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Hypertrophic Cardiomyopathy: A Brief Overview

2024; Elsevier BV; Volume: 212; Linguagem: Inglês

10.1016/j.amjcard.2023.10.075

1879-1913

Eugene Braunwald,

Congenital Heart Disease Studies

Hypertrophic cardiomyopathy (HCM) is a complex, heterogeneous disorder that affects approximately 1 in every 500 persons worldwide and about 750,000 Americans. It is characterized by left ventricular hypertrophy that is usually asymmetric, with enlarged myocytes in disarray, unexplained by loading conditions. Obstruction to left ventricular outflow occurs in approximately 60% of patients. The natural history and cardiac morphology of HCM are quite heterogeneous. Although most patients with HCM are asymptomatic or mildly symptomatic, a minority are disabled by dyspnea, angina, or syncope, develop advanced heart failure, or die suddenly. Hypertrophic cardiomyopathy (HCM) is a complex, heterogeneous disorder that affects approximately 1 in every 500 persons worldwide and about 750,000 Americans. It is characterized by left ventricular hypertrophy that is usually asymmetric, with enlarged myocytes in disarray, unexplained by loading conditions. Obstruction to left ventricular outflow occurs in approximately 60% of patients. The natural history and cardiac morphology of HCM are quite heterogeneous. Although most patients with HCM are asymptomatic or mildly symptomatic, a minority are disabled by dyspnea, angina, or syncope, develop advanced heart failure, or die suddenly. During the 19th century, 3 patients with what now appears to have been hypertrophic cardiomyopathy (HCM) were described in Paris, and in the first half of the 20th century, several small series of patients with idiopathic left ventricular hypertrophy were reported.1Braunwald E. Hypertrophic cardiomyopathy: the early years.J Cardiovasc Transl Res. 2009; 2: 341-348Google Scholar In 1957, Sir (later Lord) Russell Brock, a British cardiothoracic surgeon, operated on patients with muscular subaortic stenosis that he believed to have been secondary to chronic pressure overload, leading to what he believed was "acquired aortic subvalvular stenosis." In 1958, Teare, a forensic pathologist in London, described the hearts of 9 patients with massive hypertrophy of the interventricular septum, myocyte hypertrophy, and "bizarre and disorganized muscle bundles," 8 of whom had died suddenly and 2 of whom were siblings. Teare considered the hypertrophied septa to be hamartomas, that is, benign cardiac tumors; clearly, they had HCM.2Teare D. Asymmetrical hypertrophy of the heart in young adults.Br Heart J. 1958; 20: 1-8Google Scholar In the same year, this author (EB) and A. Glenn Morrow, Chief of Cardiac Surgery at the National Heart Institute (now the National Heart, Lung, and Blood Institute [NHLBI]), in Bethesda, Maryland studied a 27-year-old man in whom a cardiac murmur was noted at the age of 20 years and who reported exertional dyspnea and disabling angina. He presented with a loud precordial systolic murmur and a left ventricular lift on palpation. Left ventricular enlargement was present on x-ray examination, and the electrocardiogram showed left ventricular hypertrophy. Left-sided cardiac catheterization revealed a marked subaortic pressure gradient (Figure 1). Morrow and I believed that the patient had membranous subaortic stenosis, a relatively uncommon congenital anomaly that we had previously encountered and was considered resectable. To our surprise, at operation, although the left ventricle appeared enlarged on inspection, no subaortic obstruction was present in the potassium-arrested heart. However, when cardiac contraction was restarted, the left ventricular outflow pressure gradient reappeared. Several weeks later, a second patient presented with similar findings in both the cardiac catheterization laboratory and in the operating room. In our report of these 2 patients, we stated: "these features can only be explained by muscular hypertrophy of the left ventricular outflow tract of sufficient severity that flow is actually impeded during contraction."3Morrow AG Braunwald E. Functional aortic stenosis; a malformation characterized by resistance to left ventricular outflow without anatomic obstruction.Circulation. 1959; 20: 181-189Google Scholar Thus, by 1959, the key anatomic,2Teare D. Asymmetrical hypertrophy of the heart in young adults.Br Heart J. 1958; 20: 1-8Google Scholar physiologic, and some clinical features of what we now know as HCM had been described. In the early 1960s, as open-heart surgery expanded worldwide, an increasing number of patients with obstructive HCM were identified. In a broad effort to define this disorder, we studied 126 patients at the NHLBI during the decade from 1958 to 1968 (Table 1).4Braunwald E Lambrew CT Rockoff SD Ross Jr, J Morrow AG Idiopathic hypertrophic subaortic stenosis. I. A description of the disease based upon an analysis of 64 patients.Circulation. 