loss-of-function mutations. At present, gene therapy appears most promising in HCM mimics associated with enzyme deficiency, such as Fabry and Pompe disease. With the exception of selected gene defects currently under investigation, it appears unlikely that sarcomeric HCM may be amenable to gene therapy on a significant scale in the near future.
Irrespective of the underlying genotype and phenotype, cardiomyopathy patients are at increased arrhythmic risk. [5] While ion channel proteins are not mutated, nor primarily involved in their pathogenesis, the structural and functional modifications peculiar of HCM activate cellular remodelling pathways which lead to changes in membrane channel expression and gating through post-translation modifications. [6,7] Thus, HCM behaving as "acquired" channelopathies [8] represent the perfect paradigm to investigate novel antiarrhythmic targets. As mentioned, cardiovascular therapy has dramatically evolved in the last 50-60 years, thanks to ground-breaking advances in antihypertensive and heart failure agents, lipid-lowering drugs and anticoagulants. A major exception is represented by antiarrhythmic drugs: those in current use were developed decades ago, may be proarrhythmic and may cause long-term toxicity. These compounds act on sarcolemmal ion channels, effectively modulating their gating properties, but are limited by non-selectivity and narrow therapeutic ranges, especially in the context of structural heart diseases. Most are used empirically, with little comprehension of the true molecular effects in each pathological contest.
Another group of scientists is of the opinion that, these drugs can be effective in aborting arrhythmic episodes but largely incapable of radically preventing them. Specifically,
they can reduce the occurrence and duration of re-entrant conduction pathways (by acting on conduction speed) but are not as effective in reducing the cellular triggers, i.e. the sparks that set the "fire" of arrhythmias. Based on this premises, there is huge expectation for novel approaches to prevent arrhythmic propensity, by acting upstream of membrane ion channels. [9-11] A number of antiarrhythmic strategies that act upstream of sarcolemmal channels, ranging from compounds acting on sarcomere cross-bridge cycling (i.e. mavacamten) to approaches that counteract abnormal function of the sarcoplasmic reticulum, can be postulated. In particular, mavacamten and, in general, myofilament Ca2+ desensitizers have a potential role in preventing arrhythmias and, by targeting myofilament molecules involved in muscle contraction rather than membrane-bound channels or Ca2+-handling molecules, ideally avoid altering sarcolemmal function or cell signalling pathways. The antiarrhythmic potential of mavacamten though theoretically significant still lacks of dedicated preclinical mechanistic investigations. Repositioning of drugs that stabilize the sarcoplasmic reticulum by reducing the open probability of its main Ca2+ release channel (the ryanodine receptor, RyR2) is an alternative option supported by the notion that sarcoplasmic reticulum calcium leakage and post depolarizations occur more frequently in HCM myocardium compared to control tissue. [12]. Nadolol and propranolol are known to exert a more potent control of ventricular arrhythmias compared to other P-blockers, in patients with long Q-T syndrome as well as electrical storms, independent of the underlying cause. One of the main reasons is likely due to the pleiotropic effects of these two agents, compared to more selective ones. Specifically, nadolol acts as a blocker of RYR2 and reduces the occurrence of spontaneous Ca2+ leak, paving the rational for the development of novel molecules that target sarcoplasmic reticulum function.
According to scientists who are Tanya Solomon, Aleksandra Filipovska, Livia Hool, Helena Viola [15], conventionally, HCM is characterized by cardiac myocyte remodelling, disorganization of sarcomeric proteins, interstitial fibrosis and altered energy metabolism. There is now evidence to suggest that alterations in Ca2+ handling, energy metabolism, contractility and sarcomeric disorganization may precede the presentation of hypertrophy and fibrosis. Indeed, here we find that a preventative rather than corrective therapeutic approach may be more efficacious in the treatment of HCM. However, while some similarities exist, each mutation appears to lead to mutation-specific pathophysiology, which may contribute to the observed clinical phenotypic variability in sarcomere-related HCM. A clear understanding of early mutation-specific mechanisms may be required, on a cellular level, in order to determine the most effective therapeutic mode of action. Studies investigating the efficacy of diltiazem or AID-TAT peptide indicate that early treatment may be beneficial in preventing hypertrophy by normalizing cellular Ca2+ handling, and/or normalizing mitochondrial metabolic activity. On the other hand, early therapeutic intervention with MYK-461 may be effective in normalizing hypercontractility and relieve inducible HOCM, by reducing sarcomere force output. In addition to mutation-specific pathophysiology, epigenetic differences, genetic modifiers and environmental factors can also influence HCM morphology, producing a variety of clinical phenotypes from the same gene mutation. Therefore, an understanding of the physiological mechanisms underlying patient-specific pathology will also be an important consideration in the design of personalized treatment approaches, or 'precision medicine', for HCM patients.
