A Contemporary Approach to Hypertrophic Cardiomyopathy

Abstract

HomeCirculationVol. 113, No. 24A Contemporary Approach to Hypertrophic Cardiomyopathy Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBA Contemporary Approach to Hypertrophic Cardiomyopathy Carolyn Y. Ho, MD and Christine E. Seidman, MD Carolyn Y. HoCarolyn Y. Ho From the Cardiovascular Division, Brigham and Women’s Hospital (C.Y.H., C.E.S.), and Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School (C.E.S.), Boston, Mass. Search for more papers by this author and Christine E. SeidmanChristine E. Seidman From the Cardiovascular Division, Brigham and Women’s Hospital (C.Y.H., C.E.S.), and Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School (C.E.S.), Boston, Mass. Search for more papers by this author Originally published20 Jun 2006https://doi.org/10.1161/CIRCULATIONAHA.105.591982Circulation. 2006;113:e858–e862A previously healthy 32-year-old female undergoes evaluation after a syncopal episode. Physical examination reveals a systolic ejection murmur. Echocardiography demonstrates a vigorous LV with marked asymmetric septal hypertrophy, systolic anterior motion of the mitral valve, and a 50–mm Hg outflow tract gradient. Family history is notable for unexpected death in 4 paternal family members. She has 2 children (Figure 1A). Download figureDownload PowerPointFigure 1. A, HCM is a genetic cardiovascular disease. This family shows autosomal dominant inheritance with &50% of the family affected and equal numbers of affected male (▪) and female (•) family members. The case patient is indicated by an arrow. Deceased individuals are indicated by a diagonal slash (all died suddenly). B, DNA sequence analysis can identify sarcomere mutations that cause HCM. Top, The normal sequence of a portion of the cardiac troponin T gene is displayed with a triplet codon, TCC, encoding serine present. Bottom, DNA sequence obtained from a patient with HCM. The normal sequence is present on the allele inherited from the unaffected parent; the other allele shows a single base-pair substitution of a thymidine residue for the normal cytosine residue. This triplet codon, TTC, encodes phenylalanine and results in the substitution of a phenylalanine residue for the normal serine residue at amino acid position 179.The prevalence of unexplained left ventricular hypertrophy (LVH) in the general population is estimated to be 1 in 500.1,2 Hypertrophic cardiomyopathy (HCM) caused by sarcomere mutations may account for up to 60% of unexplained LVH, making HCM the most common genetic cardiovascular disorder.3–5 Accurate diagnosis of HCM is important for appropriate management of major HCM comorbidities, including atrial fibrillation, stroke, heart failure, and sudden cardiac death (SCD).6,7Clinical AspectsHCM typically is diagnosed by unexplained LVH on echocardiography. Age of onset of LVH ranges from early childhood to late adulthood and depends, in part, on the underlying genetic cause.8,9 Histopathological hallmarks of HCM are myocyte hypertrophy with disarray and increased cardiac fibrosis (Figure 2). Although small amounts of myocyte disarray and fibrosis may be seen in other forms of cardiac disease, the higher degree present in HCM is distinctive. In their absence, the diagnosis of HCM should be questioned. Download figureDownload PowerPointFigure 2. A, Histological section of normal myocardium stained with hematoxylin and eosin. Note the orderly arrangement of myocytes and scant interstitial fibrosis. B, In contrast, the histology from a patient with HCM stained with Masson’s trichrome shows characteristic myocyte disarray, hypertrophy, and increased interstitial fibrosis (stained blue). C, Patients with mutations in PRKAG2 show non–membrane-bound vacuoles in myocytes (arrows) that stain for glycogen and amylopectin. There is only mild fibrosis and no myocyte disarray. D, Mutations in LAMP2 show vacuoles with large periodic acid-Schiff–positive (PAS+) inclusions. As with PRKAG2 mutations, myocyte size is increased, not because of classic hypertrophy but rather because of the presence of glycogen-filled vacuoles.The spectrum of HCM is broad. Diagnosis of some individuals occurs incidentally during the investigation of asymptomatic murmurs or with family screening; others present with dyspnea, chest pain, or exercise intolerance. Clinical progression can be indolent or more rapidly result in refractory