1964; 30: 3-119Google Scholar We observed that the obstruction was dynamic, and modifiable by interventions that altered myocardial contractility and loading conditions. Some patients without obstruction in the basal state could be provoked to develop an outflow pressure gradient by increasing myocardial contractility through exercise or pharmacologically, and by the Valsalva maneuver and other interventions that reduced left ventricular cavity volume.Table 1Defining HCM 1958-19681958Obstruction 2o to muscular hypertrophy1960Familial association/autosomal dominant1962Variability of obstruction1963Non-obstructive form1964Medical treatment with beta blockade1964Surgical treatment by myectomy1968Impaired LV filling1968Frequency of sudden deathContributions by investigators in the intramural Division of the NHLBI to defining and characterizing HCM from 1958 to 1968. Many other clinical investigators from around the world made important contributions to the field during this decade. Open table in a new tab Contributions by investigators in the intramural Division of the NHLBI to defining and characterizing HCM from 1958 to 1968. Many other clinical investigators from around the world made important contributions to the field during this decade. Left-sided cardiac catheterization, often with selective angiography, was required for a definitive diagnosis of HCM during the 1960s. The development of echocardiography made noninvasive diagnosis possible and was rapidly applied in patients with known or suspected HCM. Echocardiography has been, and currently remains, widely used in screening, especially in the relatives of patients with known HCM. It is used to assess ventricular wall thickness, contraction and relaxation, and to detect outflow tract obstruction. In addition to 2-dimensional transthoracic echocardiography, color Doppler echocardiography for measurement of subaortic pressure gradients and transesophageal echocardiography provide important additional information. Echocardiography also identified systolic anterior motion of the anterior mitral leaflet,5Shah PM Gramiak R Kramer DH. Ultrasound localization of left ventricular outflow obstruction in hypertrophic obstructive cardiomyopathy.Circulation. 1969; 40: 3-11Google Scholar which, together with the hypertrophied septum, plays a critical role in the obstruction to left ventricular outflow. Greater structural and functional detail can be obtained by cardiac magnetic resonance; late gadolinium enhancement results from areas of myocardial fibrosis that may be indicators of the risk of serious complications, including heart failure, ventricular arrhythmias, and sudden cardiac death. The early descriptions of HCM called attention to strong familial associations in many patients. Indeed, 2 of the 9 patients described by Teare were siblings,2Teare D. Asymmetrical hypertrophy of the heart in young adults.Br Heart J. 1958; 20: 1-8Google Scholar and 2 families were represented in the first 14 patients whom we studied at the NHLBI.4Braunwald E Lambrew CT Rockoff SD Ross Jr, J Morrow AG Idiopathic hypertrophic subaortic stenosis. I. A description of the disease based upon an analysis of 64 patients.Circulation. 1964; 30: 3-119Google Scholar Family histories support autosomal dominant inheritance with variable penetrance and expression. Under the leadership of J.G. Seidman and C. Seidman, a missense mutation of a gene encoding β myosin on chromosome 14 was discovered,6Seidman CE Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history.Circ Res. 2011; 108: 743-750Google Scholar providing the first molecular basis of familial HCM. Variants of 8 other genes encoding sarcomeric proteins have been identified.7Marian AJ Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy.Circ Res. 2017; 121: 749-770Google Scholar Approximately 40% of patients with HCM exhibit this monogenic inheritance, which tends to cause more serious clinical disease than do the polygenic transmission and sporadic occurrence that are responsible for the remainder. Genetic testing and/or cascade screening of family members of affected probands is recommended. The finding that β adrenergic agonists can provoke or intensify outflow obstruction8Harrison DC Braunwald E Glick G Mason DT Chidsey CA Ross Jr, J Effects of beta-adrenergic blockade on the circulation with particular reference to observations in patients with hypertrophic subaortic stenosis.Circulation. 1964; 29: 84-98Google Scholar led to treatment with β adrenergic blockers, which cause moderate reduction of the intraventricular pressure gradient and symptoms in some patients.9Cohen LS Braunwald E. Amelioration of angina pectoris in idiopathic hypertrophic subaortic stenosis with beta-adrenergic blockade.Circulation. 1967; 35: 847-851Google Scholar The administration of L-type calcium channel blockers and of disopyramide, a negative inotropic antiarrhythmic agent, has also been beneficial.10Ommen SR Mital S Burke MA Day SM Deswal A Elliott P Evanovich LL Hung J Joglar JA Kantor P Kimmelstiel C Kittleson M Link MS Maron MS Martinez MW Miyake CY Schaff HV Semsarian C Sorajja P. