Hypertrophic Cardiomyopathy: Is a ‘Cure’ Coming . . . Or Is It Already Here?
2020; Elsevier BV; Volume: 133; Issue: 8 Linguagem: Inglês
10.1016/j.amjmed.2020.03.015
ISSN1555-7162
AutoresBarry J. Maron, Ethan J. Rowin, Martin S. Maron,
Tópico(s)Congenital Heart Disease Studies
ResumoOver its 60-year history, a consistent theme attached to hypertrophic cardiomyopathy (HCM) has been controversy concerning its prevalence, clinical course, and expectations for treatment benefit.1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar Once regarded as rare and ominous, HCM is now recognized as a common genetic disease with worldwide distribution, broad spectrum, and clinical outcome transformed over the last several years by the introduction of management strategies that favorably alter its natural history and provide a high level of care for the vast majority of patients.1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar Such major advances in HCM include contemporary diagnostic imaging leading to increased disease recognition (estimated prevalence 1:200-1:500).1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar For most of those patients with disease complications, available management strategies reliably result in reduced mortality related specifically to HCM and exclusive of significant comorbidities (ie, to 0.5% a year, less than other major disease risks of living and a 10-fold improvement over prior eras), affording a reasonable aspiration for normal life expectancy1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar (Figure 1). Large prospective follow-up studies have demonstrated what is now possible in HCM to improve or abolish limiting symptoms, with >90% of patients experiencing no or mild symptoms over long-term follow-up.1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar Treatment strategies have been developed to target patients within their specific major disease pathway:1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar 1) primary prevention of arrhythmic sudden death with prophylactically implanted defibrillators, relying on a matured risk stratification algorithm; 2) reversal of heart failure by relief of left ventricular outflow obstruction with low-risk, high-benefit surgical septal myectomy (or selectively, percutaneous alcohol ablation); 3) end-stage progression and heart transplant in a small number of patients who are nonobstructive with refractory heart failure; and 4) control of atrial fibrillation, including prevention of embolic stroke with anticoagulation prophylaxis. Notably, there is also a large expectation for permanency associated with these treatments for HCM (eg, rarely do patients experience disease progression and heart failure following implantable cardioverter-defibrillator (ICD) therapy or the recurrence of outflow obstruction after operation).1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar In addition, a substantial proportion of patients with HCM (including about 50% evaluated in tertiary centers) experience a clinically silent and benign clinical course long term without requiring significant therapeutic interventions.1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,3Maron BJ Rowin EJ Casey SA et al.Risk stratification and outcome of patients with hypertrophic cardiomyopathy ≥60 years of age.Circulation. 2013; 127: 585-593Crossref PubMed Scopus (153) Google Scholar Such innovations have been introduced to patients with HCM by clinical investigations over the last 2 decades.1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar As a result, older perceptions of HCM as grim, unrelenting and untreatable are now obsolete, replaced by a more optimistic view of this condition with greatly increased survival and reduced morbidity. Therefore, given this striking progress in which HCM has become a highly treatable disease compatible with normal longevity, we raise the relevant consideration as to whether at this time it is justifiable and reasonable to entertain the descriptive clinical term "cure" (or "curable") in reference to the vast majority of patients with this chronic disease process. A variety of definitions for medical cure (curo means "to care for") may be found, but most emphasize remedies that heal patients with persistent relief of clinical symptoms, restoration of sound and normal health, and without reduced life expectancy.4"Cure." Available at: https://www.merriam-webster.com/dictionary/cure. Accessed April 15, 2020.Google Scholar,5"Cure". In Oxford English Dictionary. Oxford: Oxford University Press.Google Scholar We favor such a definition as consistent with current HCM treatment paradigms that alter natural history, reverse the disease process, and restore long-term health, as clinically reasonable. Based on contemporary treatment strategies and the considerable available outcome data,1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar, 2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar, 3Maron BJ Rowin EJ Casey SA et al.Risk stratification and outcome of patients with hypertrophic cardiomyopathy ≥60 years of age.Circulation. 2013; 127: 585-593Crossref PubMed Scopus (153) Google Scholar,6Rowin EJ Hausvater A Link MS et al.Clinical profile and consequence of atrial fibrillation in hypertrophic cardiomyopathy.Circulation. 2017; 136: 2420-2436Crossref PubMed Scopus (127) Google Scholar,7Maron MS Rowin EJ Olivotto I et al.Contemporary natural history and management of nonobstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2016; 67: 1399-1409Crossref PubMed Scopus (110) Google Scholar we propose that 90%-95% of patients within the overall broad HCM spectrum can be returned to sound health and achieve a clinical course most consistent with our definition of cure, encompassing considerations for both mortality and morbidity. This argument includes the experience with patients from high-risk tertiary HCM referral centers, but also the many patients with HCM who may not require treatment interventions during their lifetime.1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,3Maron BJ Rowin EJ Casey SA et al.Risk stratification and outcome of patients with hypertrophic cardiomyopathy ≥60 years of age.Circulation. 