Patterns of Disease Progression in Hypertrophic Cardiomyopathy
2012; Lippincott Williams & Wilkins; Volume: 5; Issue: 4 Linguagem: Inglês
10.1161/circheartfailure.112.967026
ISSN1941-3297
AutoresIacopo Olivotto, Franco Cecchi, Corrado Poggesi, Magdi H. Yacoub,
Tópico(s)Cardiovascular Effects of Exercise
ResumoHomeCirculation: Heart FailureVol. 5, No. 4Patterns of Disease Progression in Hypertrophic Cardiomyopathy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessResearch ArticlePDF/EPUBPatterns of Disease Progression in Hypertrophic CardiomyopathyAn Individualized Approach to Clinical Staging Iacopo Olivotto, MD, Franco Cecchi, MD, Corrado Poggesi, MD and Magdi H. Yacoub, MD, FRS Iacopo OlivottoIacopo Olivotto From the Referral Center for Cardiomyopathies, Careggi University Hospital (I.O., F.C.) and Department of Physiology, University of Florence (C.P.), Florence, Italy; and Heart Science Center, Imperial College London, Harefield, United Kingdom (M.H.Y.). , Franco CecchiFranco Cecchi From the Referral Center for Cardiomyopathies, Careggi University Hospital (I.O., F.C.) and Department of Physiology, University of Florence (C.P.), Florence, Italy; and Heart Science Center, Imperial College London, Harefield, United Kingdom (M.H.Y.). , Corrado PoggesiCorrado Poggesi From the Referral Center for Cardiomyopathies, Careggi University Hospital (I.O., F.C.) and Department of Physiology, University of Florence (C.P.), Florence, Italy; and Heart Science Center, Imperial College London, Harefield, United Kingdom (M.H.Y.). and Magdi H. YacoubMagdi H. Yacoub From the Referral Center for Cardiomyopathies, Careggi University Hospital (I.O., F.C.) and Department of Physiology, University of Florence (C.P.), Florence, Italy; and Heart Science Center, Imperial College London, Harefield, United Kingdom (M.H.Y.). Originally published1 Jul 2012https://doi.org/10.1161/CIRCHEARTFAILURE.112.967026Circulation: Heart Failure. 2012;5:535–546IntroductionAfter the recent celebrations of the 50th anniversary of the modern description of hypertrophic cardiomyopathy (HCM) by Teare and Lord Brock, the time is ripe to reflect on what remains to be discovered.1–3 With the full realization that a massive amount of information relating to the disease has already been uncovered, and paying tribute to all those involved in this process, it is essential to concentrate on the gaps in our knowledge that require concerted efforts to advance the field, particularly in relation to patient management, which continues to be perceived as less than optimal.3 We believe that this is largely due to the partial disconnect between basic research, and an incomplete understanding of the fundamental mechanisms molding a continuously, often insidiously changing phenotype. A thorough comprehension of these processes requires a translational approach based on long-term clinical observation of large HCM cohorts, coupled with basic scientific research, and represents an essential step toward the development of innovative therapies which need to be both disease- and patient-specific.2,3Traditionally, the focus of HCM literature has been polarized on 2 aspects of indisputable clinical relevance: the pathogenesis, clinical consequences, and management of dynamic left ventricular (LV) outflow obstruction,1 and the issue of arrhythmic risk stratification and prevention of sudden cardiac death (SCD).4,5 By comparison, limited attention has been devoted to the life-long process of LV remodeling and progressive dysfunction that occur in a substantial proportion of HCM patients and culminates in the rare but dramatic clinical evolution termed as end-stage or burned-out phase.6–9 Consequently, the stages that precede this severe condition are still relatively unknown, representing an important target for research.3 Indeed, because of the slowly evolving nature of HCM, timely identification of patients at risk of developing advanced LV dysfunction and heart failure (HF) may allow effective preventive strategies over a time span of several years before clinical demise.7–9To aid the characterization of different phases of HCM in individual patients, we propose a simple framework for systematic clinical staging of the disease. To this purpose, 4 clinical stages are identified, with special emphasis on diagnosis, potential mechanisms, challenges for management, and targets for future investigation: these are defined as nonhypertrophic HCM, classic phenotype, adverse remodeling, and