Clinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 6 Linguagem: Inglês
10.1161/circulationaha.118.037264
ISSN1524-4539
AutoresNiccolò Maurizi, Michelle Michels, Ethan J. Rowin, Christopher Semsarian, Francesca Girolami, Benedetta Tomberli, Franco Cecchi, Martin S. Maron, Iacopo Olivotto, Barry J. Maron,
Tópico(s)Cardiac Structural Anomalies and Repair
ResumoHomeCirculationVol. 139, No. 6Clinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBClinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy Niccolò Maurizi, MD, Michelle Michels, MD, Ethan J. Rowin, MD, Christopher Semsarian, MBBS, PhD, MPH, Francesca Girolami, BsCa, Benedetta Tomberli, MD, Franco Cecchi, MD, Martin S. Maron, MD, Iacopo Olivotto, MD and Barry J. Maron, MD Niccolò MauriziNiccolò Maurizi Niccolò Maurizi, MD, Cardiomyopathy Unit, Careggi University Hospital, Viale Pieraccini 17, 50132, Florence, Italy. Email E-mail Address: [email protected] Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (N.M., F.G., B.T., F.C., I.O.). , Michelle MichelsMichelle Michels Erasmus Medical Center, Rotterdam, The Netherlands (M.M.). , Ethan J. RowinEthan J. Rowin Hypertrophic Cardiomyopathy Institute, Tufts Medical Center, Boston, MA (E.J.R., M.S.M., B.J.M.). , Christopher SemsarianChristopher Semsarian Royal Prince Alfred Hospital and Centenary Institute, University of Sydney, Australia (C.S.). , Francesca GirolamiFrancesca Girolami Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (N.M., F.G., B.T., F.C., I.O.). , Benedetta TomberliBenedetta Tomberli Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (N.M., F.G., B.T., F.C., I.O.). , Franco CecchiFranco Cecchi Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (N.M., F.G., B.T., F.C., I.O.). , Martin S. MaronMartin S. Maron Hypertrophic Cardiomyopathy Institute, Tufts Medical Center, Boston, MA (E.J.R., M.S.M., B.J.M.). , Iacopo OlivottoIacopo Olivotto Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (N.M., F.G., B.T., F.C., I.O.). and Barry J. MaronBarry J. Maron Hypertrophic Cardiomyopathy Institute, Tufts Medical Center, Boston, MA (E.J.R., M.S.M., B.J.M.). Originally published4 Feb 2019https://doi.org/10.1161/CIRCULATIONAHA.118.037264Circulation. 2019;139:830–833Increased availability of genetic testing for hypertrophic cardiomyopathy (HCM) has led to the emergence of a novel patient subset, consisting of asymptomatic genetically affected family members with normal cardiac function without left ventricular hypertrophy (LVH).1 These genotype-positive (+)–LVH-negative (–) (G+LVH–) individuals raise unresolved clinical issues concerning conversion to HCM phenotypes and risk for cardiovascular complications.2,3 Given the presumed thousands of gene carriers among HCM families, we have assessed here the clinical profiles and outcome of G+LVH– individuals in a large international multicenter cohort.A total of 203 G+LVH− individuals were identified in 128 HCM families (Table) at 4 referral centers (United States, Italy, Netherlands, and Australia) and followed prospectively. Participants were ≥12 years at initial evaluation with (1) HCM family history, (2) pathogenic/likely pathogenic sarcomere variant,4 and (3) maximal left ventricular (LV) wall thickness ≤12 mm.Table. Baseline and Follow-Up Characteristics of 203 Genotype-Positive Individuals Without LVHVariableTotal Cohort (n=203)Genotype-Positive Individuals Converting to LVH (n=21)Genotype-Positive Individuals Without LVH (n=182)P Value*Baseline characteristics Demographics Age at initial evaluation, y32±1130±1434±120.62 Age <40 y, n (%)147 (72)17 (81)131 (76)0.68 Age 40–69 y, n (%)56 (27)4 (17)52 (24)0.21 Male sex, n (%)80 (39)12 (57)68 (37)0.01 Family history of SD, n (%)89 (42)7(32)82 (43)0.55 Family history of end stage, n (%)48 (23)4 (19)44 (23)0.78 Medical history NYHA I, n (%)203 (100)21 (100)182 (100)0.49 Moderate/intense physical activity, n (%)91 (44)7 (33)84 (46)0.06 ECG, n (%) Normal ECG182 (88)11 (52)171 (92)<0.01 Q waves17 (8)9 (43)8 (4)<0.01 ST-T abnormalities11 (5)2 (10)9 (5)0.30 LVH, Sokolov-Lyon Index4 (2)2 (10)2 (1)0.05 Gene mutations, n (%) ACTN2101 (0.5) MYBPC314116 (76)125 (69) MYH7424 (19)38 (21) MYL2202 (1) MYL3101 (0.5) TNNC1101 (0.5) TNNI1202 (1) TNNI361 (5)5 (3) TNNT2606 (3) TPM1101 (0.5) Echocardiography LA diameter, mm34±834±632±80.94 Ejection fraction, %62±664±264±60.23 Max. LV thickness, mm9±210±29±20.28 LVED, mm44±744±644±80.34 TDI septal (n=151), cm/s11.2±2.511.3±1.410.8±2.70.32 TDI lateral (n=130), cm/s14.5±3.615.5±3.314.1±3.80.11Follow-up characteristics Follow-up duration, y6±26±25±30.68 Medical history NYHA I, n (%)203 (100)21 (100)182 (100)0.49 Moderate/intense physical activity, n (%)98 (48)9 (43)87 (48)0.22 ECG, n (%) Normal ECG170 (83)10 (48)160 (87)<0.01 Q waves18 (9)9 (43)8 (4)<0.01 ST-T abnormalities9 (4)2 (9)7 (4)0.10 LVH, Sokolov-Lyon Index11 (5)3 (14)9 (4)0.08 Echocardiography LA diameter, mm36±1036±934±90.29 LVED, mm45±545±545±60.45 Ejection fraction, %63±566±663±80.23 Max. LV thickness, mm11±515±110±2 40 years, and 61% were female (Table). Mean LV thickness was 9±2 (6–11) mm. LV