symptoms and heart failure. Medical treatment is first-line therapy, traditionally with either β-blockers or nondihydropyridine calcium channel blockers to facilitate diastolic filling and to reduce intracavitary gradients. The negative inotropic effect of disopyramide also may be beneficial in reducing obstructive physiology.10 Intracavitary obstruction that is significant (>50 mm Hg at rest or >100 mm Hg with provocation) and associated with refractory symptoms can be addressed by ethanol septal ablation or surgical myectomy to mechanically reduce outflow tract obstruction. An end-stage phenotype with impaired systolic function and, in some, LVH regression occurs in a small subset of HCM patients. These patients require standard therapy for advanced heart failure, including consideration for cardiac transplantation.SCD risk is increased in a small subset of patients. In the United States, HCM is the leading cause of SCD in competitive athletes.7 Assessment of an individual’s risk for SCD, although imprecise and controversial, is a critical component of management. The presence of clinical predictors (SCD in first-degree family members, identification of a malignant genotype, unexplained syncope, abnormal blood pressure response to exercise, significant ventricular ectopy on Holter monitoring, and massive [>30 mm] LVH) is associated with increased risk and should prompt consideration of implantable cardioverter-defibrillator placement in appropriate individuals.11 The positive predictive value of these risk factors individually is low, but with >2 risk factors, the annual SCD incidence approximates 3% to 5%.12,13 In contrast, in the absence of any risk factors, individuals are at low risk (annual incidence <1%) and require regular reassessment of risk profile but not intervention.12,13Genetic AspectsHCM is caused by dominant mutations in genes that encode constituents of the sarcomere (Figure 1). More than 400 individual mutations have been identified in 11 sarcomere genes summarized in Table 1 (and at http://cardiogenomics.med.harvard.edu/mutation-db.tcl),4,14,15 including cardiac β- and α-myosin heavy chains; cardiac troponins T, I, and C; cardiac myosin binding protein C; α-tropomyosin; actin; the essential and regulatory myosin light chains; and titin. HCM mutations do not show specific racial predilections and are typically “private,” ie, unique from family to family. Sarcomere mutations also account for sporadic cases of HCM. Select mutations identified in family studies have yielded some phenotypic correlates. A few families have demonstrated a high incidence of premature death or end-stage heart failure, defining their mutations as potentially “malignant.” Others are associated with distinctive HCM morphology; eg, familial inheritance of apical pattern hypertrophy has been associated with mutations in cardiac actin.16 However, there are numerous exceptions, indicating the importance of genetic modifiers and environment on ultimate phenotypic development. Integration of genotype information with comprehensive clinical evaluation and risk assessment is appropriate and necessary for optimal patient management. TABLE 1. Gene Mutations That Cause Unexplained Left Ventricular HypertrophyGeneDesignationChromosomeFrequencyNo. of MutationsPhenotypic CorrelationHCM-sarcomere proteinsβ-Myosin heavy chainβ-MHC14q1&30% to 40%>80Typically obvious disease with significant LVH; several severe phenotypes (end-stage heart failure and sudden death).α-Myosin heavy chainα-MHC14q1Rare<5Cardiac myosin binding protein CcMYBPC11q1&30% to 40%>50Typically more mild disease, but severe phenotypes have been described; associated with elderly-onset HCM.Cardiac troponin TcTnT1q3&15% to 20%>20Typically mild LVH but increased association with sudden death.Cardiac troponin IcTnI19p1<5%>10Cardiac troponin CCTnC3pRare1α-Tropomyosinα-TM15q2<5%8Myosin Essential Light ChainMLC-13pRare2Skeletal myopathyMyosin regulatory light chainMLC-212qRare8Skeletal myopathyActin11qRare5Titin2q3Rare1Metabolic cardiomyopathiesγ-Subunit AMP kinasePRKAG27q3? 