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2020; 142: e558-e631Google Scholar,11Maron BJ. Clinical course and management of hypertrophic cardiomyopathy.N Engl J Med. 2018; 379: 655-668Google Scholar Although widely used, these drugs have not been tested in large, placebo-controlled clinical trials. Left ventricular hypertrophy in HCM is now known to be caused by myocardial hypercontractility that results from an excess of actin-myosin cross-bridges in the sarcomere.12Anderson RL Trivedi DV Sarkar SS Henze M Ma W Gong H Rogers CS Gorham JM Wong FL Morck MM Seidman JG Ruppel KM Irving TC Cooke R Green EM Spudich JA. Deciphering the super relaxed state of human beta-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers.Proc Natl Acad Sci U S A. 2018; 115: E8143-E8152Google Scholar The inhibition of myosin ATPase has been shown to reduce this excess and thereby block the development of left ventricular hypertrophy in a mouse model of HCM. Mavacamten is the first-in-class myosin inhibitor that has been shown, in placebo-controlled trials, to reduce outflow pressure gradients substantially and to improve exercise capacity.13Olivotto I Oreziak A Barriales-Villa R Abraham TP Masri A Garcia-Pavia P Saberi S Lakdawala NK Wheeler MT Owens A Kubanek M Wojakowski W Jensen MK Gimeno-Blanes J Afshar K Myers J Hegde SM Solomon SD Sehnert AJ Zhang D Li W Bhattacharya M Edelberg JM Waldman CB Lester SJ Wang A Ho CY Jacoby D EXPLORER-HCM Study InvestigatorsMavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomized, double-blind, placebo-controlled, phase 3 trial.Lancet. 2020; 396: 759-769Google Scholar,14Braunwald E, Saberi S, Abraham TP, Elliott PM, Olivotto I. Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy [published online October 7, 2023]. Eur Heart J https://doi.org/10.1093/eurheartj/ehad637.Google Scholar It has been approved by the US Food and Drug Administration and by regulators in other countries for treating symptomatic obstructive HCM. Aficamten, a second myosin inhibitor,15Maron MS Masri A Choudhury L Olivotto I Saberi S Wang A Garcia-Pavia P Lakdawala NK Nagueh SF Rader F Tower-Rader A Turer AT Coats C Fifer MA Owens A Solomon SD Watkins H Barriales-Villa R Kramer CM Wong TC Paige SL Heitner SB Kupfer S Malik FI Meng L Wohltman A Abraham T REDWOOD-HCM Steering Committee and InvestigatorsPhase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2023; 81: 34-45Google Scholar is now undergoing a phase 3 trial. It is possible that myosin inhibitors will be disease-modifying, that is, change its natural history. Symptomatic patients with persistent marked obstruction despite pharmacologic treatment can be managed by septal reduction therapy—either surgical myectomy16Morrow AG Fogarty TJ Hannah 3rd, H Braunwald E Operative treatment of idiopathic hypertrophic subaortic stenosis. Techniques, and the results of preoperative and postoperative clinical and hemodynamic assessments.Circulation. 1968; 37: 589-596Google Scholar or alcohol septal ablation.17Batzner A Pfeiffer B Neugebauer A Aicha D Blank C Seggewiss H. Survival after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy.J Am Coll Cardiol. 2018; 72: 3087-3094Google Scholar Progressive, irreversible heart failure with ventricular dilatation may require cardiac transplantation. Sudden cardiac death, observed most frequently in adolescents and young adults, is caused by ventricular fibrillation and, as was shown by Maron et al,18Maron BJ Shen WK Link MS Epstein AE Almquist AK Daubert JP Bardy GH Favale S Rea RF Boriani G Estes 3rd, NA Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy.N Engl J Med. 2000; 342: 365-373Google Scholar can be prevented by implanting a cardioverter-defibrillator. Patients with a history of sustained or repetitive ventricular tachycardia, unexplained syncope, massive left ventricular hypertrophy, extensive late gadolinium enhancement or with a family history of this complication are at high risk and should receive such a device.18Maron BJ Shen WK Link MS Epstein AE Almquist AK Daubert JP Bardy GH Favale S Rea RF Boriani G Estes 3rd, NA Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy.N Engl J Med. 2000; 342: 365-373Google Scholar The next major step in managing HCM will be gene therapy to block progression or even prevent its development. Reichart and the Seidmans have shown that single-dose genetic therapies can correct or abolish pathogenic variants in mice carrying a variant myosin gene for HCM.19Reichart D Newby GA Wakimoto H Lun M Gorham JM Curran JJ Raguram A DeLaughter DM Conner DA Marsiglia JDC Kohli S Chmatal L Page DC Zabaleta N Vandenberghe L Liu DR Seidman JG Seidman C. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice.Nature Med. 2023; 29: 412-421Google Scholar After successful preclinical studies, Desai at the Cleveland Clinic has begun a clinical trial of an adeno-associated virus-based delivery of a gene that encodes a myosin binding protein C3 in a patient with HCM.20Cleveland Clinic. Cleveland Clinic performs World's first in-human gene therapy for hypertrophic cardiomyopathy. Available at: https://newsroom.clevelandclinic.org/2023/10/05/cleveland-clinic-performs-worlds-first-in-human-gene-therapy-for-hypertrophic-cardiomyopathy/. Accessed on October 17, 2023.Google Scholar The many unique features of HCM previously mentioned have attracted the attention of clinical and interventional cardiologists, cardiovascular surgeons, geneticists, radiologists, and molecular biologists. Viz.ai, an artificial intelligence company, has developed an algorithm for earlier detection of HCM,21Viz.ai. Viz.ai receives first de novo approval by the FDA for AI algorithm for hypertrophic cardiomyopathy. Available at: https://www.viz.ai/news/viz-ai-receives-the-first-de-novo-approval-by-the-fda-for-ai-algorithm-for-hypertrophic-cardiomyopathy. Accessed on October 17, 2023.Google Scholar an approach that may identify many new patients. Clinicians should have a working knowledge of key aspects of this important disorder, many of which are described in this supplement to the American Journal of Cardiology edited by Dr. Charles Pollack.