2013; 127: 585-593Crossref PubMed Scopus (153) Google Scholar The remaining 5%-10% of patients reflect the current unmet needs in this disease (ie, the subgroup of patients with nonobstructive HCM and refractory heart failure, including transplant candidates), among whom most of the small number of HCM-related deaths occur. Also, presently difficult to consider within the potentially curable group are the few patients with HCM and refractory paroxysmal atrial fibrillation, non-responders to septal myectomy, and possibly those with early onset disease and extreme phenotypes.1Maron BJ Clinical course of management of hypertrophic cardiomyopathy.N Eng J Med. 2018; 379: 655-668Crossref PubMed Scopus (253) Google Scholar,2Maron BJ Rowin EJ Casey SA Maron MS How hypertrophic cardiomyopathy became a contemporary treatable genetic disease with low morality: Shaped by 50 years of clinical research and practice.JAMA Cardiol. 2016; 1: 98-105Crossref PubMed Scopus (133) Google Scholar,6Rowin EJ Hausvater A Link MS et al.Clinical profile and consequence of atrial fibrillation in hypertrophic cardiomyopathy.Circulation. 2017; 136: 2420-2436Crossref PubMed Scopus (127) Google Scholar,7Maron MS Rowin EJ Olivotto I et al.Contemporary natural history and management of nonobstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2016; 67: 1399-1409Crossref PubMed Scopus (110) Google Scholar The principle of "curability" may initially seem counterintuitive considering the past grim reputation of a chronic disease such as HCM, and with this label seemingly more appropriate for describing acute conditions such as infectious diseases treated with antimicrobial drugs or surgical interventions permanently removing offending lesions or organs. Molecular biologists, skeptical of progress toward a principle of clinical curability that does not include correction or abolition of the basic genetic defect, have long aspired to a treatment strategy capable of complete eradication of all molecular vestiges of the HCM disease process,8Ho CY Day SM Ashley EA et al.Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: Insights from the sarcomeric human cardiomyopathy registry (SHaRe).Circulation. 2018; 138: 1387-1398Crossref PubMed Scopus (242) Google Scholar,9Toepfer C Garfinkel A Venturini G et al.Strong myosin sequestration regulates sarcomere function, cardiomyocyte energetics, and metabolism, informing the pathogenesis of hypertrophic cardiomyopathy.Circulation. 2020; 141: 828-842Crossref PubMed Scopus (79) Google Scholar insisting that treatments for HCM can only be effective when targeting and obliterating the underlying basic mechanism responsible for the disease.10Marian AJ Experimental therapies in hypertrophic cardiomyopathy.J Cardiovasc Transl Res. 2009; 2: 483-492Crossref PubMed Scopus (38) Google Scholar That goal of basic science has not yet been realized despite seminal laboratory experiments based on the sarcomere gene hypothesis, now spanning >30 years.9Toepfer C Garfinkel A Venturini G et al.Strong myosin sequestration regulates sarcomere function, cardiomyocyte energetics, and metabolism, informing the pathogenesis of hypertrophic cardiomyopathy.Circulation. 2020; 141: 828-842Crossref PubMed Scopus (79) Google Scholar Although targeted genome editing (CRISPR/Cas 9) has recently been suggested as a permanent remedy,11Ma H Marti-Gutierrez N Park S-W et al.Correction of a pathogenic gene mutation in human embryos.Nature. 2017; 548: 413-419Crossref PubMed Scopus (563) Google Scholar the clinical implications and application of this methodology to HCM may be unrealistic for a number of reasons, including the important consideration that the genes targeted for deletion may not be responsible for all aspects of this disease process.12Maron BJ Maron MS Maron BA Loscalzo J Moving beyond the sarcomere to explain heterogeneity in hypertrophic cardiomyopathy: JACC Review Topic of the Week.J Am Coll Cardiol. 2019; 73: 1978-1986Crossref PubMed Scopus (61) Google Scholar Nevertheless, there are now compelling data assembled in large patient cohorts demonstrating that clinical care with contemporary diagnosis and treatment strategies have achieved a high level of efficacy within the overall HCM disease population. These management paradigms are now widely available, personalized for individual patients with respect to specific clinical mechanisms and pathways (ie, sudden death risk, heart failure, and atrial fibrillation), thereby providing the opportunity to aggressively alter clinical course, prevent premature death, and provide normal or extended longevity associated with good quality of life. Therefore, in 2020, we believe that it is appropriate to regard HCM not only as a highly treatable condition but also as potentially curable in the vast majority of patients. This is a novel but substantiated viewpoint and the potential source of reassurance for patients with this complex cardiac disease not long ago regarded as particularly grim and unrelenting without effective treatment options. Erratum to "Hypertrophic Cardiomyopathy: Is a 'Cure' Coming … Or Is It Already Here?": American Journal of Medicine, 133 (2020):8:886-888.The American Journal of MedicineVol. 134Issue 3PreviewThe publisher regrets that the figure in the published version of this paper contained incorrect information. The two green boxes in the second row contained incorrect labels: in the darker green box above the words "Surgical Myectomy", the wording should have read "Symptomatic Heart Failure: Obstructive". The pale green box with arrow leading to "Drugs" should have read "Symptomatic Heart Failure: Nonobstructive". This is a very important clinical designation. Full-Text PDF
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