overt dysfunction (Figure 1 and Table).3,6,7,10Table. Stages of Hypertrophic Cardiomyopathy Based on Clinical and Instrumental Evidence of Disease ProgressionLVEF (by CMR)*†LGE (% of Whole LV Mass)*†Coronary Microvascular Dysfunction*†Symptoms and Functional Limitation†LV Filling Pattern and TDI†LVOTO (Resting or Provokable)†Atrial Remodeling†Atrial Fibrillation†NSVTComplex Genotypes*†OutcomePriorities for Management and ResearchStage I NonhypertrophicNormal or supernormalAbsentUnknown; possibly presentNoneNormal; TDI–E′ may be reducedAbsentAbsentNoNoUnknown; presumed rareFavorable; SCD reported but exceptionalPrevention of disease developmentStage II " Classic" phenotype>65%Absent or <5%Variable from mild to severeVariable; may be severe with LVOTO/MR or massive LVHNormal or delayed relaxation TDI–E′ usually reducedCommon (70%)Mild to moderate isolated LA dilation; severe only with LVOTO/MRRare; more common with long-standing LVOTO or in the elderlyRare3% to 5%HF-related complications uncommon; SCD 0.5%/1%/yControl of symptoms; relief of LVOT obstruction; risk stratification for SCDStage III Adverse remodeling50% to 65%10% to 15%Moderate to severeVariable; generally mild to moderatePseudonormal or restrictive TDI–E′ reducedLess common; loss of prior obstruction may be observedModerate to severe LA dilatationCommonCommonUnknown; probably intermediateUnknown; probably intermediateControl of symptoms; management of AF and HF; prevention of progression; risk stratification for SCDStage IV Overt dysfunction G). Parasternal long-axis view shows normal LV thickness values, with redundant mitral leaflets (A). Tissue Doppler imaging velocities of the mitral annulus appear reduced (B). C and D, Ten-year-old boy carrying the myosin binding protein C (MYBPC3) mutation Glu258Lys (NM_000256.3 c.772G>A). Parasternal long- and short-axis views show mild increase in septal thickness (11 mm; C and D), with presence of crypts (arrows). E, Early systolic frame shows abnormal papillary insertion into the anterior mitral leaflet (arrows). Inferolateral Q waves are evident on the ECG (F). AML indicates anterior mitral leaflet; FT, false tendon, LV, left ventricle; and VS, ventricular septum.As the capabilities offered by diagnostic techniques advance, the proportion of truly phenotype-negative individuals becomes progressively smaller. With cardiac magnetic resonance (CMR), as many as 16% genotype-positive with negative echocardiography examination appear to have some degree of LV hypertrophy.10 Thus, individuals in this stage should be considered for CMR at initial evaluation to rule out mild but significant expressions of disease.Mechanisms of DiseaseHCM is termed a disease of the sarcomere, because mutations in a number of genes encoding cardiac contractile and Z-disk proteins have been convincingly shown to cause the disease.2,3 HCM-causing mutations generally cause single amino-acid substitutions in proteins that become incorporated into the sarcomere and exert their pathological effects as poison peptides that alter normal sarcomere function in a concentration-dependent manner.2,3,15,16 An exception to this rule are most myosin binding protein C (MYBPC3) mutations, which result in insufficient protein production for normal sarcomere function (haploinsufficiency).2,17 Haploinsufficiency can be attributed to cell surveillance mechanisms, including nonsense-mediated decay of mRNA transcripts that contain premature termination codons and/or ubiquitin-mediated proteasomal degradation of misfolded proteins.17 Even before the development of LV hypertrophy, HCM-causing mutations may exert various adverse effects on cardiomyocyte intracellular calcium and energy handling, accounting for early diastolic abnormalities in nonhypertrophic HCM.11,14 Over time, the effects of HCM-causing mutations are subject to the interplay of modifier genes and environmental factors, likely crucial in determining an "awakening" of the phenotype.18,19Clinical Course and OutcomePrognosis of genotype-positive individuals in the nonhypertrophic stage is unresolved, but presumed favorable, possibly comparable to that of the healthy population.10,11 Although potentially malignant ventricular arrhythmias and SCD has been reported in nonhypertrophic HCM, such occurrence is considered exceptional.7Targets for Management and Research: Preventing Disease DevelopmentNo evidence-based treatment is available for nonhypertrophic HCM. Avoiding emphasis on competitive activity may