4Ventricular preexcitation and conduction disease.Linked lysosome-associated membrane proteinLAMP2X?6Ventricular preexcitation, elevated liver transaminases, cognitive impairmentBeyond LVH: Redefining the Phenotype of HCMAlthough an HCM gene mutation is present at birth, it may be decades before LVH becomes clinically detectable. With gene-based diagnosis and newer imaging techniques, there is increased recognition that LVH is not the most specific nor sensitive manifestation of HCM. Studies of preclinical individuals with sarcomere gene mutations demonstrate that diastolic abnormalities, detected by Doppler tissue imaging, develop in advance of LVH.17,18 These results indicate that altered diastolic function is not, as previously considered, a secondary consequence of increased fibrosis and hypertrophy but rather a primary and early manifestation of sarcomere dysfunction resulting from an underlying genetic mutation.Ongoing research in animal models of HCM has illuminated disease mechanisms. Promising results have been seen with therapeutic strategies to manipulate intracellular calcium handling in prehypertrophic mice,19 as well as with treatment targeted against myocardial fibrosis (with angiotensin II receptor blockers, aldosterone antagonists, and HMG-CoA reductase inhibitors) in animals with overt HCM.20–22 Translation into human clinical protocols may be beneficial and presents an exciting new treatment paradigm with a goal of altering phenotype rather than merely palliating symptoms.New Causes of Inherited Cardiac HypertrophyMetabolic Cardiomyopathies: Deficits of Myocardial EnergeticsGenetic studies of familial and sporadic unexplained LVH accompanied by conduction abnormalities (progressive AV block, atrial fibrillation, ventricular pre-excitation/Wolff-Parkinson-White syndrome) have identified metabolic cardiomyopathies. These genetic forms of hypertrophy reflect mutations in the γ2 regulatory subunit (PRKAG2) of AMP-activated protein kinase, an enzyme involved with glucose metabolism, or in the X-linked lysosome-associated membrane protein (LAMP2) gene.5,23,24These clinical entities are distinct from HCM caused by sarcomere protein mutations, despite the shared feature of LVH. A high prevalence of conduction system disease (with the requirement of permanent pacing in 30% of patients in 1 series) characterizes PRKAG2 mutations.24LAMP2 mutations are X-linked, resulting in male predominance. LAMP2 mutations are further distinguished by profound LVH seen on the ECG and echocardiogram (typically concentric) (Movie) and ventricular pre-excitation. In addition, LAMP2 mutations are associated with early-onset LVH (often in childhood) with rapid progression of heart failure and a poor prognosis.5 The histopathology of PRKAG2 and LAMP2 mutations shows prominent non–membrane-bound vacuoles containing glycogen and amylopectin rather than the myocardial disarray or interstitial fibrosis characteristic of HCM (Figure 2). Although incompletely defined, the molecular signaling pathways triggered by PRKAG2 and LAMP2 mutations are almost certainly different from those produced by sarcomere gene mutations, suggesting that clinical approaches should not be predicated on HCM management tenets.Contemporary Diagnosis of HCMGenetic testing allows accurate diagnosis and precise identification of mutations in sarcomere proteins, PRKAG2 and LAMP2, independently of age, family history, or clinical manifestations. As such, incorporating genotype assessment can importantly enhance the contemporary evaluation of unexplained LVH. This is currently accomplished by bidirectional DNA sequence analysis of sarcomere genes to identify potential disease-associated sequence variants (Figure 1B).The identification of a sarcomere gene mutation provides a definitive diagnosis of HCM and establishes the precise genetic cause. Mutation confirmation in family members can be accomplished simply and identify family members at risk for disease development. Mutation carriers without clinical manifestations are at risk for developing HCM and require longitudinal clinical follow-up, as summarized in Table 2. All mutation carriers should be counseled about the 50% chance of transmission of the mutation to offspring. Family members who do not carry a mutation are not at risk for developing HCM or transmitting HCM to offspring. Longitudinal clinical follow-up is not required. TABLE 2. Approach for Family Clinical Screening for Hypertrophic CardiomyopathyFirst Degree Relatives (Offspring, Parents, and Siblings)Screening (PE, Echocardiogram, ECG)If genetic testing results are available, continue serial clinical evaluation as above if the genotype is positive; if negative, no further clinical evaluation is required.PE indicates