end-diastolic cavity dimension, left atrial size, and ejection fraction were normal (Table).Of the 128 families, 62 (52%) included ≥1 relatives with sudden death or end-stage HCM. However, no adverse cardiovascular events occurred in any study patient including death, HCM-related complications/events, or cardiac symptoms, over a follow-up of 6±2 years (739 person-years).Over a follow-up of 5±3 years, 90% of patients (n=182) (nonconverters) did not convert to LVH. At most recent evaluation, patients were 37±16 years old; 37 were (18%) were >50 years, including 10 patients >60 years old (range to 69). For the group, LV wall thickness increased 1±2 mm but remained ≤12 mm; 22 of 182 (12%) patients developed ECG abnormalities.Over 6±2 years, 21 individuals (10%) (converters) converted to the HCM phenotype, defined as maximal LV wall thickness ≥13 mm, usually in the anterior ventricular septum (mean 15±2; 13–17), but without hypertension; the conversion rate was 0.3%/y. At the most recent evaluation, patients were 39±10 years old; 43 (21%) were >50 years, including 16 (8%) >60 years.LVH converters and nonconverters did not differ in LV thickness at entry (10±2 versus 9±2 mm, P=0.28). Based on serial echocardiograms, LVH conversions occurred with similar frequency by decade (7%–13%; average, 10) although delayed to ≥50 years in 4 patients and to 40 to 49 years in 4 others (P=0.76).ECG results were abnormal in 24 (21%), most commonly pathological Q waves (n=17) and ST-T abnormalities (n=11). LVH converters had abnormal ECGs more commonly than nonconverters (48% versus 8%; P 200 patients, we found no evidence of adverse disease consequences in any patient. This important observation should represent a source of reassurance to G+LVH– individuals and clinicians.However, we cannot exclude the possibility that, with extended surveillance, disease-related complications and conversion to LVH could occur in additional patients.2,5 Nevertheless, the average age of the study population is 39 years, and ≈20% are already >50 years old (including 5% who are >60 years old), suggesting that many G+LVH– patients will achieve normal longevity without HCM-related complications or development of LVH.Ten percent of the study group has converted to a HCM phenotype, with a similar frequency in younger and older patients. ECG abnormalities, particularly Q waves, often preceded LVH, serving as a predictor of phenotypic conversion in some patients.2,3,5 These findings need to be confirmed by larger cohort studies, given the relatively small number of converters in the cohort. Present underrecognition of LVH could be related to the large number of patients <18 years who could yet convert to HCM,2,3 exclusion of relatives with LVH at initial evaluation, or CMR not being a routine part of the study design.2In conclusion, in the present multicenter cohort, G+LVH– individuals demonstrated a benign clinical course with virtually no demonstrable risk for disease-related morbidity/mortality, including almost 20% who have already achieved relatively advanced age. This observation and uncommon conversion to the HCM phenotype suggest that many gene carriers can anticipate normal longevity.Sources of FundingDr Olivotto is supported by the Italian Ministry of Health: RF-2013-02356787 (Left ventricular hypertrophy in aortic valve disease and hypertrophic cardiomyopathy: genetic basis, biophysical correlates and viral therapy models), NET-2011-02347173 (Mechanisms and treatment of coronary microvascular dysfunction in patients with genetic or secondary left ventricular hypertrophy), and "Monitoraggio e prevenzione delle morti improvvisecardiache giovanili in Regione Toscana" Acronimo ToRSADE (Tuscany Registry of Sudden cArdiac Death) (Bando FAS Salute 2014).DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circData sharing: Data are not available online. The data that support the findings of this study are available from the corresponding author on reasonable request.Niccolò Maurizi, MD, Cardiomyopathy Unit, Careggi University Hospital, Viale Pieraccini 17, 50132, Florence, Italy. Email niccolo.[email protected]comReferences1. Maron BJ, Semsarian C. Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy.Eur Heart J. 2010; 31:1551–1553. doi: 10.1093/eurheartj/ehq111CrossrefMedlineGoogle Scholar2. Christiaans I, Birnie E, Bonsel GJ, Mannens MM, Michels M, Majoor-Krakauer D, Dooijes D, van Tintelen JP, van den Berg MP, Volders PG, Arens YH, van den Wijngaard A, Atsma DE, Helderman-van den Enden AT, Houweling AC, de Boer K, van der Smagt JJ, Hauer RN, Marcelis CL, Timmermans J, van Langen IM, Wilde AA. 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February 5, 2019Vol 139, Issue 6 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.037264PMID: 30715937 Originally publishedFebruary 4, 2019 Keywordselectrocardiographyhypertrophy, left ventricularcardiomyopathy, hypertrophicgeneticsechocardiographymortalityPDF download Advertisement SubjectsCardiomyopathyGeneticsMortality/Survival
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