be considered in these individuals, although this issue remains highly controversial.10,19 Pharmacological strategies aimed at preventing development of LV hypertrophy have been proposed, based on encouraging preclinical data with agents such as statins, losartan, and diltiazem.20,21 A randomized trial with diltiazem is currently underway to test this hypothesis in humans.22 It is hoped that new genetic technologies, allowing cost-effective screening in HCM families, will contribute to our understanding of the prevalence and outcome of individuals with nonhypertrophic HCM and allow pharmacological trials on a larger scale.20Stage II: The "Classic" HCM PhenotypeDefinition and Diagnosis"Classic" HCM phenotype is defined as the phase in which the hypertrophic phenotype is fully expressed and the LV is hyperdynamic (as defined by an ejection fraction [EF] >65%), in the absence of extensive fibrotic changes suggesting unfavorable progression. More than three-quarters of HCM patients in cross-sectional studies belong to this stage (Figure 1).23–25 The distribution of LV hypertrophy is typically regional and asymmetrical, generally involving the basal septum and anterior wall, but can develop in all imaginable patterns within the LV and involve the right ventricle and papillary muscles3,7,10 (Figure 3 and Table). Besides cardiac hypertrophy, the HCM phenotype includes a constellation of mitral valve and subvalvar abnormalities, subaortic, midventricular and right ventricular outflow obstruction, atrial remodeling, coronary myocardial bridging, crypts, and autonomic nervous system abnormalities.1,2,7,13 At the microscopic level, HCM is characterized by classic features such as myocardial disarray, microvascular remodeling, and interstitial fibrosis.3,10Download figureDownload PowerPointFigure 3. "Classic" hypertrophic cardiomyopathy (HCM) phenotype. A and B, This adult female patient with unknown genetic status remained totally asymptomatic over more than 2 decades, without treatment. Except mild left atrial remodeling, no changes in cardiac morphology or function were evident. C and D, Cardiac magnetic resonance (CMR) short-axis spin-echo (C) and delayed enhanced images (D) from a 66-year-old female HCM patient with the MYBPC3 mutation Tyr340X (NM_000256.3 c.1020C>G). Asymmetrical septal hypertrophy is evident, with limited areas of LGE at the right ventricular junction (red arrows). E, CMR long-axis image from a severely symptomatic 27-year-old male HCM patient with the MYH7 mutation Arg694Cys (NM_000257.2 c.2080C>T), massive LV hypertrophy, small left ventricular (LV) cavity size, and dynamic outflow obstruction. VS indicates ventricular septum.The LV in "classic" HCM is characterized by small or normal-sized cavity and enhanced contractility. In a recent CMR study, resting LV ejection fraction (EF) in more than 300 unselected HCM patients averaged 71%.23 In the presence of altered LV geometry and marked mitral valve abnormalities, enhanced contractility represents a determinant of dynamic LV outflow obstruction, occurring in resting conditions or under provocation in about 70% of patients.1,7 Although regional diastolic abnormalities are almost always present, the transmitral filling pattern may be normal or only mildly abnormal (delayed relaxation); more severe degrees of diastolic impairment are less common and generally occur in patients with severe outflow obstruction or massive LV hypertrophy and restrictive pathophysiology.7,9,23 Late gadolinium enhancement (LGE) at CMR is present in less than half of HCM patients with "classic" phenotype and occupies a small percentage of the LV, with a median value of 2%23 (Figure 3D and Figure 4), suggesting that collagen deposition at this stage reflects an exaggerated activation of the matrix rather than a reparative process.14Download figureDownload PowerPointFigure 4. Relation of left ventricular (LV) ejection fraction (EF) to frequency and extent of cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) in 310 patients with hypertrophic cardiomyopathy (HCM). Left panel: top, Prevalence of LGE in 4 LVEF subgroups. Center, Box plot representing extent of LGE expressed as absolute mass in grams. Black boxes represent interquartile range; horizontal white lines represent median for each subgroup. Bottom, Box plot representing LGE expressed as percentage of overall LV mass. Right panel, LGE in 4-chamber vertical long-axis images of representative patients from the 4 LVEF categories. Top