physical examination; FH, family history.Under 12 years of ageDefinitive findings rare; screening optional unless patient has malignant FH or is a competitive athlete or there is suspicion of early onset LVH. Consider screening every 5 yearsAge 12 to 22 yearsRepeat every 12 to 24 monthsAge 23 years or olderRepeat every 5 years (or until genetic testing confirms diagnosis)Despite the power and specificity of genetic diagnosis, there are important current limitations. Mutations in sarcomere genes account for &60% of cases of inherited LVH; expanding the screen to include PRKAG2 and LAMP2 will slightly increase diagnostic yield. Nonetheless, mutations will not be detected in all individuals with unexplained LVH, and a negative analysis does not exclude a genetic origin. Discovery of other genes that cause LVH will continue to improve gene-based diagnosis. Increasingly, efforts to determine the molecular mechanisms by which gene mutations produce HCM will inspire clinical trials of new strategies for disease prevention and rational treatment. Through its ability to identify preclinical individuals with gene mutations, genetic diagnosis will play a crucial role in these endeavors by targeting preventive therapy to patients at high risk for disease development.Case ConclusionGenetic testing was performed on this patient, and an Arg92Trp mutation was identified in the cardiac troponin T gene. She received an implantable cardioverter-defibrillator on the basis of her syncopal episode, her family history, and the identification of this mutation (associated with SCD in other families25). Family mutation confirmation testing revealed that her father (previously diagnosed with atrial fibrillation and mild LVH) and 1 of her 2 children (clinically unaffected at 14 years of age) carry the mutation.The online-only Data Supplement, which contains a movie, can be found at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.591982/DC1.Sources of FundingDrs Ho and Seidman received research grants from the National Institutes of Health. Dr Seidman also received a research grant from Howard Hughes Medical Institute.DisclosuresNone.Additional ResourcesCardioGenomics Home Page for sarcomere gene mutations. Available at: http://cardiogenomics.med.harvard.edu. Accessed May 31, 2006.FootnotesCorrespondence to Carolyn Ho, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115. E-mail [email protected] References 1 Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA study. Circulation. 1995; 92: 785–789.CrossrefMedlineGoogle Scholar2 Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang Y, Shen L, Cai Y, Zhen Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in China: a population-based echocardiographic analysis of 8080 adults. Am J Med. 2004; 116: 14–18.CrossrefMedlineGoogle Scholar3 Van Driest SL, Ellsworth EG, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ. Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. Circulation. 2003; 108: 445–451.LinkGoogle Scholar4 Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003; 107: 2227–2232.LinkGoogle Scholar5 Arad M, Maron BJ, Gorham JM, Johnson WH Jr, Saul JP, Perez-Atayde AR, Spirito P, Wright GB, Kanter RJ, Seidman CE, Seidman JG. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. 2005; 352: 362–372.CrossrefMedlineGoogle Scholar6 Maron BJ, Mitten MJ, Quandt EF, Zipes DP. Competitive athletes with cardiovascular disease: the case of Nicholas Knapp. N Engl J Med. 1998; 339: 1632–1635.CrossrefMedlineGoogle Scholar7 Maron BJ. Sudden death in young athletes. N Engl J Med. 2003; 349: 1064–1075.CrossrefMedlineGoogle Scholar8 Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation. 2002; 105: 446–451.CrossrefMedlineGoogle Scholar9 Rosenzweig A, Watkins H, Hwang DS, Miri M, McKenna W, Traill TA, Seidman JG, Seidman CE. Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes. N Engl J Med. 1991; 325: 1753–1760.CrossrefMedlineGoogle Scholar10 Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005; 45: 1251–1258.CrossrefMedlineGoogle Scholar11 Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA 3rd, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000; 342: 365–373.CrossrefMedlineGoogle Scholar12 Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000; 36: 2212–2218.CrossrefMedlineGoogle Scholar13 Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD, McKenna WJ. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet. 2001; 357: 420–424.CrossrefMedlineGoogle Scholar14 Seidman JG, Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001; 104: 557–567.CrossrefMedlineGoogle Scholar15 Charron P, Heron D, Gargiulo M, Richard P, Dubourg O, Desnos M, Bouhour JB, Feingold J, Carrier L, Hainque B, Schwartz K, Komajda M. Genetic testing and genetic counseling in hypertrophic cardiomyopathy: the French experience. J Med Genet. 2002; 39: 741–746.CrossrefMedlineGoogle Scholar16 Arad M, Penas-Lado M, Monserrat L, Maron BJ, Sherrid M, Ho CY, Barr S, Karim A, Olson TM, Kamisago M, Seidman JG, Seidman CE. Gene mutations in apical hypertrophic cardiomyopathy. Circulation. 2005; 112: 2805–2811.LinkGoogle Scholar17 Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, Quinones MA, Roberts R, Marian AJ. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation. 2001; 104: 128–130.CrossrefMedlineGoogle Scholar18 Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, Seidman CE, Solomon SD. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002; 105: 2992–2997.LinkGoogle Scholar19 Semsarian C, Ahmad I, Giewat M, Georgakopoulos D, Schmitt JP, McConnell BK, Reiken S, Mende U, Marks AR, Kass DA, Seidman CE, Seidman JG. The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. J Clin Invest. 2002; 109: 1013–1020.CrossrefMedlineGoogle Scholar20 Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, Quinones MA, Zoghbi WA, Entman ML, Roberts R, Marian AJ. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation. 2001; 104: 317–324.CrossrefMedlineGoogle Scholar21 Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001; 103: 789–791.CrossrefMedlineGoogle Scholar22 Tsybouleva N, Zhang L, Chen S, Patel R, Lutucuta S, Nemoto S, DeFreitas G, Entman M, Carabello BA, Roberts R, Marian AJ. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation. 2004; 109: 1284–1291.LinkGoogle Scholar23 Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, Salmon A, Ostman-Smith I, Watkins H. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet. 2001; 10: 1215–1220.CrossrefMedlineGoogle Scholar24 Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, McGarry K, Seidman JG, Seidman CE. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest. 2002; 109: 357–362.CrossrefMedlineGoogle Scholar25 Moolman JC, Corfield VA, Posen B, Ngumbela K, Seidman C, Brink PA, Watkins H. Sudden death due to troponin T mutations. J Am Coll Cardiol. 1997; 29: 549–555.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Sadeghpour A and Alizadehasl A (2022) Echocardiography Practical Cardiology, 10.1016/B978-0-323-80915-3.00008-9, (67-110), . Zampieri M, Berteotti M, Ferrantini C, Tassetti L, Gabriele M, Tomberli B, Castelli G, Cappelli F, Stefàno P, Marchionni N, Coppini R and Olivotto I (2021) Pathophysiology and Treatment of Hypertrophic Cardiomyopathy: New Perspectives, Current Heart Failure Reports, 10.1007/s11897-021-00523-0, 18:4, (169-179), Online publication date: 1-Aug-2021. Vogiatzi G, Pantazis A and Tousoulis D Antithrombotic Treatment in Cardiomyopathies, Current Pharmaceutical Design, 10.2174/1381612826666200429230726, 26:23, (2762-2768) Fox A, Sharma S, Mounsey J, Durieux M, Whitlock R and Bennett-Guerrero E (2018) Molecular and Genetic Cardiovascular Medicine and Systemic Inflammation Kaplan's Essentials of Cardiac Anesthesia, 10.1016/B978-0-323-49798-5.00006-1, (94-111), . Sadeghpour A and Alizadehasl A (2018) Echocardiographic Assessment of Native Valvular Heart Disease Case-Based Textbook of Echocardiography, 10.1007/978-3-319-67691-3_17, (217-237), . Roos J, Daniels M, Morris E, Hyry H and Cox T (2018) Heterogeneity in a large pedigree with Danon disease: Implications for pathogenesis and management, Molecular Genetics and Metabolism, 10.1016/j.ymgme.2017.06.008, 123:2, (177-183), Online publication date: 1-Feb-2018. Kakimoto Y, Tanaka M, Hayashi H, Yokoyama K and Osawa M (2018) Overexpression of miR-221 in sudden death with cardiac hypertrophy patients, Heliyon, 10.1016/j.heliyon.2018.e00639, 4:6, (e00639), Online publication date: 1-Jun-2018. Sadeghpour A and Alizadehasl A (2018) Echocardiography Practical Cardiology, 10.1016/B978-0-323-51149-0.00005-5, (67-111), . Boudoulas K and Boudoulas H (2017) An Evolution of Management in Hypertrophic Cardiomyopathy: Myectomy, Alcohol Septal Ablation, Mitral Valve Replacement, MitraClip, Cardiology, 10.1159/000455068, 137:1, (54-57), . Li T, Jiang S, Yang Z, Ma