Strategies for treatment should therefore rely on data from relatively unselected populations, as well as from studies at tertiary care referral centers, and on the clinical experience of physicians who have focused their investigative efforts on this disease and
acquired particular expertise in its management. Molecular studies of the genetic alterations responsible for hypertrophic cardiomyopathy also provide insight into the heterogeneity of its clinical features. The disease can be caused by a mutation in one of four genes that encode proteins of the cardiac sarcomere: the b-myosin heavy-chain, cardiac troponin T, a-tropomyosin, and myosin-binding protein C genes [16-19] In addition, mutations in the two genes encoding the myosin light chains have been reported in what appears to be a rare form of hypertrophic cardiomyopathy,38 and other genes that cause the disease are likely to be found. [20] This etiologic complexity is further compounded by intragenic heterogeneity; more than 50 disease-causing mutations have been identified in these genes of the sarcomere. Hence, the precise molecular defect responsible for hypertrophic cardiomyopathy often differs in unrelated patients. The diverse clinical and genetic features of hypertrophic cardiomyopathy make it impossible to define precise guidelines for management. As in many diseases, it is often necessary to individualize therapy. In hypertrophic cardiomyopathy, the treatment of symptoms to improve quality of life and the identification of patients who are at high risk for sudden death and require aggressive therapy are two distinct issues that must be addressed by largely independent strategies.
Pharmacologic therapy to improve diastolic filling and possibly reduce myocardial ischemia is the primary means of relieving symptoms in hypertrophic cardiomyopathy; it is also the sole therapeutic option for patients without obstruction of the left ventricular outflow, who constitute the great majority of patients with this disease. Invasive interventions to abolish the outflow gradient should be considered only for the minority of patients (about 5 percent) who have both marked outflow obstruction and severe symptoms unresponsive to medical therapy.
Patients with symptomatic oHCM are generally offered first-line pharmacotherapy with ^-blockers or the non-dihydropyridine calcium-channel blockers. [21-23] Disopyramide is effective as an add-on therapy, although it can be poorly tolerated. These medications have been the mainstay of treatment for decades and share in common their negative inotropic effect resulting in reduction of SAM/septal contact and LVOT obstruction. Despite their utility, current guideline-directed pharmacotherapies were never designed for the treatment of HCM and have limited evidence. In fact, there have been no randomized trials that demonstrate the efficacy of any agent over placebo in HCM, [24] and currently propranolol is the only Food and Drug Administration-approved drug based on a small study from 1966. [25] Moreover, non-obstructive HCM (noHCM), representing ~30% of HCM, remains poorly addressed with no known disease-modifying therapies. Recent evidence has also demonstrated important gender differences in HCM, with women being older and more symptomatic at presentation, and perhaps having lower survival when compared to men.
Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited myocardial disorder, transformed over the last several years into a treatable condition with the emergence of effective management options that alter natural history at all ages. Now available are a matured risk stratification algorithm selecting patients for prophylactic implantable defibrillators that prevent arrhythmic sudden death; low-risk, high-benefit surgical myectomy to reverse progressive heart failure symptoms due to left ventricular outflow obstruction; anticoagulation prophylaxis to prevent atrial fibrillation-mediated embolic stroke; and heart transplant for refractory end-stage disease in the absence of obstruction. Those strategies have resulted in reduction of HCM-related morbidity and reduction of mortality to 0.5% per year.
After more than half a century, advances in therapeutics and understanding of the disease spectrum and its relevant mechanisms, pursued relentlessly by clinical investigators and practitioners using evidence-based and guideline-directed strategies, have transformed HCM. Once considered a hopelessly heterogeneous and uniformly progressive condition with poor prognosis and limited management options, HCM is recognized in 2021 as a relatively common and highly treatable cardiac disease compatible with normal or extended longevity. Thanks to the capability to selectively predict future adverse events and change the clinical course of the disease with therapy, HCM has evolved from a disease of limited palliative pharmacotherapy and occasional high-risk surgery, to a disease now dominated by more definitive device and interventional treatment innovations employed along specific disease pathways. This progress has brought about a striking reduction in morbidity and HCM-related mortality of 0.5% per year. Consequently, HCM has become arguably the least frequent of the major disease-related risks of living
Conclusion: Well actually, in this article we have reviewed the current status of cardiomyopathy. We also discussed the treatment options for this disease. We have analyzed the opinions and conclusions of several scientists on this topic. We believe that this article can be an impetus for further in-depth research.
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