left, Twenty-year-old woman with end-stage progression showing extensive transmural myocardial fibrosis (LGE occupying 43% of LV wall; arrows). Top right, Sixty-one–year-old woman with low-normal EF showing transmural LGE occupying 24% of the LV. Bottom left, Thirty-five–year-old man with preserved systolic function showing limited nontransmural fibrosis occupying 8% of the LV. Bottom right, Forty-five–45-year-old man with supernormal systolic function showing absence of LGE. FW indicates free wall; LA, left atrium; and VS, ventricular septum. Reproduced from Olivotto et al.23Mechanisms of DiseaseHCM-causing mutations are believed to trigger LV hypertrophy in response to compromised cardiomyocyte energetic balance,2,21 due to the excess ATP utilization required to generate isometric tension within the sarcomere.26 Additional disease mechanisms involve impairment of mechanisms that switch off contraction at low cytosolic [Ca2+], leading to incomplete relaxation and diastolic dysfunction while increasing energetic compromise.26–28 Chronic dysregulation of cardiomyocyte Ca2+ homeostasis may cause multiple downstream effects involving secondary activation of Ca2+-regulated signaling pathways, cardiac remodeling and, possibly, apoptosis.29Furthermore, sarcomeres and their Z-disk components are now recognized centers of mechano-sensation, mechano-transmission, and mechano-transduction.30 In HCM, altered sarcomere mechanics due to faster force generation kinetics, hypercontractility, or incomplete relaxation may trigger hypertrophy and adverse remodeling by activating these sensors.22 Of note, the abnormal sarcomere contractile status is held responsible for the persistent increase in sympathetic stimulation observed in HCM patients, itself a potential codeterminant of hypertrophy.31 Finally, coronary microvascular dysfunction is a consistent feature of HCM, subtended by marked remodeling of the small coronary vessels, which appears to be genetically regulated and relatively independent of hypertrophy.7,9,32 Although a powerful long-term predictor of progression to LV dysfunction and failure, microvascular dysfunction is not a sign of disease progression per se and, in "classic" HCM, it is not associated with evidence of permanent ischemic damage and replacement fibrosis.7,9Clinical Course and OutcomeOnce the "classic" HCM phenotype has developed, most patients experience long periods of clinical stability and may never undergo significant degrees of adverse remodeling or disease progression during their lifetime7,10 (Figure 3A and 3B). Rather, a slow, almost imperceptible remodeling process occurs over the decades, overlapping changes related to physiological ageing.33 Symptoms may vary and include dyspnea on effort, angina, atypical chest pain, syncope, and palpitations.10,34 However, severe functional limitation is generally limited to individuals with severe LV outflow obstruction or restrictive physiology24 (Figure 3E). Life expectancy is relatively favorable, with an annual cardiovascular mortality around 1%.7,10,34 Although SCD rates are low in this subset, a subgroup of patients remain at high risk and should be identified by appropriate workup.4,5,10Targets for Management and Research: Preserving StabilityManagement in this stage focuses on relief of LV outflow obstruction and prevention of SCD. A detailed analysis of these issues goes beyond the scope of the present work: both have been the object of ongoing debate over decades and are extensively reviewed elsewhere.4,5,10,12,34 Furthermore, long-term management strategies in patients with "classic" HCM include regular clinical scrutiny for signs of disease progression, prevention of cardiac comorbidity, and control of conventional risk factors such as sedentary lifestyle, hypertension, dyslipidemia, and diabetes.10,19 In selected patients, such as those with exercise limitation and angina in the absence of obstruction, evaluation of microvascular function by PET may prove valuable in order to assess risk of long-term disease progression.9Pharmacological treatment in this stage is mostly based on the time-honored use of β-blockers, calcium channel blockers, disopyramide, and amiodarone for control of symptoms, dynamic LV obstruction, and arrhythmias.10,34 Specific treatments targeting cardiomyocyte energy deficiency and microvascular dysfunction are being investigated.20,21,35 However, patients with "classic" HCM phenotype are not ideal candidates for the