Z, Yi W, Wang D and Yang Y (2016) Targeting the energy guardian AMPK: another avenue for treating cardiomyopathy?, Cellular and Molecular Life Sciences, 10.1007/s00018-016-2407-7, 74:8, (1413-1429), Online publication date: 1-Apr-2017. Bellchambers J, Neves E and Pottle A (2017) Inherited cardiac conditions: examining two patient cases, British Journal of Cardiac Nursing, 10.12968/bjca.2017.12.8.387, 12:8, (387-396), Online publication date: 2-Aug-2017. Ammirati E, Contri R, Coppini R, Cecchi F, Frigerio M and Olivotto I (2016) Pharmacological treatment of hypertrophic cardiomyopathy: current practice and novel perspectives, European Journal of Heart Failure, 10.1002/ejhf.541, 18:9, (1106-1118), Online publication date: 1-Sep-2016. Al-Harazi O, Al Insaif S, Al-Ajlan M, Kaya N, Dzimiri N and Colak D (2016) Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network, Journal of Genetics and Genomics, 10.1016/j.jgg.2015.11.002, 43:6, (349-367), Online publication date: 1-Jun-2016. (2016) Guidelines for Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy (JCS 2012) – Digest Version –, Circulation Journal, 10.1253/circj.CJ-66-0122, 80:3, (753-774), . Mango R, Luchetti A, Sangiuolo R, Ferradini V, Briglia N, Giardina E, Ferrè F, Helmer Citterich M, Romeo F, Novelli G and Sangiuolo F (2016) Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome, Circulation Journal, 10.1253/circj.CJ-15-0685, 80:4, (938-949), . Bai F, Caster H, Dawson J and Kawai M (2015) The immediate effect of HCM causing actin mutants E99K and A230V on actin–Tm–myosin interaction in thin-filament reconstituted myocardium, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2014.10.014, 79, (123-132), Online publication date: 1-Feb-2015. Hernández-Romero D, Jover E, Martínez C, Andreu-Cayuelas J, Orenes-Piñero E, Romero-Aniorte A, Casas T, Cánovas S, Montero-Argudo J, Valdés M, de la Morena G and Marín F (2015) TWEAK and NT-proBNP levels predict exercise capacity in hypertrophic cardiomyopathy, European Journal of Clinical Investigation, 10.1111/eci.12394, 45:2, (179-186), Online publication date: 1-Feb-2015. Hernández-Romero D, Orenes-Piñero E, García-Honrubia A, Climent V, Romero-Aniorte A, Martínez C, García-Bautista M, Martínez M, Feliu E, González J, Cánovas S, Montero-Argudo J, Valdés M and Marín F (2015) Involvement of the −420C>G RETN polymorphism in myocardial fibrosis in patients with hypertrophic cardiomyopathy , Journal of Internal Medicine, 10.1111/joim.12334, 278:1, (50-58), Online publication date: 1-Jul-2015. Zheng C, Wang J, Liu J, Pei M, Huang C and Wang Y (2014) System-level multi-target drug discovery from natural products with applications to cardiovascular diseases, Molecular Diversity, 10.1007/s11030-014-9521-y, 18:3, (621-635), Online publication date: 1-Aug-2014. Aly M, Brouwer W, Kleijn S, van Rossum A and Kamp O (2014) Three-dimensional speckle tracking echocardiography for the preclinical diagnosis of hypertrophic cardiomyopathy, The International Journal of Cardiovascular Imaging, 10.1007/s10554-014-0364-5, 30:3, (523-533), Online publication date: 1-Mar-2014. Saberi S and Day S (2013) Hypertrophic Cardiomyopathy Inpatient Cardiovascular Medicine, 10.1002/9781118484784.ch15, (187-196) OKADA S, SUZUKI Y, ARIMURA T, KIMURA A, NARUMI H and HASEGAWA S (2014) A novel de novo mutation of β-cardiac myosin heavy chain gene found in a twelve-year-old boy with hypertrophic cardiomyopathy, Journal of Genetics, 10.1007/s12041-014-0414-8, 93:2, (557-560), Online publication date: 1-Aug-2014. Dunn K, Caleshu C, Cirino A, Ho C and Ashley E (2013) A Clinical Approach to Inherited Hypertrophy, Circulation: Cardiovascular Genetics, 6:1, (118-131), Online publication date: 1-Feb-2013.Valente A, Lakdawala N, Powell A, Evans S, Cirino A, Orav E, MacRae C, Colan S and Ho C (2013) Comparison of Echocardiographic and Cardiac Magnetic Resonance Imaging in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers Without Left Ventricular Hypertrophy, Circulation: Cardiovascular Genetics, 6:3, (230-237), Online publication date: 1-Jun-2013. Coats C and Elliott P (2013) Genetic biomarkers in hypertrophic cardiomyopathy, Biomarkers in Medicine, 10.2217/bmm.13.79, 7:4, (505-516), Online publication date: 1-Aug-2013. Orenes-Piñero E, Hernández-Romero D, De Torre C, Vilchez J, Martínez M, Romero-Aniorte A, Climent V, García-Honrubia A, Valdés M and Marín F (2013) Identification and confirmation