assessment of therapeutic interventions aimed at improving long-term outcome because of the low event rate, requiring large patient populations and very extended observation times.36 More rewarding efforts are directed at investigating the effects of treatment on symptomatic status, myocardial energetic profile, microvascular function, and development of fibrosis.3,20,22,26,35Stage III: Adverse RemodelingDefinition and DiagnosisAdverse remodeling is defined by the presence of unfavorable structural modifications, superimposed to the "classic" HCM phenotype, translating into increasing LV fibrosis and worsening function (ie, an LVEF in the low-normal range of 50% to 65%), with relatively preserved clinical and hemodynamic balance. Rather than being an "average" process, this seems to represent a selective pathway followed by about 15% to 20% of HCM patients, a smaller proportion of whom will ultimately progress to overt dysfunction and heart failure6–8,23 (Figure 1). Both the extent and time-course of LV remodeling are extremely heterogeneous: adverse changes may be observed at any age, including infancy and adolescence, and may lead to overt dysfunction and advanced HF in a brief span of time37,38 but more often occur gradually over years or decades.7,8The definition of this intermediate stage of disease progression is based on a combination of several structural and functional features including an LVEF in the low-normal range,23 moderate to severe diastolic function,24-25 marked atrial dilatation,39 moderate areas of LGE,7,16,23,40 severe microvascular dysfunction,9 thinning of the LV walls,8 onset of atrial fibrillation (AF),41 spontaneous reduction or loss of LV outflow obstruction,8,42 and LV apical aneurisms.43 Each of these features has been described separately in HCM cohorts, generally associated with adverse outcome. However, they show a consistent trend to cluster in individual patients, as though representing different aspects of disease progression in the same subset (Figure 5 and Figure 6). Because HCM is extremely heterogeneous, not all these "red flags" are expected to coexist in single patient and at the same time.6,7 Rather, they might be seen as elements of an ideal cumulative score: the higher the score, the more likely the departure from a "classic" HCM phenotype toward adverse remodeling and progression.6–9,23–25,39–41,43,44Download figureDownload PowerPointFigure 5. Adverse remodeling. Thirty-two–year-old woman with unknown genetic status and history of increasing dyspnea on effort. End-diastolic echocardiographic (A and B) and cardiac magnetic resonance (CMR) views (C and D) showing severe left ventricular (LV) hypertrophy, prevalently localized at the midapical portions, and left atrial dilatation. End-systolic CMR images (E and F) show preserved systolic function causing cavity obliteration. Diastolic function is markedly impaired (G), with pseudonormalized, triphasic LV filling pattern (top), prominent pulmonary vein reverse A wave (middle), and severely reduced mitral annulus tissue Doppler imaging velocity (bottom). End-diastolic long-axis images in H show substantial LGE involving the septum. AW indicates anterior wall; PW, posterior wall; and VS, ventricular septum.Download figureDownload PowerPointFigure 6. Adverse remodeling. A through C, Thirty-two–year-old man with unknown genetic status and paroxysmal atrial fibrillation. Four-chamber and short-axis cardiac magnetic resonance views (A and B) show marked biatrial dilatation, mild left ventricular (LV) hypertrophy with normal cavity dimensions, and low-normal LV ejection fraction (EF) (56%). Delayed-enhanced images (C) show substantial late gadolinium enhancement (LGE) involving the ventricular septum (VS), apex, and free wall (red arrows). D and E, Fifty-seven–year-old man with the MYBPC3 mutation c.407 to 1G>A. Echocardiographic 4-chamber view shows biatrial dilatation and smoke effect in diastole (asterisk). A restrictive LV filling pattern is evident (E, top), reflecting significant progression compared with the pseudonormalized pattern documented 4 years previously (bottom). LVEF was 62%. RA indicates right atrium; RV, right ventricle; AW, anterior wall; and DT, deceleration time.Adverse LV remodeling in HCM patients is subtended by variable and sometimes striking patterns of intramyocardial fibrosis, visualized by CMR as LGE, varying from moderate to large, confluent, infarct-like patches occupying significant proportions of the LV.7,9–11,16,23,40 LGE generally shows a typical midwall localization, with sparing of the subendocardial region, but may be transmural when severe (Figures 5 and 6).44 When substantial, the extent of LGE is inversely related to LVEF, supporting the view of discrete fibrosis as an expression of cardiomyocyte loss followed by a reparative process, ie, a scar.23,44In HCM patients with low-normal LVEF values of 50% to 65% (representing 15% of the total cohort in one study), LGE was present in 67%, and constituted a median of 5% of the LV mass, with an interquartile range of 2% to 20%.23 Such values significantly exceeded those seen in patients with hyperdynamic LV and overlapped with patients exhibiting overt systolic dysfunction and LVEF <50% (Figure 4), suggesting that HCM patients with adverse LV remodeling and low-normal systolic function represent the reservoir from which advanced disease progression and the so-called "end-stage" disease will evolve.6–8,23Mechanisms of DiseaseAdverse LV remodeling in HCM appears triggered from within and probably reflects the interplay of microvascular ischemia, cardiomyocyte energy depletion and apoptosis, leading to progressive myocyte loss and fibrous substitution of the myocardium.2,3,6,9,21,26 Of note, severe HCM progression is distinctively more prevalent in patients with complex genotypes, reflecting profound derangement of sarcomere mechanics and cardiomyocyte energetics.3,15,16 Conversely, external triggers of adverse remodeling are seldom evident; factors such as viral myocarditis or epicardial coronary disease have been emphasized but are only anecdotally associated with disease progression.7Clinical Course and OutcomeThe clinical correlates of adverse remodeling may vary widely, ranging from mild to severe manifestations. Congestive symptoms may become evident, in the absence of LV outflow obstruction, paralleled by marked impairment of cardiopulmonary exercise testing and elevated titers of natriuretic peptides.45 However, symptoms can be deceivingly mild and hinder the fact that disease progression has begun.7,25 The onset of AF, relatively frequent in this phase, represents both an epiphenomenon and an important determinant of further cardiac remodeling and functional deterioration.41,46The present attempt to describe a specific subset of HCM patients with early evidence of disease progression represents a novel concept which has not been assessed in longitudinal studies. As a result, the long-term outcome of this subset is unresolved. Based on studies addressing individual features of disease progression such as LA dilatation, AF, microvascular dysfunction, and LGE, it is plausible to expect cardiac mortality rates of about 3% to 5% per year, intermediate between the low risk associated with "classic" HCM phenotype, and the high risk associated with overt LV dysfunction.9,24,25,39–41Targets for Management and Research: Opposing DeteriorationHCM patients with adverse cardiac remodeling should be considered at risk of further progression toward overt dysfunction and HF. Because such progression may occur over very extended periods of time,7,9 close clinical surveillance with CMR, cardiopulmonary testing, and serial proBNP titration may prove valuable, potentially allowing for preventive treatment.20,35 Specifically, the information provided by contrast-CMR is crucial for the identification of patients in transition from stages II to III and from stages III to IV,23 although the advisable frequency of scans during follow-up remains to be determined.10Adequately designed, prospective trials are urgently required to test which therapeutic strategies may have a potential impact on HCM progression.3 Because of higher expected rates of cardiac events and HF-related complications, longitudinal studies focusing on patients with evidence of adverse remodeling may allow sufficient statistical power to assess outcome.36 At present, it is plausible to consider timely implementation of treatments that have proven effective in other causes of LV dysfunction, such as modulators of the renin-angiotensin-aldosterone system.10,34 The timing of therapy switch from "classic" HCM pharmacopea to antiremodeling HF treatment is challenging, and should take in account all the clinical "red flags" delineated above.7,23 Too often, HF therapy is withheld in HCM patients until overt systolic dysfunction is evident, and the greatest potential is probab
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